Katri Räikkönen

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Accumulating research shows that prenatal exposure to maternal stress increases the risk for behavioral and mental health problems later in life. This review systematically analyzes the available human studies to identify harmful stressors, vulnerable periods during pregnancy, specificities in the outcome and biological correlates of the relation between maternal stress and offspring outcome. Effects of maternal stress on offspring neurodevelopment, cognitive development, negative affectivity, difficult temperament and psychiatric disorders are shown in numerous epidemiological and case-control studies. Offspring of both sexes are susceptible to prenatal stress but effects differ. There is not any specific vulnerable period of gestation; prenatal stress effects vary for different gestational ages possibly depending on the developmental stage of specific brain areas and circuits, stress system and immune system. Biological correlates in the prenatally stressed offspring are: aberrations in neurodevelopment, neurocognitive function, cerebral processing, functional and structural brain connectivity involving amygdalae and (pre)frontal cortex, changes in hypothalamo-pituitary-adrenal (HPA)-axis and autonomous nervous system.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Personality can be thought of as a set of characteristics that influence people's thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in 10 discovery samples (17,375 adults) and five in silico replication samples (3294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data of ≈ 2.4M single-nucleotide polymorphisms (SNPs; directly typed and imputed using HapMap data) were available. In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P=2.8 × 10(-8) and 3.1 × 10(-8)) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P=4.9 × 10(-8)). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.

We evaluated whether psychosocial factors that are related to cardiovascular disease and type 2 diabetes predict prospectively the risk for the metabolic syndrome using the different clinical criteria available for defining the syndrome.Women were enrolled in a population-based prospective cohort study called the Healthy Women Study and were followed for an average of 15 years after baseline. Metabolic syndrome was defined via the World Health Organization, the National Cholesterol Education Program Adult Treatment Panel III, and the International Diabetes Foundation clinical criteria.Among women who did not have the metabolic syndrome at the baseline, the risk for the metabolic syndrome defined in multiple ways varied from 1.21- to 2.12-fold ([95% CI 1.00-4.25], P < 0.05) for more severe depressive symptoms or very stressful life event(s). These associations were largely the same, regardless of the clinical criteria used to define the metabolic syndrome. Those who at the baseline reported feeling frequently and intensely angry, tense, or stressed also had an increased risk for developing the metabolic syndrome at least by one definition (relative risk 1.19-1.66 [1.00-2.39]).These are the first data to demonstrate that psychosocial factors predict the risk for developing the metabolic syndrome by multiple definitions. Psychosocial factors may play a causal role in the chain of events leading to the metabolic syndrome.

Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth.We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry.DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Maternal antenatal corticosteroid treatment is standard care to accelerate fetal maturation when birth before 34 weeks is imminent. Recently, expansion of the indications beyond 34 gestational weeks has been debated. However, data about long-term outcomes remain limited, especially among infants who after treatment exposure are born at term.To study if antenatal corticosteroid treatment is associated with mental and behavioral disorders in children born at term (≥37 weeks 0 days' gestation) and preterm (<37 weeks 0 days' gestation) and if unmeasured familial confounding explains these associations.Population-based retrospective cohort study using nationwide registries of all singleton live births in Finland surviving until 1 year and a within-sibpair comparison among term siblings. Children were born between January 1, 2006, and December 31, 2017, and followed up until December 31, 2017.Maternal antenatal corticosteroid treatment.Primary outcome was any childhood mental and behavioral disorder diagnosed in public specialized medical care settings.Of the 674 877 singleton children born in Finland during the study period, 670 097 were eligible for analysis. The median length of follow-up was 5.8 (interquartile-range, 3.1-8.7) years. Of the 14 868 (2.22%; 46.1% female) corticosteroid treatment-exposed children, 6730 (45.27%) were born at term and 8138 (54.74%) were born preterm; of the 655 229 (97.78%; 48.9% female) nonexposed children, 634 757 (96.88%) were born at term and 20 472 (3.12%) were born preterm. Among the 241 621 eligible term-born maternal sibpairs nested within this population, 4128 (1.71%) pairs were discordant for treatment exposure. Treatment exposure, compared with nonexposure, was significantly associated with higher risk of any mental and behavioral disorder in the entire cohort of children (12.01% vs 6.45%; absolute difference, 5.56% [95% CI, 5.04%-6.19%]; adjusted hazard ratio [HR], 1.33 [95% CI, 1.26-1.41]), in term-born children (8.89% vs 6.31%; absolute difference, 2.58% [95% CI, 1.92%-3.29%]; HR, 1.47 [95% CI, 1.36-1.69]), and when sibpairs discordant for treatment exposure were compared with sibpairs concordant for nonexposure (6.56% vs 4.17% for within-sibpair differences; absolute difference, 2.40% [95% CI, 1.67%-3.21%]; HR, 1.38 [95% CI, 1.21-1.58]). In preterm-born children, the cumulative incidence rate of any mental and behavioral disorder was also significantly higher for the treatment-exposed compared with the nonexposed children, but the HR was not significant (14.59% vs 10.71%; absolute difference, 3.38% [95% CI, 2.95%-4.87%]; HR, 1.00 [95% CI, 0.92-1.09]).In this population-based cohort study, exposure to maternal antenatal corticosteroid treatment was significantly associated with mental and behavioral disorders in children. These findings may help inform decisions about maternal antenatal corticosteroid treatment.

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.We sought to identify differential DNA methylation in newborns and children related to childhood asthma.Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Significance Prenatal stress exposure is associated with a wide range of health problems later in life. This may be mediated in part via glucocorticoid (GC) exposure during fetal development known to impact neurogenesis and induce epigenetic changes. Using a human fetal hippocampal progenitor cell line to assess the effects of GCs, we observe that exposure to GCs early during neurogenesis results in lasting changes in DNA methylation (DNAm). Lasting DNAm alterations are associated with significantly enhanced transcriptional response to a subsequent GC exposure. Our data suggest that early exposure to GCs changes the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

This study tested whether dispositional measures of optimism, pessimism, and anxiety affected ambulatory blood pressure (BP) and mood and whether any cardiovascular effects of dispositions were moderated by mood. Pessimistic and anxious adults had higher BP levels and felt more negative and less positive than did optimists or low anxious adults throughout the monitoring. The few times that optimists did feel negative were associated with levels of BP as high as those observed among pessimists or anxious individuals, regardless of their mood. To the extent that trait anxiety measures neuroticism, these findings suggest that neuroticism is directly related to health indicators rather than simply to illness behavior. Furthermore, the results suggest that pessimism has broad physiological and psychological consequences.

OBJECTIVE. It has been hypothesized that sleep deprivation may manifest in children as behavioral symptoms rather than as tiredness, but only a few studies have investigated this hypothesis. The objective of our study was to evaluate whether short sleep is associated with behavioral symptoms of attention-deficit/hyperactivity disorder in 7- to 8-year-old children. METHODS. We performed a cross-sectional study of children born in 1998 in Helsinki, Finland. The participants included 280 (146 girls, 134 boys) children with a mean age of 8.1 years (SD: 0.3; range: 7.4–8.8). Sleep quality was measured by using actigraphs. The Sleep Disturbance Scale for Children and the Attention-Deficit/Hyperactivity Disorder Rating Scale IV were administered to parents. RESULTS. Children whose average sleep duration as measured by actigraphs was short (&amp;lt;10th percentile, ie, &amp;lt;7.7 hours) and had a higher hyperactivity/impulsivity score (9.7 vs 7.8 or 7.5) and a higher attention-deficit/hyperactivity disorder total score (17.3 vs 14.5 or 13.1) but a similar inattention score (7.6 vs 6.7 or 5.6) compared with children sleeping 7.7 to 9.4 hours or &amp;gt;9.4 hours. In multivariate statistical models, short sleep duration remained a statistically significant predictor of hyperactivity/impulsivity, and sleeping difficulties were associated with hyperactivity/impulsivity, inattention, and the total score. There were no significant interactions between short sleep and sleeping difficulties. CONCLUSIONS. Children's short sleep duration and sleeping difficulties increase the risk for behavioral symptoms of attention-deficit/hyperactivity disorder.

Personality traits are basic dimensions of behavioral variation, and twin, family, and adoption studies show that around 30% of the between-individual variation is due to genetic variation. There is rapidly growing interest in understanding the evolutionary basis of this genetic variation. Several evolutionary mechanisms could explain how genetic variation is maintained in traits, and each of these makes predictions in terms of the relative contribution of rare and common genetic variants to personality variation, the magnitude of nonadditive genetic influences, and whether personality is affected by inbreeding. Using genome-wide single nucleotide polymorphism (SNP) data from > 8000 individuals, we estimated that little variation in the Cloninger personality dimensions (7.2% on average) is due to the combined effect of common, additive genetic variants across the genome, suggesting that most heritable variation in personality is due to rare variant effects and/or a combination of dominance and epistasis. Furthermore, higher levels of inbreeding were associated with less socially desirable personality trait levels in three of the four personality dimensions. These findings are consistent with genetic variation in personality traits having been maintained by mutation-selection balance.

Objective: Optimistic people report a higher quality of life, engage in more active coping and adopt more health-promoting behaviors than people low in optimism, ie, pessimism. We evaluated whether pessimists are more likely to show progression in carotid disease than optimists. Methods: A total of 209 middle-aged healthy premenopausal women enrolled in an epidemiological study of cardiovascular risk factors and had carotid scans 10.4 years and 13.5 years later when they were at least 5 years postmenopausal. Women completed the Life Orientation Test (LOT), a measure of pessimistic and optimistic attitudes, at study entry and at the time of the first carotid scan. Analyses evaluated the association of LOT scores and change in carotid intima medial thickness (IMT) across 3 years. Results: Multiple linear regression analyses showed that the higher the pessimism scores at study entry, the greater the increase in mean IMT (β = 0.17, p < .007). A comparison of those in the lowest quartile of LOT scores (most optimistic) with those in the other three quartiles showed that the most optimistic group had less progression than the remaining more pessimistic women (mean percent increase = 1.3 and 6.0 for mean IMT, F = 15.4, p < .001). Women who were chronically optimistic at study entry and at the first carotid scan (bottom quartiles at both times) had less progression in mean IMT than did those who were chronically pessimistic (top quartiles at both times). Conclusions: Optimistic women are less likely to show progression of carotid disease in mid-life than are pessimists. LOT = Life Orientation Test; IMT = intima medial thickness; HWS = Healthy Women Study; DBP = diastolic blood pressure; SBP = systolic blood pressure; HDL-C = high-density lipoprotein cholesterol; BMI = body mass index; HT = hormone therapy; ANCOVA = analyses of covariance.

We examined the association between psychosocial stress-related variables and insulin resistance syndrome (IRS) risk-factor clustering. In 90 middle-aged male volunteers, psychosocial stress-related variables, defined as feelings of excessive tiredness and as personality and behavioral factors reflecting a stress-inducing life-style (type A behavior, hostility, and anger), were significantly correlated with the hyperinsulinemia, hyperglycemia, dyslipidemia, hypertension, increased abdominal obesity, and increased plasminogen activator inhibitor-1 (PAI-1) antigen comprising the IRS. The correlations remained significant after adjusting for body mass index (BMI), age, educational level, smoking status, alcohol consumption, and physical activity. However, the different stress-related factors reflected different risk-factor clustering profiles. Type A behavior was associated with normotension and a normal metabolic profile (canonical r = .50, chi2(36) = 59.1, P = .008). Hostility was related to elevated systolic blood pressure (SBP) and elevated triglycerides (TGs) (canonical r = .38, chi2(14) = 23.2, P = .052), whereas feelings of excessive tiredness were related to abdominal obesity, augmented glycemic responses to glucose ingestion, dyslipidemia, and increased PAI-1 antigen (canonical r = .39, chi2(24) = 36.8, P = .046). Although hostility and feelings of excessive tiredness have partly overlapping but clearly different clinical and metabolic correlates, their combination represents a full-blown IRS. Thus, even though insulin resistance is presumably to some extent genetically determined, these results suggest that considering psychosocial stress may be beneficial in understanding IRS risk-factor clustering.

<h3>Background</h3> Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. <h3>Methods</h3> In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (<i>p</i><1×10⁻⁵) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. <h3>Results</h3> The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest <i>p</i> = 1.05×10⁻⁷). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (<i>n</i> = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, <i>p</i> = 9.19×10⁻³). This 5q21 region reached genome-wide significance (<i>p</i> = 4.78×10⁻⁸) in the overall meta-analysis combining discovery and replication studies (<i>n</i> = 51,258). <h3>Conclusions</h3> The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach.Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress.Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA).Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis.The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers.Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Objective: Children with very low birth weight (<1500 g) are at increased risk for attention deficit hyperactivity disorder (ADHD). Whether this increased risk continues into adulthood is unknown. The authors assessed behavioral symptoms of ADHD in a well-characterized cohort of very-low-birth-weight young adults who were either small for gestational age (less than two standard deviations below the Finnish mean) or appropriate for gestational age (within two standard deviations of the mean). Method: A total of 162 very-low-birth-weight subjects (small for gestational age: N=52; appropriate for gestational age: N=110) and 172 term comparison subjects 18 to 27 years of age completed the Adult Problem Questionnaire, which yielded six exploratory factor analysis-derived subscales. Participants were also asked about substance use. Results: Very-low-birth-weight adults in the small for gestational age subgroup scored higher on the executive dysfunctioning and emotional instability subscales of the Adult Problem Questionnaire than did those in the appropriate for gestational age subgroup and the comparison group. The appropriate for gestational age and comparison groups had similar scores on these subscales. On the alcohol use subscale of the Adult Problem Questionnaire, both the appropriate and small for gestational age subgroups scored lower than comparison subjects and also reported fewer risk-taking behaviors (alcohol, smoking, and use of recreational drugs) than did comparison subjects. Conclusions: Rather than very low birth weight per se, intrauterine growth retardation, as reflected by small for gestational age status in the very-low-birth-weight subjects, confers a risk for behavioral and emotional adversity related to ADHD in young adulthood.

Objective To study the effect of aspirin in the prevention of pre‐eclampsia in high‐risk women. Design Randomised, double‐blinded, placebo‐controlled trial. Setting Maternity clinics in ten Finnish hospitals participating in the PREDO Project. Sample A total of 152 women with risk factors for pre‐eclampsia and abnormal uterine artery Doppler velocimetry. Methods Participants were randomised to start either aspirin 100 mg/day or placebo at 12 + 0 to 13 + 6 weeks + days of gestation. Because of the limited power of this trial, we also conducted a meta‐analysis of randomised controlled trials that included data on 346 women with abnormal uterine artery Doppler flow velocimetry, and aspirin 50–150 mg/day started at or before 16 weeks of gestation. Main outcome measure Pre‐eclampsia, gestational hypertension and birthweight standard deviation (SD) score. Outcome measures for the meta‐analysis were pre‐eclampsia, severe pre‐eclampsia, preterm (diagnosed &lt;37 + 0 weeks of gestation) and term pre‐eclampsia. Results From the 152 randomised women, 121 were included in the final analysis. Low‐dose aspirin did not reduce the rate of pre‐eclampsia (relative risk [RR] 0.7, 95% CI 0.3–1.7); gestational hypertension (RR 1.6, 95% CI 0.6–4.2); early‐onset pre‐eclampsia (diagnosed &lt;34 + 0 weeks of gestation) (RR 0.2, 95% CI 0.03–2.1); or severe pre‐eclampsia (RR 0.4, 95% CI 0.1–1.3); and the results were not statistically significant in an intention‐to‐treat analysis. However, our meta‐analysis, including the current data, suggested that low‐dose aspirin initiated before 16 weeks of gestation reduces the risk of pre‐eclampsia (RR 0.6, 95% CI 0.4–0.8) and severe pre‐eclampsia (RR 0.3, 95% CI 0.1–0.7). Conclusions Our trial showed no statistically significant effect of aspirin in preventing pre‐eclampsia in high‐risk women. However, our meta‐analysis suggested that aspirin may reduce the incidence of pre‐eclampsia.

Neuroendocrine alterations, with well-known links with health, may offer insight into why poor sleep is associated with poor health. Yet, studies testing associations between sleep and neuroendocrine activity in children are scarce.The aim of this study was to determine whether actigraphy-based sleep pattern is associated with hypothalamic-pituitary-adrenocortical axis and sympatho-adrenal-medullary system activity in children.We conducted a cross-sectional study in a birth cohort in Helsinki, Finland.We studied 282 8-yr-old children.We measured diurnal salivary cortisol and salivary cortisol and alpha-amylase (a sympatho-adrenal-medullary system marker) responses to the Trier Social Stress Test for Children (TSST-C).Children with short (<or=7.7 h) vs. average sleep duration (7.8-9.3 h) displayed higher cortisol awakening response and nadir (P < 0.042). Those with low (<or=77.4%) vs. average-high sleep efficiency (>77.4%) displayed higher diurnal cortisol levels across the entire day (P < 0.03), higher cortisol levels after the TSST-C stressor (P < 0.04), and higher overall alpha-amylase levels across the entire TSST-C protocol (P < 0.05). The effects were not confounded by factors that may alter sleep or hormonal patterns.Poor sleep may signal altered neuroendocrine functioning in children. The findings may offer insight into the pathways linking poor sleep with poor health.

Little is known about the mental health outcomes of very low-birth-weight (VLBW) (< 1500 g) infants in young adulthood.To test whether young adults aged 18 to 27 years with VLBW differ from term control subjects in depressive symptoms, current use of antidepressant medication, and the rate of depression diagnosed by a physician.Retrospective longitudinal study.Academic research.A total of 162 VLBW young adults (response rate, 65.1%) and 172 term control subjects (response rate, 54.8%) born between February 22, 1978, and November 8, 1985, in Helsinki, Finland.Antidepressant use, history of physician-diagnosed depression, Beck Depression Inventory score, and Center for Epidemiologic Studies Depression Scale score.The VLBW participants reported 20.1% (95% confidence interval [CI], -40.8% to -5.1%) lower CES-D scores than the controls (P =.02). However, this finding was confined to 110 VLBW participants who were born appropriate for gestational age (birth weight > or = -2 SDs according to Finnish birth weight charts), whose Center for Epidemiologic Studies Depression Scale scores were 29.1% (95% CI, -53.7% to -8.4%) lower than those of the controls (P =.004). Furthermore, VLBW participants born appropriate for gestational age were 4.8 (95% CI, 1.3-10.0) times less likely to report a depression diagnosis than controls (P =.02). In contrast, 52 VLBW participants born small for gestational age (birth weight < -2 SDs according to Finnish birth weight charts) reported 36.2% (95% CI, 1.1%-83.5%) higher Beck Depression Inventory scores (P =.04), were 4.0 (95% CI, 1.1-14.3) times more likely to use antidepressants (P =.03), and were 2.5 (95% CI, 1.0-6.3) times more likely to report a depression diagnosis (P =.04) compared with controls.This is the first study (to our knowledge) to show that intrauterine growth pattern may modify associations between VLBW and depression. Intrauterine growth retardation rather than VLBW per se may pose a risk of depression in young adulthood.

Animal models have linked early maternal separation with lifelong changes in hypothalamic-pituitary-adrenocortical (HPA) axis activity. Although this is paralleled in human studies, this is often in the context of other life adversities, for example, divorce or adoption, and it is not known whether early separation in the absence of these factors has long term effects on the HPA axis.The Finnish experience in World War II created a natural experiment to test whether separation from a father serving in the armed forces or from both parents due to war evacuation are associated with alterations in HPA axis response to psychosocial stress in late adulthood.282 subjects (M=63.5 years, SD=2.5), of whom 85 were non-separated, 129 were separated from their father, and 68 were separated from both their caregivers during WWII, were enlisted to participate in a Trier Social Stress Test (TSST), during which we measured salivary cortisol and, for 215 individuals, plasma cortisol and ACTH concentrations. We used mixed models to study whether parental separation is associated with salivary and plasma cortisol or plasma ACTH reactivity, and linear regressions to analyse differences in the baseline, or incremental area under the cortisol or ACTH curves.Participants separated from their father did not differ significantly from non-separated participants. However, those separated from both parents had higher average salivary cortisol and plasma ACTH concentrations across all time points compared to the non-separated group. They also had higher salivary cortisol reactivity to the TSST. Separated women had higher baselines in plasma cortisol and ACTH, whereas men had higher reactivity in response to stress during the TSST. Participants who had experienced the separation in early childhood were more affected than children separated during infancy or school age.Separation from parents during childhood may alter an individual's stress physiology much later in adult life.

It remains unclear whether it is more detrimental to be born too early or too small in relation to symptoms of attention deficit/hyperactivity disorder (ADHD). Thus, we tested whether preterm birth and small body size at birth adjusted for gestational age are independently associated with symptoms of ADHD in children.A longitudinal regional birth cohort study comprising 1535 live-born infants between 03/15/1985 and 03/14/1986 admitted to the neonatal wards and 658 randomly recruited non-admitted infants, in Finland. The present study sample comprised 828 children followed up to 56 months. The association between birth status and parent-rated ADHD symptoms of the child was analysed with multiple linear and logistic regression analyses.Neither prematurity (birth < 37 weeks of gestation) nor lower gestational age was associated with ADHD symptoms. However, small for gestational age (SGA < -2 standard deviations [SD] below the mean for weight at birth) status and lower birth weight SD score were significantly, and independently of gestational age, associated with higher ADHD symptoms. Those born SGA, relative to those born AGA, were also 3.60-times more likely to have ADHD symptoms scores above the clinical cut-off. The associations were not confounded by factors implicated as risks for pregnancy and/or ADHD.Intrauterine growth restriction, reflected in SGA status and lower birth weight, rather than prematurity or lower gestational age per se, may increase risk for symptoms of ADHD in young children.

Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

The aim of the study was to investigate whether weight, length, BMI (kilograms per meter squared), and head circumference at birth and their postnatal growth are associated with cognitive abilities at 56 months of age among infants born at term.Our sample was composed of 1056 Finnish children born at term, (37 to 41 weeks) free of any major impairments. Weight, length, and head circumference were measured at birth and at 5, 20, and 56 months of age, and BMI was calculated. We assessed cognitive abilities by conducting tests of general reasoning, visual-motor integration, verbal competence, and language comprehension at 56 months of age.Firstly, for every 1 SD lower in weight or BMI at birth, general reasoning and/or visual-motor integration was >1.20 points lower, and for every 1 SD lower in length or head circumference at birth, abilities across all of the cognitive domains were >1.31 points lower. Second, for every 1 SD slower gain in weight or BMI from birth to 5 months, general reasoning and visual-motor integration decreased by >0.97 points; for every 1 SD slower gain in length from 5 to 20 months and from 20 to 56 months, respectively, visual-motor integration, and verbal competence and language comprehension decreased by >1.03 points; and for every 1 SD slower increase in head circumference from birth to 5 months and from 5 to 20 months, respectively, visual-motor integration and language comprehension decreased by >1.17 points. Third, tests for nonlinear relationships revealed that, in some cases, large body size and faster growth were also associated with lower scores in cognitive tests.Our findings suggest that, even within the range of children born at term, prenatal and postnatal growth in body size are associated with individual differences in cognitive abilities.

Overexposure to glucocorticoids may link prenatal adversity with detrimental outcomes in later life. Glycyrrhiza, a natural constituent of licorice, inhibits placental 11-beta-hydroxysteroid dehydrogenase type 2, the feto-placental "barrier" to higher maternal levels of cortisol. The authors studied whether prenatal exposure to glycyrrhiza in licorice exerts detrimental effects on cognitive performance (subtests of the Wechsler Intelligence Scale for Children III as well as the Children's Developmental Neuropsychological Assessment and the Beery Developmental Test of Visual-Motor Integration) and psychiatric symptoms (Child Behavior Checklist) in 321 Finnish children 8.1 years of age born in 1998 as healthy singletons at 35-42 weeks of gestation. In comparison to the group with zero-low glycyrrhiza exposure (0-249 mg/week), those with high exposure (>or=500 mg/week) had significant decrements in verbal and visuospatial abilities and in narrative memory (range of mean differences in standard deviation units, -0.31 to -0.41; P < 0.05) and significant increases in externalizing symptoms and in attention, rule-breaking, and aggression problems (range of odds ratios, 2.15 to 3.43; P < 0.05). The effects on cognitive performance appeared dose related. Data are compatible with adverse fetal "programming" by overexposure to glucocorticoids and caution against excessive intake of licorice-containing foodstuffs during pregnancy.

The developing foetus makes adaptations to an adverse in utero environment which may lead to permanent changes in structure and physiology, thus ‘programming’ the foetus to risk of ill health in later life. Epidemiological studies have shown associations between low birth weight, a surrogate marker of an adverse intrauterine environment, and a range of diseases in adult life including cardiometabolic and psychiatric disease. These associations do not apply exclusively to low birth weight babies but also to newborns within the normal birth weight range. Early life stress, including stressors in the prenatal and early postnatal period, is a key factor that can have long-term effects on offspring health. Animal studies show this is mediated through changes in the maternal and foetal hypothalamic-pituitary-adrenal axes resulting in foetal exposure to excess glucocorticoids. Data in humans are more limited but support that the biological effects of stress in utero may be transmitted through changes in glucocorticoid action or metabolism. Common contemporary physical and social stressors of maternal obesity and socio-economic deprivation impact on the maternal response to pregnancy and the prevailing hormonal milieu that the developing foetus will be exposed to. Prenatal stress may also be compounded by early postnatal stresses such as childhood maltreatment with resultant adverse effects for the offspring. Understanding of the mechanisms whereby these stressors are transmitted from mother to foetus will not only improve our knowledge of normal foetal development but will also help identify novel pathways for early intervention either in the periconceptional, pregnancy or the early postpartum period.

Objective Maternal depressive symptoms during pregnancy are associated with increased risk of psychiatric problems in children. A more precise understanding of the timing of the symptoms during pregnancy and their independence of other prenatal and postnatal factors in predicting child psychopathology risk is needed. We examined whether maternal depressive symptoms during pregnancy predict child psychiatric problems, whether these associations are trimester- or gestational-week−specific and/or independent of pregnancy disorders, and whether maternal depressive symptoms after pregnancy mediate or add to the prenatal effects. Method The study sample comprised 2,296 women and their children born in Finland between 2006-2010, participating in the prospective pregnancy cohort study Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) and followed up from 1.9 to 5.9 years of age. The women completed the Center for Epidemiologic Studies Depression Scale biweekly between gestational weeks+days 12+0/13+6 and 38+0/39+6 or delivery. In the follow-up, they completed the Beck Depression Inventory−II and Child Behavior Checklist 1½−5. Results Maternal depressive symptoms during pregnancy predicted significantly higher internalizing (0.28 SD unit per SD unit increase [95% CI = 0.24−0.32]), externalizing (0.26 [0.23−0.30]), and total problems (0.31 [0.27−0.35]) in children. These associations were nonspecific to gestational week and hence pregnancy trimester, independent of pregnancy disorders, and independent of, although partially mediated by, maternal depressive symptoms after pregnancy. Psychiatric problems were greatest in children whose mothers reported clinically significant depressive symptoms across pregnancy trimesters and during and after pregnancy. Conclusion Maternal depressive symptoms during pregnancy predict increased psychiatric problems in young children. Preventive interventions from early pregnancy onward may benefit offspring mental health. Maternal depressive symptoms during pregnancy are associated with increased risk of psychiatric problems in children. A more precise understanding of the timing of the symptoms during pregnancy and their independence of other prenatal and postnatal factors in predicting child psychopathology risk is needed. We examined whether maternal depressive symptoms during pregnancy predict child psychiatric problems, whether these associations are trimester- or gestational-week−specific and/or independent of pregnancy disorders, and whether maternal depressive symptoms after pregnancy mediate or add to the prenatal effects. The study sample comprised 2,296 women and their children born in Finland between 2006-2010, participating in the prospective pregnancy cohort study Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) and followed up from 1.9 to 5.9 years of age. The women completed the Center for Epidemiologic Studies Depression Scale biweekly between gestational weeks+days 12+0/13+6 and 38+0/39+6 or delivery. In the follow-up, they completed the Beck Depression Inventory−II and Child Behavior Checklist 1½−5. Maternal depressive symptoms during pregnancy predicted significantly higher internalizing (0.28 SD unit per SD unit increase [95% CI = 0.24−0.32]), externalizing (0.26 [0.23−0.30]), and total problems (0.31 [0.27−0.35]) in children. These associations were nonspecific to gestational week and hence pregnancy trimester, independent of pregnancy disorders, and independent of, although partially mediated by, maternal depressive symptoms after pregnancy. Psychiatric problems were greatest in children whose mothers reported clinically significant depressive symptoms across pregnancy trimesters and during and after pregnancy. Maternal depressive symptoms during pregnancy predict increased psychiatric problems in young children. Preventive interventions from early pregnancy onward may benefit offspring mental health.

Author(s): Felix, Janine F; Joubert, Bonnie R; Baccarelli, Andrea A; Sharp, Gemma C; Almqvist, Catarina; Annesi-Maesano, Isabella; Arshad, Hasan; Baiz, Nour; Bakermans-Kranenburg, Marian J; Bakulski, Kelly M; Binder, Elisabeth B; Bouchard, Luigi; Breton, Carrie V; Brunekreef, Bert; Brunst, Kelly J; Burchard, Esteban G; Bustamante, Mariona; Chatzi, Leda; Cheng Munthe-Kaas, Monica; Corpeleijn, Eva; Czamara, Darina; Dabelea, Dana; Davey Smith, George; De Boever, Patrick; Duijts, Liesbeth; Dwyer, Terence; Eng, Celeste; Eskenazi, Brenda; Everson, Todd M; Falahi, Fahimeh; Fallin, M Daniele; Farchi, Sara; Fernandez, Mariana F; Gao, Lu; Gaunt, Tom R; Ghantous, Akram; Gillman, Matthew W; Gonseth, Semira; Grote, Veit; Gruzieva, Olena; Haberg, Siri E; Herceg, Zdenko; Hivert, Marie-France; Holland, Nina; Holloway, John W; Hoyo, Cathrine; Hu, Donglei; Huang, Rae-Chi; Huen, Karen; Jarvelin, Marjo-Riitta; Jima, Dereje D; Just, Allan C; Karagas, Margaret R; Karlsson, Robert; Karmaus, Wilfried; Kechris, Katerina J; Kere, Juha; Kogevinas, Manolis; Koletzko, Berthold; Koppelman, Gerard H; Kupers, Leanne K; Ladd-Acosta, Christine; Lahti, Jari; Lambrechts, Nathalie; Langie, Sabine AS; Lie, Rolv T; Liu, Andrew H; Magnus, Maria C; Magnus, Per; Maguire, Rachel L; Marsit, Carmen J; McArdle, Wendy; Melen, Erik; Melton, Phillip; Murphy, Susan K; Nawrot, Tim S; Nistico, Lorenza; Nohr, Ellen A; Nordlund, Bjorn; Nystad, Wenche; Oh, Sam S; Oken, Emily; Page, Christian M; Perron, Patrice; Pershagen, Goran

Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood.Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day.This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.

Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.

Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.

The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 × 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed α-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders.

CONTEXT: Preterm birth increases the risk for mental disorders in adulthood, yet findings on self-reported or subclinical mental health problems are mixed. OBJECTIVE: To study self-reported mental health problems among adults born preterm at very low birth weight (VLBW; ≤1500 g) compared with term controls in an individual participant data meta-analysis. DATA SOURCES: Adults Born Preterm International Collaboration. STUDY SELECTION: Studies that compared self-reported mental health problems using the Achenbach Young Adult Self Report or Adult Self Report between adults born preterm at VLBW (n = 747) and at term (n = 1512). DATA EXTRACTION: We obtained individual participant data from 6 study cohorts and compared preterm and control groups by mixed random coefficient linear and Tobit regression. RESULTS: Adults born preterm reported more internalizing (pooled β = .06; 95% confidence interval .01 to .11) and avoidant personality problems (.11; .05 to .17), and less externalizing (–.10; –.15 to –.06), rule breaking (–.10; –.15 to –.05), intrusive behavior (–.14; –.19 to –.09), and antisocial personality problems (–.09; –.14 to –.04) than controls. Group differences did not systematically vary by sex, intrauterine growth pattern, neurosensory impairments, or study cohort. LIMITATIONS: Exclusively self-reported data are not confirmed by alternative data sources. CONCLUSIONS: Self-reports of adults born preterm at VLBW reveal a heightened risk for internalizing problems and socially avoidant personality traits together with a lowered risk for externalizing problem types. Our findings support the view that preterm birth constitutes an early vulnerability factor with long-term consequences on the individual into adulthood.

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10−4). The strongest combined association was at rs1823125 (P=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Objectives We examined temporal associations between objectively-measured physical activity (PA) during the day and in the evening, and sleep quantity and quality. Study Design PA and sleep were measured by actigraphs for an average of one week in an epidemiological cohort study of 275 eight-year-old children. Results For each one standard deviation (SD) unit of increased PA during the day, sleep duration was decreased by 0.30, sleep efficiency by 0.16, and sleep fragmentation increased by 0.08 SD units that night. For each one SD unit increase in sleep duration and efficiency the preceding night, PA the following day decreased by 0.09 and 0.16 SD units, respectively. When we contrasted days with a high amount of moderate to vigorous activity during the day or in the evening to days with a more sedentary profile, the results were essentially similar. However, moderate to vigorous PA in the evening shortened sleep latency. Conclusions The relationship between a higher level of PA and poorer sleep is bidirectional. These within-person findings challenge epidemiological findings showing that more active people report better sleep. Since only a few studies using objective measurements of both PA and sleep have been conducted in children, further studies are needed to confirm/refute these results.

Temperament has a strongly heritable component, yet multiple independent genome-wide studies have failed to identify significant genetic associations. We have assembled the largest sample to date of persons with genome-wide genotype data, who have been assessed with Cloninger's Temperament and Character Inventory. Sum scores for novelty seeking, harm avoidance, reward dependence and persistence have been measured in over 11,000 persons collected in four different cohorts. Our study had >80% power to identify genome-wide significant loci (P<1.25 × 10(-8), with correction for testing four scales) accounting for ≥0.4% of the phenotypic variance in temperament scales. Using meta-analysis techniques, gene-based tests and pathway analysis we have tested over 1.2 million single-nucleotide polymorphisms (SNPs) for association to each of the four temperament dimensions. We did not discover any SNPs, genes, or pathways to be significantly related to the four temperament dimensions, after correcting for multiple testing. Less than 1% of the variability in any temperament dimension appears to be accounted for by a risk score derived from the SNPs showing strongest association to the temperament dimensions. Elucidation of genetic loci significantly influencing temperament and personality will require potentially very large samples, and/or a more refined phenotype. Item response theory methodology may be a way to incorporate data from cohorts assessed with multiple personality instruments, and might be a method by which a large sample of a more refined phenotype could be acquired.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10−8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders. A genome-wide association study of 1.7 million individuals identified 41 genetic variants associated with left-handedness and 7 associated with ambidexterity. The genetic correlation between the traits was low, thereby implying different aetiologies.

OBJECTIVE Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345–248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870–135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate–adjusted P value threshold of 0.05. CONCLUSIONS Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10-9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10-9).This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

Abstract Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P &lt; 1.06 × 10 − 7 , of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and 'programming' of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors.Bi-weekly self-ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 ± 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother-rated at 15.6 ± 4.2 days.Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13-0.69, p = 0.005], HSD1B11 (0.30, 0.03-0.57, p = 0.03), NR3C1 (0.44, 0.19-0.68, p = 0.001) and SLC6A4 (0.26, 0.00-0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05).Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors.

Maternal antenatal depression may compromise the fetal developmental milieu and contribute to individual differences in aging and disease trajectories in later life. We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems.A total of 694 mothers from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) Study provided information on history of depression diagnosed before pregnancy; 581 completed the Center for Epidemiological Studies Depression Scale throughout pregnancy, and 407 completed the Child Behavior Checklist at child's age 3.7 years (SD = 0.75 year). DNA methylation (DNAm) GA of fetal cord blood DNA was based on the methylation profile of 148 selected cytosine linked to guanine by phosphate (CpG) sites. Epigenetic GA was calculated as the arithmetic difference between DNAm GA and chronological GA and adjusted for chronological GA.Maternal history of depression diagnosed before pregnancy (mean difference = -0.25 SD units, 95% CI = -0.46 to -0.03) and greater antenatal depressive symptoms (-0.08 SD unit per 1-SD unit increase, 95% CI = -0.16 to -0.004) were associated with child's lower epigenetic GA. Child's lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys.Maternal antenatal depression is associated with lower epigenetic GA in offspring. This lower epigenetic GA seems to be associated with a developmental disadvantage for boys, who, in early childhood, show greater psychiatric problems.

Evidence regarding the associations between sleep duration and quality, and neurocognitive function in adolescents remains scanty. This study examined the associations in early adolescence between: sleep duration; efficiency; fragmentation; wake-after-sleep-onset (WASO); catch-up sleep; intelligence; memory; and executive function, including attention. This study included 354 girls and boys with a mean age 12.3 years (SD = 0.5) from a birth cohort born in 1998. Sleep was measured with accelerometers for an average of eight nights. Cognitive function was evaluated with subtests from the Wechsler Intelligence Scale for Children-III (WISC-III), the Developmental Neuropsychological Assessment 2 (NEPSY-2), the Wisconsin Card Sorting Task (WCST), Conners' Continuous Performance Task (CPT), and the Trail Making Test (TMT). In girls, a higher WASO and fragmentation index were associated with poorer executive functioning (higher number of perseverative errors in the WCST), and longer catch-up sleep was associated with longer reaction times and better performance in one verbal intelligence test (Similarities subtest of the WISC-III). In boys, shorter sleep duration, lower efficiency, higher WASO, higher sleep fragmentation and shorter catch-up sleep were associated with lower executive functioning (more commission errors, shorter reaction times, and had lower D Prime scores in CPT). In adolescent girls, poorer sleep quality was only weakly associated with poorer executive functioning, while in boys, poorer sleep quantity and quality were associated with an inattentive pattern of executive functioning. The amount of catch-up sleep during weekends showed mixed patterns in relation to neurocognitive function.

IMPORTANCEDepressive disorders arise from a combination of genetic and environmental risk factors.Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression.Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers.OBJECTIVE To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood. DESIGN, SETTING, AND PARTICIPANTSTo date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted.The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts.Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study.Results of EWAS were pooled using sample-size weighted meta-analysis.Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts. MAIN OUTCOMES AND MEASURESWhole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire. RESULTSThe discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years.The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years.The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57× 10 -08 ; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10 -09 ; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10 -08 ; n = 11 256; chromosome = 15q26.1).The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10 -03 ) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10 -04 ) was associated with major depression.CONCLUSIONS AND RELEVANCE This study identifies 3 methylated sites associated with depressive symptoms.All 3 findings point toward axon guidance as the common disrupted pathway in depression.The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression.Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R 2 =0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.

We studied if late preterm birth (34 weeks 0 days-36 weeks 6 days of gestation) is associated with performance on the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) in late adulthood and if maximum attained lifetime education moderated these associations.Participants were 919 Finnish men and women born between 1934 and 1944, who participated in the Helsinki Birth Cohort Study. They underwent the CERAD-NB at a mean age of 68.1 years. Data regarding gestational age (late preterm versus term) were extracted from hospital birth records, and educational attainment data were gathered from Statistics Finland.After adjustment for major confounders, those born late preterm scored lower on word list recognition (mean difference: -0.33 SD; P = .03) than those born at term. Among those who had attained a basic or upper secondary education, late preterm birth was associated with lower scores on word list recognition, constructional praxis, constructional praxis recall, clock drawing, Mini-Mental State Examination, and memory total and CERAD total 2 compound scores (mean differences: >0.40 SD; P values <.05), and had a 2.70 times higher risk of mild cognitive impairment (Mini-Mental State Examination score: <26 points) (P = .02). Among those with tertiary levels of education, late preterm birth was not associated with CERAD-NB scores.Our findings offer new insight into the lifelong consequences of late preterm birth, and they add late preterm birth as a novel risk factor to the list of neurocognitive impairment in late adulthood. Our findings also suggest that attained lifetime education may mitigate aging-related neurocognitive impairment, especially among those born late preterm.

Maternal depressive symptoms during and after pregnancy predict poorer child neurodevelopment. The effects of timing, symptom severity, and additive influences remain unclear.A total of 2,231 mothers of the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Center for Epidemiological Studies Depression Scale biweekly up to 14 times during pregnancy and twice up to 12 months after pregnancy. At child's age 1.9-5.7 years, the mothers completed the Beck Depression Inventory-II on their concurrent depressive symptoms and Ages and Stages Questionnaire on child developmental milestones.Higher mean maternal depressive symptoms, each biweekly score, and consistently clinically relevant symptomatology during pregnancy predicted lower total developmental milestones, fine and gross motor, communication, problem solving, and personal/social skills scores in children. Although maternal depressive symptoms up to 12 months after pregnancy and in early childhood also predicted lower developmental milestones scores, developmental milestones scores were the lowest in children whose mothers' depressive symptoms were above the clinical cutoff either only during pregnancy, both during and up to 12 months after pregnancy, or at each three time-points.Maternal depressive symptoms during pregnancy, in the first year postpartum and in early childhood are associated with poorer child neurodevelopment. Our findings further suggest that antenatal and postpregnancy depression have additive effects on neurodevelopment. Children of mothers with the most chronic and severe depressive symptoms during pregnancy had the most neurodevelopmental disadvantages. Our findings emphasize the adverse effects of maternal depression during and after pregnancy and in early childhood on child neurodevelopment.

A recent study has shown that it is possible to accurately estimate gestational age (GA) at birth from the DNA methylation (DNAm) of fetal umbilical cord blood/newborn blood spots. This DNAm GA predictor may provide additional information relevant to developmental stage. In 814 mother-neonate pairs, we evaluated the associations between DNAm GA and a number of maternal and offspring characteristics. These characteristics reflect prenatal environmental adversity and are expected to influence newborn developmental stage.DNAm GA acceleration (GAA; i.e., older DNAm GA than chronological GA) of the offspring at birth was associated with maternal age of over 40 years at delivery, pre-eclampsia and fetal demise in a previous pregnancy, maternal pre-eclampsia and treatment with antenatal betamethasone in the index pregnancy, lower neonatal birth size, lower 1-min Apgar score, and female sex. DNAm GA deceleration (GAD; i.e., younger DNAm GA than chronological GA) of the offspring at birth was associated with insulin-treated gestational diabetes mellitus (GDM) in a previous pregnancy and Sjögren's syndrome. These findings were more accentuated when the DNAm GA calculation was based on the raw difference between DNAm GA and GA than on the residual from the linear regression of DNAm GA on GA.Our findings show that variations in the DNAm GA of the offspring at birth are associated with a number of maternal and offspring characteristics known to reflect exposure to prenatal environmental adversity. Future studies should be aimed at determining if this biological variation is predictive of developmental adversity.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications—in our case, CpG methylation—and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Identifying risk factors for major depression and depressive symptoms in youths could have important implications for prevention efforts. This study examined the association of polygenic risk scores (PRSs) for a broad depression phenotype derived from a large-scale genome-wide association study (GWAS) in adults, and its interaction with childhood abuse, with clinically relevant depression outcomes in clinical and epidemiological youth cohorts.The clinical cohort comprised 279 youths with major depression (mean age=14.76 years [SD=2.00], 68% female) and 187 healthy control subjects (mean age=14.67 years [SD=2.45], 63% female). The first epidemiological cohort included 1,450 youths (mean age=13.99 years [SD=0.92], 63% female). Of those, 694 who were not clinically depressed at baseline underwent follow-ups at 6, 12, and 24 months. The replication epidemiological cohort comprised children assessed at ages 8 (N=184; 49.2% female) and 11 (N=317; 46.7% female) years. All cohorts were genome-wide genotyped and completed measures for major depression, depressive symptoms, and/or childhood abuse. Summary statistics from the largest GWAS to date on depression were used to calculate the depression PRS.In the clinical cohort, the depression PRS predicted case-control status (odds ratio=1.560, 95% CI=1.230-1.980), depression severity (β=0.177, SE=0.069), and age at onset (β=-0.375, SE=0.160). In the first epidemiological cohort, the depression PRS predicted baseline depressive symptoms (β=0.557, SE=0.200) and prospectively predicted onset of moderate to severe depressive symptoms (hazard ratio=1.202, 95% CI=1.045-1.383). The associations with depressive symptoms were replicated in the second epidemiological cohort. Evidence was found for an additive, but not an interactive, effect of the depression PRS and childhood abuse on depression outcomes.Depression PRSs derived from adults generalize to depression outcomes in youths and may serve as an early indicator of clinically significant levels of depression.

Birth before 32 weeks' gestation (very preterm [VPT]) and birth weight below 1500 g (very low birth weight [VLBW]) have been associated with lower cognitive performance in childhood. However, there are few investigations of the association of neonatal morbidities and maternal educational levels with the adult cognitive performance of individuals born VPT or VLBW (VPT/VLBW).To assess differences in adult IQ between VPT/VLBW and term-born individuals and to examine the association of adult IQ with cohort factors, neonatal morbidities, and maternal educational level among VPT/VLBW participants.Systematic review of published data from PubMed and meta-analysis of individual participant data (IPD) of cohorts from 2 consortia (Research on European Children and Adults Born Preterm [RECAP] and Adults Born Preterm International Collaboration [APIC]).The meta-analysis included prospective longitudinal cohort studies that assessed the full-scale IQ of adults born VPT or VLBW and respective control groups comprising term-born adults.The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for analyses of individual participant data and identified 8 studies that provided data from 2135 adults (1068 VPT/VLBW and 1067 term-born participants) born between 1978 and 1995. Meta-analyses of IPD were performed using a 1-stage approach, treating VPT birth or VLBW and cohort as random effects.Full-scale IQ scores were converted to z scores within each cohort using the combined SD of VPT/VLBW participants and a control group of term-born participants, with scores centered on the mean of the control group.A total of 426 records were identified and screened. After exclusions, 13 studies were included in the aggregate meta-analysis. The IPD meta-analysis included 8 of the 9 RECAP and APIC cohorts with adult IQ data. The mean (SD) age among the 8 IPD cohorts was 24.6 (4.3) years, and 1163 participants (54.5%) were women. In unadjusted analyses, VPT/VLBW participants had mean adult IQ scores that were 0.78 SD (95% CI, -0.90 to -0.66 SD) lower than term-born participants, equivalent to a difference of 12 IQ points. Among VPT/VLBW participants, lower gestational age (score difference per week of gestation, 0.11; 95% CI, 0.07-0.14), lower birth weight z scores (score difference per 1.0 SD, 0.21; 95% CI, 0.14-0.28), the presence of neonatal bronchopulmonary dysplasia (score difference, -0.16; 95% CI, -0.30 to -0.02) or any grade of intraventricular hemorrhage (score difference, -0.19; 95% CI, -0.33 to -0.05), and lower maternal educational level (score difference, 0.26; 95% CI, 0.17-0.35) were all significantly associated with lower IQ scores in adulthood.In this IPD meta-analysis, lower gestational age, lower weight for gestational age, neonatal morbidities, and lower maternal educational levels were all important risk factors associated with lower IQ among young adults born VPT or VLBW.

Abstract Early life stress (ELS) may increase the risk of anxiety throughout the life course. Whether this effect extends to late adulthood is poorly known. In our study comprising 1872 participants from the Helsinki Birth Cohort Study born in 1934–1944, we investigated the association of various forms of ELS and their accumulation with self-reported anxiety symptoms at the age of 65–77 years. Data on childhood socioeconomic status and separation from parents were based on national registers for all participants. Information on self-reported emotional and physical trauma, parental divorce, and death of a family member in childhood was obtained from 1277 participants. We found that experiencing emotional trauma, physical trauma, and low socioeconomic status in childhood were associated with increased anxiety symptoms in late adulthood [B = 0.44 (95% CI = 0.31–0.58); B = 0.33 (95% CI = 0.20–0.46); B = 0.10 (95% CI = 0.01–0.19), respectively]. These associations remained significant even after controlling for other forms of ELS. Accumulation of early life stress also increased the levels of late-adulthood anxiety symptoms and the risk of anxiety regarded as clinically significant. Screening for potentially stressful childhood experiences in elderly populations may help identifying individuals with increased anxiety symptoms and planning preventive and therapeutic interventions for those exposed to ELS.

Abstract Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4–15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7–11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance ( p &lt; 0.05) in either of the EWAS were correlated between timepoints ( ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms ( p &lt; 1 × 10 –7 ), including ERC2 and CREB5 . Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2 , which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5 , which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p &lt; 1 × 10 −7 . In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

BackgroundData on psychiatric disorders in survivors born very preterm (VP; <32 weeks) or very low birthweight (VLBW; <1500 g) are sparse. We compared rates of psychiatric diagnoses between VP/VLBW and term-born, normal birthweight (term/NBW) control participants.MethodsThis individual participant data (IPD) meta-analysis pooled data from eligible groups in the Adults born Preterm International Collaboration (APIC). Inclusion criteria included: 1) VP/VLBW group (birth weight <1500 g and/or gestational age <32 weeks), 2) normal birth weight/term-born control group (birth weight >2499 g and/or gestational age ≥37 weeks), and 3) structured measure of psychiatric diagnoses using DSM or ICD criteria. Diagnoses of interest were Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Anxiety Disorder, Mood Disorder, Disruptive Behaviour Disorder (DBD), Eating Disorder, and Psychotic Disorder. A systematic search for eligible studies was conducted (PROSPERO Registration Number 47555).FindingsData were obtained from 10 studies (1385 VP/VLBW participants, 1780 controls), using a range of instruments and approaches to assigning diagnoses. Those born VP/VLBW had ten times higher odds of meeting criteria for ASD (odds ratio [OR] 10·6, 95% confidence interval [CI] 2·50, 44·7), five times higher odds of meeting criteria for ADHD (OR 5·42, 95% CI 3·10, 9·46), twice the odds of meeting criteria for Anxiety Disorder (OR 1·91, 95% CI 1·36, 2·69), and 1·5 times the odds of meeting criteria for Mood Disorder (OR 1·51, 95% CI 1·08, 2·12) than controls. This pattern of findings was consistent within age (<18 years vs. ≥18 years) and sex subgroups.InterpretationOur data suggests that individuals born VP/VLBW might have higher odds of meeting criteria for certain psychiatric disorders through childhood and into adulthood than term/NBW controls. Further research is needed to corroborate our results and identify factors associated with psychiatric disorders in individuals born VP/VLBW.FundingAustralia's National Health & Medical Research Council; CAPES (Coordenação de Aperfeiçoamento de Pessoal deNível Superior) - International Cooperation General Program; Canadian Institutes of Health Research Team Grant; National Council for Scientific and Technological Development (CNPq); Academy of Finland; Sigrid Juselius Foundation; Signe and Ane Gyllenberg Foundation; European Union's Horizon 2020 research and innovation programme: Project RECAP-Preterm; European Commission Dynamics of Inequality Across the Life-course: structures and processes (DIAL); Neurologic Foundation of New Zealand; MRC programme grant; Health Research Council of New Zealand; National Institutes of Health, USA; The Research Council of Norway; Joint Research Committee between St. Olavs Hospital and Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU); Liaison Committee between Central Norway Regional Health Authority and NTNU.

In the context of the importance of elucidating the determinants of the initial, newborn setting of telomere length (TL), it is increasingly evident that maternal stress and stress-related processes during pregnancy play a major role. Although psychological resilience may function as a buffer, research in this area has not yet examined its potential role vis-à-vis that of stress. The authors examined the relationship between maternal psychological resilience during pregnancy and newborn TL.In a sample of 656 mother-child dyads from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort, multiple serial assessments were conducted over the course of pregnancy to quantify maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. TL was measured using quantitative polymerase chain reaction in leukocytes extracted from cord blood shortly after birth. Linear regression was used to predict newborn TL from maternal resilience during pregnancy, adjusting for other potential determinants.Maternal stress significantly predicted shorter newborn TL (β=-0.079), and positivity significantly predicted longer TL (β=0.135). Maternal resilience (positivity accounting for stress) was significantly and positively associated with newborn TL (β=0.114, 95% CI=0.035, 0.189), with each standard deviation increase in resilience predicting 12% longer newborn TL.The results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.

Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Corticosteroids administered to women at risk of imminent preterm birth is one of the most effective ways to improve the prognosis of infants born preterm. Scant data about long-term neurodevelopmental and neurosensory outcomes among the treatment-exposed children are mixed, suggesting that not all domains of neurodevelopmental and neurosensory function may be equally affected. Moreover, the long-term outcomes may vary according to whether the treatment-exposed children are being born preterm (<37 weeks and 0 days) or term (≥37 weeks and 0 days).To study whether antenatal corticosteroid treatment is associated with psychological developmental and neurosensory disorders in children born term and preterm and whether the associations persist in a sibling-comparison design.This population-based retrospective register-linkage study comprised all singleton live births in Finland between January 1, 2006, and December 31, 2017, followed up until December 31, 2018, as well as a sibling comparison among term sibling pairs. Data were analyzed from March 21, 2021, to July 7, 2022.Antenatal corticosteroid treatment.Cox proportional hazards regression models were used to estimate the associations between antenatal corticosteroid treatment and physician-diagnosed specific developmental disorders of speech and language, scholastic skills, and motor function; pervasive developmental disorder; other or unspecified psychological developmental disorder; disorders of vison and hearing; epilepsy; and cerebral palsy.The study population comprised 670 097 singleton children (342 562 boys [51.1%]) followed up for a median of 5.8 years (IQR, 3.1-8.7 years). Of the 14 868 treatment-exposed children (2.2%; 53.9% boys), 6730 (45.3%) were born term, and 8138 (54.7%) were born preterm, and of the 655 229 nonexposed children (97.8%; 51.1% boys), 634 757 (96.9%) were born term, and 20 472 (3.1%) were born preterm. Of the 241 621 eligible maternal sibling pairs born term, 4128 (1.7%) were discordant for treatment exposure. Compared with nonexposure in the entire population, treatment exposure was significantly associated with higher adjusted hazard ratios (aHRs) for specific developmental disorders of speech and language (aHR, 1.38 [95% CI, 1.27-1.50]; P < .001), specific developmental disorders of scholastic skills (aHR, 1.32 [95% CI, 1.13-1.54]; P = .004), specific developmental disorder of motor function (aHR, 1.32 [95% CI, 1.18-1.49]; P < .001), pervasive developmental disorder (aHR, 1.35 [95% CI, 1.17-1.56]; P < .001), other or unspecified disorder of psychological development (aHR, 1.88 [95% CI, 1.58-2.25]; P < .001), and vision or hearing loss (aHR, 1.22 [95% CI, 1.04-1.43]; P = .02). Compared with nonexposure in the term-born group, treatment exposure was significantly associated with higher aHRs for specific developmental disorders of speech and language (aHR, 1.47 [95% CI, 1.31-1.66]; P < .001), specific developmental disorders of scholastic skills (aHR, 1.28 [95% CI, 1.01-1.63]; P = .04), specific developmental disorder of motor function (aHR, 1.38 [95% CI, 1.12-1.70]; P < .001), pervasive developmental disorder (aHR, 1.42 [95% CI, 1.16-1.75]; P < .001), other or unspecified disorder of psychological development (aHR, 1.92 [95% CI, 1.51-2.43]; P < .001), epilepsy (aHR, 1.57 [95% CI, 1.22-2.01]; P < .001), and cerebral palsy (aHR, 2.18 [95% CI, 1.47-3.23]; P < .001). The hazard for any psychological developmental and neurosensory disorder was significantly higher for the treatment-exposed sibling compared with the nonexposed cosibling (absolute difference, 1.2% [95% CI, 0.03%-2.4%]; P < .001; aHR, 1.22 [95% CI, 1.04-1.42]; P = .01). Antenatal corticosteroids were not associated with either significant benefit or risk in the preterm group.This study suggests that the possible long-term psychological developmental and neurosensory harms warrant careful consideration of risks and benefits when deciding on maternal antenatal corticosteroid treatment.

Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.

The authors studied the occurrence of common lifestyle risk factors, namely, nonprudent diet, smoking, physical inactivity, and frequent inebriation by alcohol in a cohort of young adults aged 18, 21, and 24 years (n = 484) as part of the Cardiovascular Risk in Young Finns Study in 1986. Risk habits showed significant clustering; the number of subjects was greater than expected in groups with zero and three of four risk habits and less than expected in the group with only one or two risk habits. Stepwise logistic regression analysis was used to find independent determinants for this clustering from a set of socioeconomic, demographic, and behavioral (type A components) determinants. The logistic model suggested several independent risk factors for risk habit clustering. These included male sex, aggressiveness, and past unemployment. Paying a lot of attention to health habits, higher education (being a student), good self-perceived health, and a high sense of responsibility seemed to be protective factors against risk habit clustering. The accumulation of risk habits was also associated with an atherogenic lipid and blood pressure profile (clustering of high density lipoprotein cholesterol/total cholesterol ratio, triglycerides, and diastolic blood pressure in their extreme tertiles). These findings show that common risk habits cluster among young adults. Knowledge about the determinants of this clustering will aid in the planning of future preventive strategies against cardiovascular diseases in young people.

The aim of the study was to test the hypotheses that the trajectory of psychological risk (ie, persistent or increasing measures of depression and anxiety symptoms, anger, and low social support over time) increases the risk for the development of hypertension and that blood pressure levels fluctuate with psychological changes in women. Initially, healthy normotensive middle-aged women (n=541; 90.6% white, 8.9% African American) were followed across an average of 9.2 years of follow-up. Psychological characteristics were assessed repeatedly via standardized questionnaires, and Cox proportional hazards and random regression models were used to analyze their impact, adjusting for hypertension risk factors (age, race, years of education, parental history of hypertension, baseline blood pressure, body mass index, physical activity, alcohol use, and cigarette smoking). Seventy-five women became hypertensive during the follow-up period. Baseline levels of depression, anxiety, anger, and social support did not predict subsequent hypertension. A high level of anxiety throughout the follow-up, an increase in the level of feelings of anger, and a decrease in the level of social support over the follow-up were significant predictors of hypertension incidence (all P<0.05), although covariate adjustment reduced some of the significance levels to nonsignificance. In women, increases in depressive symptoms were significantly associated (P=0.003) with concurrent increases in the level of systolic blood pressure, especially among hypertensive patients (P=0.0001). Increasing levels of anger, decreasing levels of social support, and high anxiety increase the likelihood of women's development of hypertension in midlife. These results emphasize the importance of evaluating the trajectory of psychological risk during the period of evolving hypertension.

We examined whether dispositional optimism and pessimism (overall LOT-R and optimism and pessimism component scores) of 694 adults aged 24 and 27 were associated with socioeconomic status (SES) measured concurrently and in childhood at ages 3 and 6. SES measures included education, occupational status and unemployment, and income. Concurrent adulthood SES was associated with the overall LOT-R and optimism and the pessimism component scores. Childhood family SES predicted overall LOT-R and pessimism component scores, even after controlling statistically for the adulthood SES. Social mobility between SES of family of origin and current SES also influenced the scores. The current findings suggest that the foundation of dispositional optimism and pessimism is related to early SES of the family.

Despite the significance of childhood trauma for later life, there is little evidence on the long-term consequences of parent-child separation. World War II created a unique natural experiment that allowed the authors to test whether 1) evacuation to temporary foster care unaccompanied by either parent and 2) separation from the father because of his military service predicted depressive symptoms later on. Members of the Helsinki 1934–1944 Birth Cohort (n = 1,658) filled out the Beck Depression Inventory (BDI) at the ages of 61.6 (standard deviation: 2.9) and 63.4 (standard deviation: 2.9) years. The mean of the two BDI scores was used as the dependent variable. The data on separation experiences were extracted from the Finnish National Archives and from a survey among the participants. Former evacuees (n = 410) reported 20% (95% confidence interval: 8.7, 33.1) more severe depressive symptoms, and the odds ratio was 1.7 (95% confidence interval: 1.1, 2.6) for having at least mild (BDI score: ≥10) symptoms over time compared with those who were not separated. Those separated from their father because of the father's military assignment (n = 744) did not differ from those who were not separated.

Continuity of temperament from 6 months (the IBQ) to 5.5 years (the CBQ) was explored in Finnish children (n=231) within the theoretical framework deviced by Rothbart. Activity level, smiling and laughter, distress to limitations and fear showed significant differential homotypic and heterotypic continuity, while soothability and duration of orienting showed significant differential heterotypic continuity. On the level of latent superconstructs, infant positive and negative affectivity accounted for 4.6, 22.3, and 6.0% of the variance in childhood extraversion, effortful control and negative affectivity, respectively. Infant and childhood temperament clustered into profile types named "resilient", "undercontrolled", and "overcontrolled" mirroring ipsative continuity. These findings give empirical credence to Rothbart's theory by replicating and extending previous findings in significant ways.

Background: Behavioural disorders with a neurodevelopmental background, such as attention deficit hyperactivity disorder (ADHD), have been associated with a non‐optimal foetal environment, reflected in small body size at birth. However, the evidence stems from highly selected groups with birth outcomes biased towards the extreme low end of the distribution in birth weight. Whether a similar association exists among the normal range of term birth is unclear. Methods: The ADHD Rating Scale was filled in by the biological mothers and fathers of children aged five to six years who were born healthy at term. Information on weight (kg), height (cm), head circumference (cm), and gestational age at birth were obtained from hospital records, and the ponderal index (kg/m 3 ), a commonly used measure of thinness, and head circumference‐to‐length ratio were calculated. Results: Behavioural symptoms of ADHD were predicted by a lower ponderal index, a smaller head circumference, and a smaller head circumference‐to‐length ratio ( β ’s: −.12 to −.14, p ’s &lt; .05). Adjustments for length of gestation, mother's age, tobacco and alcohol use during pregnancy, pre‐pregnancy body mass index (BMI), or parity, the monthly gross income of the family, child's BMI at the age of five to six years or gender did not change the associations. Conclusion: These results suggest that physiological adaptation in utero , indicated by small body size at birth, within term gestational range may increase the susceptibility to behavioural symptoms of ADHD.

Stress may play a role in the pathogenesis of the metabolic syndrome. However, the scant evidence available is not population-based, restricting the external validity of the findings. Our aim was to test associations between stressful life events, their accumulation, and the metabolic syndrome in a large population-based cohort. We also tested associations between stress and the individual components related to the metabolic syndrome.This was a population-based, random sample of 3,407 women and men aged 18-78 years residing in Western Finland. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III and International Diabetes Federation criteria. The severity of 15 stressful life events pertaining to finance, work, social relationships, health, and housing was self-rated.In comparison with subjects not reporting any extremely stressful life events, those reporting work- or finance-related events had an increased odds for having the metabolic syndrome. The risk was further increased according to accumulation of stressful finance-related events and to having at least three stressful life events in any of the life domains assessed. Accumulation of stressful life events was associated with insulin resistance, obesity, and triglycerides. The associations were not confounded by sex, age, lifestyle, or family history of diabetes.Life events perceived as stressful, particularly those related to finance and work, may be a signal for poor metabolic health.

Low socioeconomic status (SES) environments may impede the development of a bank of resources, labeled reserve capacity, and may also be stressful, thereby depleting available reserves. In consequence, lower SES persons may experience more negative emotions, leading to adverse health consequences. The authors tested the reserve capacity model in relation to the metabolic syndrome.There were 401 initially healthy women who followed longitudinally for 12 years. Self-reported characteristics, stressors, and cardiovascular risk factors were measured repeatedly. Structural equation modeling was used to evaluate hypothesized relationships.Metabolic syndrome factor.Confirmatory factor analysis verified reserve capacity as the aggregate of optimism, self-esteem, and social support, and negative emotion as the aggregate of depressive symptoms, anger, and tension. Structural equation modeling showed two pathways to the metabolic syndrome factor, (chi2(59) = 111.729, p < .0001 chi2/df = 1.894; CFI = .956; RMSEA = .047): direct from low SES to the metabolic syndrome factor (B = -0.19, t = -3.24, p = .001); and indirect, from low SES to low reserve capacity to high negative emotions to the metabolic syndrome factor (B = -0.024, t = -2.05, p = .04).Low SES may increase risk for metabolic syndrome, in part, through reserve capacity and negative emotions.

Background. Early life experiences might have long-term effects on health.Aim. To assess prevalence of cardiovascular disease and diabetes in later life among individuals exposed to traumatic separation in early childhood due to World War II.Methods. Of the participants of the Helsinki Birth Cohort 1934–44 Study (n=2003), 320 had been evacuated abroad to temporary foster care in childhood. The remaining participants served as controls. The mean age at evacuation was 4.8 (SD=2.4) years and the mean duration of the evacuation was 1.7 (SD=1.0) years.Results. Cardiovascular morbidity was higher among the former war evacuees (14.7% versus 7.9%; odds ratio (OR)=2.0, 95% confidence interval (95% CI) 1.4–2.9; P<0.001). A similar difference in prevalence of type 2 diabetes was observed (19.7% versus 14.8%; OR=1.4, 95% CI 1.1–1.9, P=0.025). The former war evacuees were also more likely to be hypertensive (P<0.05). The effects on morbidity were not explained by age at testing or socio-economic circumstances in childhood or adulthood.Conclusion. Early life traumatic events may extend lifelong effects on health. This study is among the first to show that early life trauma predicts higher prevalence of cardiovascular disease and type 2 diabetes in late adulthood, in a longitudinal clinical study setting.

OBJECTIVE. We investigated whether very low birth weight (&amp;lt;1500 g) is associated with the risk of sleep-disordered breathing in young adulthood. METHODS. The study was a retrospective longitudinal study of 158 young adults born with very low birth weight and 169 term-born control subjects (aged 18.5–27.1 years). The principal outcome variable was sleep-disordered breathing defined as chronic snoring. RESULTS. The crude prevalence of chronic snoring was similar in both groups: 15.8% for the very low birth weight group versus 13.6% for the control group. However, after controlling for the confounding variables in multivariate logistic regression models (age, gender, current smoking, parental education, height, BMI, and depression), chronic snoring was 2.2 times more likely in the very low birth weight group compared with the control group. In addition, maternal smoking during pregnancy was significantly and independently of very low birth weight related to risk of sleep-disordered breathing. Maternal preeclampsia, standardized birth weight, and, for very low birth weight infants, small-for-gestational-age status were not related to sleep-disordered breathing. CONCLUSIONS. Premature infants with very low birth weight have a twofold risk of sleep-disordered breathing as young adults. In addition, maternal smoking during pregnancy increases the risk of sleep-disordered breathing by more than twofold.

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13 835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case–Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

People born at a low birth weight are at increased risk of chronic adult disease including coronary heart disease, type 2 diabetes, cognitive decline and depression. Recent human and animal research has suggested programming of physiological stress response as an important linking mechanism. We review evidence from human studies, focusing on biological markers as early life indicators and laboratory-induced stress response as an outcome. Several studies show that indicators such as birth weight or length of gestation are associated with alterations in blood pressure, autonomic nervous system and hypothalamic-pituitary-adrenal axis (HPAA) response. In most studies these associations vary according to sex: low birth weight seems to be associated with higher autonomic nervous system response more clearly in females and with higher peripheral vascular resistance and HPAA response in males. The published studies have established the validity of the concept of early life programming of stress response. We believe that important future directions include focusing on specific early life exposures as predictors and on stress response in everyday life as an outcome.

<h3>Objective</h3> To study the effects of very low birth weight (VLBW, <1500 g) birth on physical activity, an important protective and modifiable factor. <h3>Study design</h3> VLBW participants (n = 163) with no major disability and 188 individuals born at term (mean age, 22.3 years; range, 18.5–27.1) completed a standardized questionnaire of physical activity. <h3>Results</h3> VLBW participants reported less leisure-time conditioning physical activity. They were 1.61-fold more likely to "not exercise much," 1.61-fold more likely to exercise infrequently (once a week or less), 2.75-fold more likely to exercise with low intensity (walking), and 3.11-fold more likely to have short exercise sessions (<30 minutes). The differences were present even in subjects with no history of bronchopulmonary dysplasia or asthma and were only slightly attenuated when adjusted for height, parental education, lean body mass, and percent body fat. <h3>Conclusions</h3> Unimpaired adults who were VLBW exercise less during their leisure time than adults born at term. Promoting physical activity may be particularly important in the VLBW population to counteract the risks of chronic disease in adult life.

Abstract Given the ethical limitations of exposing children to experimentally manipulated adverse experiences, evidence of the effects of childhood traumas on subsequent life history are based mostly on women's retrospective reports and animal studies. Only a few prospective studies have assessed the life‐long consequences of childhood trauma. We asked whether a traumatic separation from both parents during childhood is associated with reproductive and marital traits later in life, measured by age of onset of menarche, timing of menopause, period of fertile years, age at first childbirth, birth spacing, number of children, and history of divorce. We studied members of the 1934–1944 Helsinki Birth Cohort, including 396 former war evacuees from varying socioeconomic backgrounds, who were sent unaccompanied by their parents to temporary foster families in Sweden and Denmark, and 503 participants who had no separation experiences. Data on separation experiences, number of children, and divorces experienced came from national registers, and the remaining data from a survey among the participants aged 61.6 years (SD = 2.9). Former evacuees had earlier menarche, earlier first childbirth (men), more children by late adulthood (women), and shorter interbirth intervals (men), than the non‐separated. A traumatic experience in childhood is associated with significant alterations in reproductive and marital traits, which characterize both women and men. The implications are relevant to the 9.2 million child refugees living throughout the world today. Am. J. Hum. Biol., 2008. © 2008 Wiley‐Liss, Inc.

Background Patients with schizophrenia have excess cardiovascular morbidity and mortality. Previous studies suggest that this may be partly due to inadequate somatic treatment and care, such as non-optimal use of lipid-lowering and antihypertensive pharmacotherapy, but longitudinal studies on such aetiological pathways are scarce. Method We investigated the use of lipid-lowering and antihypertensive pharmacotherapy, and the risk of hospitalization for and death from coronary heart disease and stroke among patients with schizophrenia in a birth cohort of 12 939 subjects (Helsinki Birth Cohort Study). This cohort was followed for over 30 adult years by using national databases on cardio- and cerebrovascular hospitalizations and mortality and on reimbursement entitlements and use of drugs for treatment of hypertension, dyslipidaemia, coronary heart disease and diabetes. Results Individuals with schizophrenia had a higher risk of hospitalization for coronary heart disease [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.03–2.57], and mortality from this disease was markedly higher (HR 2.92, 95% CI 1.70–5.00), particularly among women ( p =0.001 for women, p =0.008 for men). Women with schizophrenia had also marginally increased stroke mortality ( p =0.06). However, patients with schizophrenia used less lipid-lowering (odds ratio 0.47, 95% CI 0.27–0.80) and antihypertensive drug treatment (HR 0.37, 95% CI 0.22–0.61). Conclusions In this longitudinal study, coronary heart disease morbidity was increased and coronary heart disease mortality markedly increased in patients, especially in women with schizophrenia. These patients nevertheless received less antihypertensive and lipid-lowering treatment.

Overexposure to glucocorticoids has been proposed as a mechanism by which prenatal adversity 'programs' the function of the hypothalamic-pituitary-adrenocortical axis (HPAA), thereby increasing the risk of adult diseases. Glycyrrhizin, a natural constituent of licorice, potently inhibits 11β-hydroxysteroid dehydrogenase type 2, the feto-placental barrier to the higher maternal cortisol levels. We studied if maternal consumption of glycyrrhizin in licorice associates with HPAA function in children. Diurnal salivary cortisol and salivary cortisol during the Trier Social Stress Test for Children (TSST-C) were measured in children (n=321, mean age=8.1, SD=0.3 years) whose mothers consumed varying levels of glycyrrhizin in licorice during pregnancy; exposure-level groups were labeled high (≥500 mg/week), moderate (250-499 mg/week) and zero-low (0-249 mg/week). In comparison to the zero-low exposure group, children in the high exposure group had 19.2% higher salivary cortisol awakening peak, 33.1% higher salivary cortisol awakening slope, 15.4% higher salivary cortisol awakening area under the curve (AUC), 30.8% higher baseline TSST-C salivary cortisol levels, and their salivary cortisol levels remained high throughout the TSST-C protocol (P-values <0.05). These effects appeared dose-related. Our findings lend support to prenatal 'programming' of HPAA function by overexposure to glucocorticoids.

Summary We tested the relationship of objectively measured sleep quantity and quality with positive characteristics of the child. Sleep duration, sleep latency and sleep efficiency were measured by an actigraph for an average of seven (range = 3–14) consecutive nights in 291 8‐year‐old children (standard deviation = 0.3 years). Children’s optimism, self‐esteem and social competence were rated by parents and/or teachers. Sleep duration showed a non‐linear, reverse J‐shaped relationship with optimism ( P = 0.02), such that children with sleep duration in the middle of the distribution scored higher in optimism compared with children who slept relatively little. Shorter sleep latency was related to higher optimism ( P = 0.01). The associations remained when adjusting for child’s age, sex, body mass index, and parental level of education and optimism. In conclusion, sufficient sleep quantity and good sleep quality are related to children’s positive characteristics. Our findings may inform why sleep quantity and quality and positive characteristics are associated with wellbeing in children.

Objective We hypothesized that, as compared with a matched control group born at term, young adults with very low birth weight (VLBW <1.5 kg) would have higher 24-hour ambulatory blood pressure. Study design We studied 118 18- to 27-year-old subjects born with VLBW within the greater Helsinki area and 120 term-born control subjects with similar age, sex, and birth hospital. The mean birth weight for VLBW subjects was 1.1 kg (standard deviation [SD], 0.2) and for controls, 3.6 kg (SD, 0.5). Gestational ages were 29.2 (SD, 2.3) and 40.1 (SD, 1.0) weeks. Current education of higher-educated parents served as an indicator of childhood socioeconomic status. Ambulatory blood pressure was measured during a 24-hour period with an oscillometric device (Spacelabs 90207). Results VLBW subjects had, with sex, age, and body mass index adjustment, a 2.4 mm Hg (95% confidence interval, 0.2 to 4.6) higher 24-hour systolic pressure. We found hypertension in 11 VLBW subjects and in 3 term-born subjects, giving an adjusted odds ratio of 4.0 (1.1 to 14.8). When socioeconomic status was taken into account, results remained unchanged. Conclusions Higher rates of hypertension and higher 24-hour blood pressure among young adults with VLBW may indicate higher risk for adverse cardiovascular outcomes. We hypothesized that, as compared with a matched control group born at term, young adults with very low birth weight (VLBW <1.5 kg) would have higher 24-hour ambulatory blood pressure. We studied 118 18- to 27-year-old subjects born with VLBW within the greater Helsinki area and 120 term-born control subjects with similar age, sex, and birth hospital. The mean birth weight for VLBW subjects was 1.1 kg (standard deviation [SD], 0.2) and for controls, 3.6 kg (SD, 0.5). Gestational ages were 29.2 (SD, 2.3) and 40.1 (SD, 1.0) weeks. Current education of higher-educated parents served as an indicator of childhood socioeconomic status. Ambulatory blood pressure was measured during a 24-hour period with an oscillometric device (Spacelabs 90207). VLBW subjects had, with sex, age, and body mass index adjustment, a 2.4 mm Hg (95% confidence interval, 0.2 to 4.6) higher 24-hour systolic pressure. We found hypertension in 11 VLBW subjects and in 3 term-born subjects, giving an adjusted odds ratio of 4.0 (1.1 to 14.8). When socioeconomic status was taken into account, results remained unchanged. Higher rates of hypertension and higher 24-hour blood pressure among young adults with VLBW may indicate higher risk for adverse cardiovascular outcomes.

We examined whether small body size at birth and prenatal tobacco or alcohol exposure predict poor sleep and more sleep disturbances in children.An epidemiologic cohort study of 289 eight-year-old children born at term.Sleep duration and efficiency were measured by actigraphy for 7 consecutive nights (mean = 7.1, SD = 1.2). We used both continuous measures of poor sleep and binary variables of short sleep and low sleep efficiency ( < or = 10th percentiles). Parents completed the Sleep Disturbance Scale for Children. Lower birth weight and shorter length at birth were associated with lower sleep efficiency. For every 1-SD decrease in weight and length at birth, the odds for low sleep efficiency increased by 1.7 fold (95% confidence interval [CI]: 1.1 to 2.7) and 2.2 fold (95% CI: 1.3 to 3.7), respectively. For every 1-SD decrease in ponderal index at birth, the risk of parent-reported sleep disorders increased by 1.4 fold (95% CI: 1.0 to 2.0). Moreover, children exposed prenatally to alcohol had a 2.9-fold (95% CI: 1.1 to 7.6) and 3.6-fold (95% CI: 1.3 to 10.0) increased risk for having short sleep and low sleep efficiency, respectively. The associations were not confounded by sex, gestational length, prenatal and perinatal complications, body mass index at 8 years, asthma, allergies, or parental socioeconomic status.Poor sleep in children may have prenatal origins. Possible mechanisms include alcohol consumption during pregnancy and other conditions associated with small body size at birth.

Slow childhood growth is associated with poorer intellectual ability. The critical periods of growth remain uncertain. Among 2,786 Finnish male military conscripts (1952-1972) born in 1934-1944, the authors tested how specific growth periods from birth to age 20 years predicted verbal, visuospatial, and arithmetic abilities at age 20. Small head circumference at birth predicted poorer verbal, visuospatial, and arithmetic abilities. The latter 2 measures were also associated with lower weight and body mass index (weight (kg)/height (m)(2)) at birth (for a 1-standard-deviation (SD) decrease in test score per SD decrease in body size > or = 0.05, P's < 0.04). Slow linear growth and weight gain between birth and age 6 months, between ages 6 months and 2 years, or both predicted poorer performance on all 3 tests (for a 1-SD decrease in test score per SD decrease in growth > or = 0.05, P's < 0.03). Reduced linear growth between ages 2 and 7 years predicted worse verbal ability, and between age 11 years and conscription it predicted worse performance on all 3 tests. Prenatal brain growth and linear growth up to 2 years after birth form a first critical period for intellectual development. There is a second critical period, specific for verbal development, between ages 2 and 7 years and a third critical period for all 3 tested outcomes during adolescence.

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

The present study examined how sleep duration and sleep quality are associated with cognitive performance in 8-year-old children using standardized neurocognitive tests. Two hundred ninety children aged 7.4–8.8 years participated in the study. Sleep duration and quality were measured using actigraphs and the Sleep Disturbance Scale for Parents. Cognitive performance was measured using four subtests of the Wechsler Intelligence Scale for Children III, the Beery Developmental Test of Visual-Motor Integration (VMI), and the Narrative memory subtest of the Developmental Neuropsychological Assessment for Children. When adjusting for age, sex, and maternal education, shorter sleep duration, but not sleep quality, was associated with lower visuospatial abilities (p-values ⩽0.043). Sleep duration and quality were not associated with verbal abilities (p-values ⩾0.18). With regard to the individual test results, shorter sleep duration was associated with worse performance in Visual-Motor Integration (p = 0.028), and when excluding children with high depression scores the same was also true with Block Design (p-values ⩽0.047). Moreover, poor sleep efficiency was associated with worse performance in Similarities (p = 0.004). In a community sample of 8-year-old children, those who slept less or had poorer sleep quality had lower test scores in cognitive tasks, particularly those pertaining to visuospatial performance, although the association was not very strong.

There is evidence that positive personality characteristics, such as optimism and self-esteem, are important for health. Less is known about possible determinants of positive personality characteristics. To test the relationship of optimism and self-esteem with insomnia symptoms and sleep duration. Sleep parameters, optimism, and self-esteem were assessed by self-report in a community-based sample of 1,805 adults aged between 30 and 84 years in the USA. Moderation of the relation between sleep and positive characteristics by gender and age as well as potential confounding of the association by depressive disorder was tested. Individuals with insomnia symptoms scored lower on optimism and self-esteem largely independent of age and sex, controlling for symptoms of depression and sleep duration. Short sleep duration (<6 h) was related to lower optimism and self-esteem when compared to individuals sleeping 7–8 h, controlling depressive symptoms. Long sleep duration (>9 h) was also related to low optimism and self-esteem independent of age and sex. Good and sufficient sleep is associated with positive personality characteristics. This relationship is independent of the association between poor sleep and depression.

ObjectivesTo examine whether faster growth from birth to term (40 postmenstrual weeks) and during the first year thereafter was associated with better neurocognitive abilities in adults born preterm with very low birth weight (VLBW; <1500 g).Study designWeight, length, and head circumference data of 103 VLBW participants of the Helsinki Study of Very Low Birth Weight Adults were collected from records. Measures at term and at 12 months of corrected age were interpolated. The participants underwent tests of general neurocognitive ability, executive functioning, attention, and visual memory at mean age of 25.0 years.ResultsFaster growth from birth to term was associated with better general neurocognitive abilities, executive functioning, and visual memory in young adulthood. Effect sizes in SD units ranged from 0.23-0.43 per each SD faster growth in weight, length, or head circumference (95% CI 0.003-0.64; P values <.05). After controlling for neonatal complications, faster growth in head circumference remained more clearly associated with neurocognitive abilities than weight or length did. Growth during the first year after term was not consistently associated with neurocognitive abilities.ConclusionsWithin a VLBW group with high variability in early growth, faster growth from birth to term is associated with better neurocognitive abilities in young adulthood. Neurocognitive outcomes were predicted, in particular, by early postnatal head growth. To examine whether faster growth from birth to term (40 postmenstrual weeks) and during the first year thereafter was associated with better neurocognitive abilities in adults born preterm with very low birth weight (VLBW; <1500 g). Weight, length, and head circumference data of 103 VLBW participants of the Helsinki Study of Very Low Birth Weight Adults were collected from records. Measures at term and at 12 months of corrected age were interpolated. The participants underwent tests of general neurocognitive ability, executive functioning, attention, and visual memory at mean age of 25.0 years. Faster growth from birth to term was associated with better general neurocognitive abilities, executive functioning, and visual memory in young adulthood. Effect sizes in SD units ranged from 0.23-0.43 per each SD faster growth in weight, length, or head circumference (95% CI 0.003-0.64; P values <.05). After controlling for neonatal complications, faster growth in head circumference remained more clearly associated with neurocognitive abilities than weight or length did. Growth during the first year after term was not consistently associated with neurocognitive abilities. Within a VLBW group with high variability in early growth, faster growth from birth to term is associated with better neurocognitive abilities in young adulthood. Neurocognitive outcomes were predicted, in particular, by early postnatal head growth.

<h3>Objective:</h3> Although severely preterm birth has been associated with impaired neurocognitive abilities in children, follow-up studies in adulthood are scarce. We set out to study whether adults born with very low birth weight (VLBW) (&lt;1,500 g), either small for gestational age (SGA) (birth weight ≤−2 SD) or appropriate for gestational age (AGA), differ in a range of neurocognitive abilities and academic performance from adults born at term and not SGA. <h3>Methods:</h3> As part of the Helsinki Study of Very Low Birth Weight Adults, 103 VLBW (37 SGA) and 105 term-born control adults (mean age 25.0, range 21.4–29.7 years) without major neurosensory impairments participated in the follow-up study in 2007–2008. The test battery included measures of general cognitive ability as well as executive functioning and related abilities. Academic performance was self-reported. <h3>Results:</h3> With adjustment for sex and age, the VLBW group scored lower or performed slower than the control group in some indices of all tests (these mean differences ranged from 0.3 to 0.5 SD units, <i>p</i> ≤ 0.03) and they had received remedial education at school more frequently; however, no differences existed in self-reported academic performance. The differences were evident in both VLBW-SGA and VLBW-AGA groups. Further covariate adjustments for parental education, current head circumference, and head circumference at birth and, in tests of executive functioning and related abilities, adjustment for IQ estimate had minor effects on the results. <h3>Conclusions:</h3> In comparison with control adults, VLBW adults scored lower on several neurocognitive tests. Poorer neurocognitive performance is associated with VLBW irrespective of the intrauterine growth pattern.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Processing speed is an important cognitive function that is compromised in psychiatric illness (e.g., schizophrenia, depression) and old age; it shares genetic background with complex cognition (e.g., working memory, reasoning). To find genes influencing speed we performed a genome-wide association scan in up to three cohorts: Brisbane (mean age 16 years; N = 1659); LBC1936 (mean age 70 years, N = 992); LBC1921 (mean age 82 years, N = 307), and; HBCS (mean age 64 years, N =1080). Meta-analysis of the common measures highlighted various suggestively significant (p < 1.21 × 10⁻⁵) SNPs and plausible candidate genes (e.g., TRIB3). A biological pathways analysis of the speed factor identified two common pathways from the KEGG database (cell junction, focal adhesion) in two cohorts, while a pathway analysis linked to the GO database revealed common pathways across pairs of speed measures (e.g., receptor binding, cellular metabolic process). These highlighted genes and pathways will be able to inform future research, including results for psychiatric disease.

Hypertensive disorders may affect the fetal developmental milieu and thus hint at mechanisms by which prenatal adversity associates with mental disorders in later life. We examined if hypertension without proteinuria and preeclampsia in pregnancy predict serious mental disorders in the offspring, and if sex, childhood socioeconomic status, length of gestation and parity modify these associations.We included 5970 women and men born after a normotensive, hypertensive or preeclamptic pregnancy defined by using mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals. Mental disorders requiring hospitalization or contributing to death were identified from the Finnish Hospital Discharge and Causes of Death Registers between years 1969 and 2004.In comparison to the offspring born after normotensive pregnancies, offspring born after pregnancies complicated by hypertension without proteinuria were at 1.19-fold (CI: 1.01-1.41, P-value = 0.04) higher risk of any mental disorder and 1.44- (CI: 1.11-1.88, P-value < 0.01) and 1.39-fold (CI: 0.99-1.93, P-value = 0.05) higher risk of mood and anxiety disorder, respectively. In contrast, preeclampsia was associated, with a lower risk of any mental disorder in the male offspring (P-value = 0.02; P-value = 0.04 for interaction 'sex × normotension/preeclampsia').Hypertension without proteinuria in pregnancy was associated with a higher risk of serious mental disorders in the offspring in adulthood. Preeclampsia seems to, in turn, associate with lower risk of severe mental disorders in male offspring.

In a large, prospective epidemiological study we tested whether exposure to severe early life stress increases the risk of severe mental disorders in adulthood, and whether childhood socioeconomic background and sex modify these associations. Among the 12,747 participants of the Helsinki Birth Cohort Study, born 1934–1944, 1719 were recorded as separated temporarily from their parents in childhood. The separations took place during World War II when Finnish children were voluntarily evacuated unaccompanied by their parents to temporary foster care abroad (mean age at and length of separation 4.6 and 1.7 years, respectively). Severe mental disorders were identified from the Finnish Hospital Discharge and Causes of Death Registers between years 1969 and 2004. Compared to the non-separated, the separated had higher risks of mental, substance use and personality disorder (P-values ≤ 0.05). The risk of any mental and substance use disorder was, however, highest in the separated and lowest in the non-separated with an upper childhood socioeconomic background; individuals with a lower childhood socioeconomic background showed an intermediate risk regardless of their separation status (P-values for interactions ≤0.05). Temporary separation from parents poses a risk of severe mental disorders later in life. Children with an upper childhood socioeconomic background may be particularly sensitive to this type of early life stress, while for children with a lower childhood socioeconomic background it may not add to the risk already associated with lower socioeconomic position in childhood.

We examined associations between pubertal maturation and sleep in early adolescence, at age 12 y, and continuity and change in actigraphy-based sleep and parent-reported sleep disorders from age 8 to 12 y. We also explored longitudinal associations between actigraph estimates of sleep and sleep disorders.A cohort study of children born in 1998 and tested at ages 8 y (standard deviation [SD] = 0.3) and 12 y (SD = 0.5).A total of 348 children participated in cross-sectional analyses. We had longitudinal actigraphy data for 188 children and repeated parent reports of sleep disorders for 229 children.At age 8 y, participants wore actigraphs for 7.1 nights (SD = 1.2, range 3-14) on average and at age 12 y for 8.4 nights (SD = 1.7, range 3-11). Sleep disorders were parent-rated based on the Sleep Disturbance Scale for Children. Pubertal maturity was self-reported at age 12 y using the continuous Pubertal Development Scale and the picture-assisted categorical Tanner scales.Significant mean-level changes toward shorter but higher quality sleep occurred over time. Sleep variables had low to high rank-order stability over time. Sleep disorders were highly stable from age 8 to 12 y. Actigraphy-based sleep and parent-rated sleep disorders showed no association either in cross-section or longitudinally. Pubertal maturation was not associated with worse sleep.Sleep in early adolescence can be anticipated from childhood sleep patterns and disorders, but is not associated with pubertal maturity. Although sleep duration becomes shorter, sleep quality may improve during early adolescence. Parent-rated sleep disorders are distinct from actigraph estimates of sleep.

Hypertensive pregnancy disorders may affect the fetal developmental milieu and thus hint at mechanisms that link prenatal conditions with later developmental outcomes of the offspring. Here, we systematically review studies that have tested whether maternal pre-eclampsia, gestational hypertension, and hypertensive pregnancy disorders as a single diagnostic entity are associated with cognitive functioning of the offspring. Twenty-six studies were eligible for this review. Of them, 19 provided detailed methodological information deemed necessary to be included for a more detailed review. An overall conclusion is that, in the general population, maternal hypertensive disorders may be associated with lower cognitive ability of the offspring. Studies that extend to adulthood show the most consistent pattern of findings. It is possible that the associations arise during the lifetime or that the findings reflect improvements in management of these disorders. Evidence is, however, insufficient to conclude whether these associations are dissimilar in the offspring exposed to maternal pre-eclampsia and gestational hypertension, due to the varied criteria used across the different studies to distinguish between these conditions. The existing studies also vary in the definition of control groups, and very few have taken into account important confounding factors, including maternal pre-pregnancy obesity and lifestyle behaviors. Given the mixed pattern of findings and limitations related to internal and external validity, further studies are clearly warranted to clarify the associations.

Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Preterm birth is associated with an increased risk of type 2 diabetes in adult life. The mechanisms are poorly known.We studied insulin sensitivity and secretion in adults born preterm at very low birth weight (VLBW; < 1500 g).Longitudinal Birth Cohort Study (Helsinki Study of Very Low Birth Weight Adults).The study was conducted at Uusimaa, Finland.One hundred seven adults born at VLBW and 100 controls born at term not small for gestational age (SGA), group-matched for sex, age, and birth hospital. The mean age was 25.0 years.We performed a 14-sample intravenous glucose tolerance test and calculated insulin sensitivity (Si), insulin secretory response (AIR), and disposition index, by Minimal Model (Minmod Millennium®).Compared with controls, VLBW adults had lower Si (mean difference -11.9%, 95% CI -22.1 to -0.4%, adjusted for sex, age, and body mass index) and higher AIR (19.9%; 4.4-37.7%). The association with Si attenuated when further adjusted for height, parental diabetes, parental education, smoking, maternal smoking, hormonal contraception, and physical activity, but the association with AIR remained. Disposition index was similar. There was no difference between the 40 VLBW adults born SGA and the remaining VLBW adults.Adults born preterm at VLBW have lower insulin sensitivity than their term-born peers with a similar body size. In young adulthood, this remains compensated by higher insulin secretion. We suggest that this represents an early stage in the pathway leading to type 2 diabetes. Our results underline the importance of a healthy lifestyle and prompt vigilance in the screening of type 2 diabetes and impaired glucose tolerance in adults born preterm.