George McMahon

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

Here 106 genomic loci associated with age at menarche, a marker of puberty timing in females, are identified; these loci show enrichment for genes involved in nuclear hormone receptor function, body mass index, and rare disorders of puberty, and for genes located in imprinted regions, with parent-of-origin specific effects at several loci. The age at which females first experience menstruation, called menarche, is a heritable trait associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and general mortality. This large-scale genome-wide association study identifies 123 signals at 106 genomic loci associated with age at menarche. New findings include parent-of-origin-specific allelic associations (both maternally and paternally driven) at three imprinted loci and the implication of retinoic acid and GABAB receptor II signalling and lysine-specific histone demethylation. These data bring new insights into the genetic architecture of puberty timing and suggest a model involving thousands of genetic variants. Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

John Perry, Ken Ong and colleagues analyze genotype data on ∼370,000 women and identify 389 independent signals that associate with age at menarche, implicating ∼250 genes. Their analyses suggest causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10−8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.

Struan Grant and colleagues perform a meta-analysis of genome-wide association studies to identify loci influencing childhood obesity. They discover variants near OLFM4 and HOXB5 associated with this trait and show that these loci are also associated with increased body mass index in adults. Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10−6 in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10−9; odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10−9; OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI1.

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Time spent in "sports/outdoor activity" has shown a negative association with incident myopia during childhood. We investigated the association of incident myopia with time spent outdoors and physical activity separately.Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed by noncycloplegic autorefraction at ages 7, 10, 11, 12, and 15 years, and classified as myopic (≤-1 diopters) or as emmetropic/hyperopic (≥-0.25 diopters) at each visit (N = 4,837-7,747). Physical activity at age 11 years was measured objectively using an accelerometer, worn for 1 week. Time spent outdoors was assessed via a parental questionnaire administered when children were aged 8-9 years. Variables associated with incident myopia were examined using Cox regression.In analyses using all available data, both time spent outdoors and physical activity were associated with incident myopia, with time outdoors having the larger effect. The results were similar for analyses restricted to children classified as either nonmyopic or emmetropic/hyperopic at age 11 years. Thus, for children nonmyopic at age 11, the hazard ratio (95% confidence interval, CI) for incident myopia was 0.66 (0.47-0.93) for a high versus low amount of time spent outdoors, and 0.87 (0.76-0.99) per unit standard deviation above average increase in moderate/vigorous physical activity.Time spent outdoors was predictive of incident myopia independently of physical activity level. The greater association observed for time outdoors suggests that the previously reported link between "sports/outdoor activity" and incident myopia is due mainly to its capture of information relating to time outdoors rather than physical activity.

Rachel Freathy and colleagues report results of a large-scale genome-wide association study of birth weight. They identify four loci newly associated with this trait and find overlap between birth weight–associated loci and those influencing adult height and metabolism. Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

David Hinds and colleagues report results of a genome-wide association meta-analysis of self-reported allergy. They identify 16 shared susceptibility loci for allergic traits, including 8 loci previously associated with asthma. Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P < 5 × 10−8, including 8 loci previously associated with asthma, as well as 4p14 near TLR1, TLR6 and TLR10 (rs2101521, P = 5.3 × 10−21); 6p21.33 near HLA-C and MICA (rs9266772, P = 3.2 × 10−12); 5p13.1 near PTGER4 (rs7720838, P = 8.2 × 10−11); 2q33.1 in PLCL1 (rs10497813, P = 6.1 × 10−10), 3q28 in LPP (rs9860547, P = 1.2 × 10−9); 20q13.2 in NFATC2 (rs6021270, P = 6.9 × 10−9), 4q27 in ADAD1 (rs17388568, P = 3.9 × 10−8); and 14q21.1 near FOXA1 and TTC6 (rs1998359, P = 4.8 × 10−8). We identified one locus with substantial evidence of differences in effects across allergies at 6p21.32 in the class II human leukocyte antigen (HLA) region (rs17533090, P = 1.7 × 10−12), which was strongly associated with cat allergy. Our study sheds new light on the shared etiology of immune and autoimmune disease.

Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Offspring birth weight from 18 studies.Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Craniofacial morphology is highly heritable, but little is known about which genetic variants influence normal facial variation in the general population. We aimed to identify genetic variants associated with normal facial variation in a population-based cohort of 15-year-olds from the Avon Longitudinal Study of Parents and Children. 3D high-resolution images were obtained with two laser scanners, these were merged and aligned, and 22 landmarks were identified and their x, y, and z coordinates used to generate 54 3D distances reflecting facial features. 14 principal components (PCs) were also generated from the landmark locations. We carried out genome-wide association analyses of these distances and PCs in 2,185 adolescents and attempted to replicate any significant associations in a further 1,622 participants. In the discovery analysis no associations were observed with the PCs, but we identified four associations with the distances, and one of these, the association between rs7559271 in PAX3 and the nasion to midendocanthion distance (n-men), was replicated (p = 4 × 10(-7)). In a combined analysis, each G allele of rs7559271 was associated with an increase in n-men distance of 0.39 mm (p = 4 × 10(-16)), explaining 1.3% of the variance. Independent associations were observed in both the z (nasion prominence) and y (nasion height) dimensions (p = 9 × 10(-9) and p = 9 × 10(-10), respectively), suggesting that the locus primarily influences growth in the yz plane. Rare variants in PAX3 are known to cause Waardenburg syndrome, which involves deafness, pigmentary abnormalities, and facial characteristics including a broad nasal bridge. Our findings show that common variants within this gene also influence normal craniofacial development.

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.

Background Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose–response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects. Methods and Findings The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity. In observational analysis, a 3.3 kg/m2 (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6×10−16), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7×10−29), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0×10−4). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (∼5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI. Conclusions Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation. Please see later in the article for the Editors' Summary

Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and > 2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10(-10), and rs2769264, P = 2.63 × 10(-20)); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10(-28) at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10(-12); rs2120019, P = 1.55 × 10(-18); and rs4826508, P = 1.40 × 10(-12), respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Vincent Jaddoe and colleagues report a genome-wide association study for infant head circumference. They identify variants in SBNO1 and near HMGA2 that are associated with this phenotype. To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10−9) and rs1042725 on chromosome 12q15 (P = 2.8 × 10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P = 3.8 × 10−7 for rs7980687 and P = 1.3 × 10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10−6). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume2, Parkinson's disease and other neurodegenerative diseases3,4,5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological epidemiology. Few of the methodological developments in MR have considered the specific situation of using genetic IVs to test the causal effect of exposures in pregnant women on postnatal offspring outcomes. In this paper, we describe specific ways in which the IV assumptions might be violated when MR is used to test such intrauterine effects. We highlight the importance of considering the extent to which there is overlap between genetic variants in offspring that influence their outcome with genetic variants used as IVs in their mothers. Where there is overlap, and particularly if it generates a strong association of maternal genetic IVs with offspring outcome via the offspring genotype, the exclusion restriction assumption of IV analyses will be violated. We recommend a set of analyses that ought to be considered when MR is used to address research questions concerned with intrauterine effects on post-natal offspring outcomes, and provide details of how these can be undertaken and interpreted. These additional analyses include the use of genetic data from offspring and fathers, examining associations using maternal non-transmitted alleles, and using simulated data in sensitivity analyses (for which we provide code). We explore the extent to which new methods that have been developed for exploring violation of the exclusion restriction assumption in the two-sample setting (MR-Egger and median based methods) might be used when exploring intrauterine effects in one-sample MR. We provide a list of recommendations that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes and use an illustrative example with real data to demonstrate how our recommendations can be applied and subsequent results appropriately interpreted.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ∼1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations.From two large Danish cohorts we selected all extremely overweight young men and women (n = 2,633), and equal numbers of population-based controls (n = 2,740, drawn randomly from the same populations as the extremes, representing ∼212,000 individuals). We followed up novel (at the time of the study) association signals (p<0.001) from the discovery cohort in a genome-wide study of 5,846 Europeans, before attempting to replicate the most strongly associated 28 SNPs in an independent sample of Danish individuals (n = 20,917) and a population-based cohort of 15-year-old British adolescents (n = 2,418). Our discovery analysis identified SNPs at three loci known to be associated with BMI with genome-wide confidence (P<5×10(-8); FTO, MC4R and FAIM2). We also found strong evidence of association at the known TMEM18, GNPDA2, SEC16B, TFAP2B, SH2B1 and KCTD15 loci (p<0.001), and nominal association (p<0.05) at a further 8 loci known to be associated with BMI. However, meta-analyses of our discovery and replication cohorts identified no novel associations.Our results indicate that the detectable genetic variation associated with extreme overweight is very similar to that previously found for general BMI. This suggests that population-based study designs with enriched sampling of individuals with the extreme phenotype may be an efficient method for identifying common variants that influence quantitative traits and a valid alternative to genotyping all individuals in large population-based studies, which may require tens of thousands of subjects to achieve similar power.

Abstract We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance ( P &lt; 5 × 10 −8 ), while five of the 21 lead SNPs reach suggestive significance ( P &lt; 1 × 10 −5 ) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease ( r g ≈ 0.15–0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (| r g | ≈ 0.1–0.3) and positive genetic correlations with physical activity ( r g ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment ( r g ≈−0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction.

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

Abstract Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4 ; P = 6.3E–04).

To estimate associations between smoking initiation, smoking persistence and smoking heaviness and caffeine consumption in two population-based samples from the Netherlands and the United Kingdom.Observational study employing data on self-reported smoking behaviour and caffeine consumption.Adults from the general population in the Netherlands and the United Kingdom.Participants from the Netherlands Twin Register [NTR: n = 21 939, mean age 40.8, standard deviation (SD) = 16.9, 62.6% female] and the Avon Longitudinal Study of Parents and Children (ALSPAC: n = 9086, mean age 33.2, SD = 4.7, 100% female).Smoking initiation (ever versus never smoking), smoking persistence (current versus former smoking), smoking heaviness (number of cigarettes smoked) and caffeine consumption in mg per day through coffee, tea, cola and energy drinks.After correction for age, gender (NTR), education and social class (ALSPAC), smoking initiation was associated with consuming on average 52.8 [95% confidence interval (CI) = 45.6-60.0; NTR] and 59.5 (95% CI = 51.8-67.2; ALSPAC) mg more caffeine per day. Smoking persistence was also associated with consuming more caffeine [+57.9 (95% CI = 45.2-70.5) and +83.2 (95% CI = 70.2-96.3) mg, respectively]. Each additional cigarette smoked per day was associated with 3.7 (95% CI = 1.9-5.5; NTR) and 8.4 (95% CI = 6.9-10.0; ALSPAC) mg higher daily caffeine consumption in current smokers. Smoking was associated positively with coffee consumption and less strongly with cola and energy drinks. For tea, associations were positive in ALSPAC and negative in NTR.There appears to be a positive association between smoking and caffeine consumption in the Netherlands and the United Kingdom.

It has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood.We used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample). In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21-0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome. A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21-0.30) at age 7 and 0.03 SD (95% CI -0.26-0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC. When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19-0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11-0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates.Our findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Abstract Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n = 4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p = 1.7 × 10−9) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p = 1.3 × 10−8) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n = 5597 for femoral neck; n = 4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p = 1.3 × 10−11; ESR1/C6orf97 joint p = 1.4 × 10−10). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p &amp;lt; 1 × 10−5). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. © 2013 American Society for Bone and Mineral Research.

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10−9), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10−5) and short adult stature (p = 7.5 × 10−6) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

Purpose.: More time outdoors is associated with a lesser risk of myopia, but the underlying mechanism is unclear. We tested the hypothesis that 25-hydroxyvitamin D (vitamin D) mediates the protective effects of time outdoors against myopia. Methods.: We analyzed data for children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort: noncycloplegic autorefraction at age 7 to 15 years; maternal report of time outdoors at age 8 years and serum vitamin D2 and D3 at age 10 years. A survival analysis hazard ratio (HR) for incident myopia was calculated for children spending a high- versus low-time outdoors, before and after controlling for vitamin D level (N = 3677). Results.: Total vitamin D and D3, but not D2, levels were higher in children who spent more time outdoors (mean [95% confidence interval (CI)] vitamin D in nmol/L: Total, 60.0 [59.4–60.6] vs. 56.9 [55.0–58.8], P = 0.001; D3, 55.4 [54.9–56.0] vs. 53.0 [51.3–54.9], P = 0.014; D2, 5.7 [5.5–5.8] vs. 5.4 [5.1–5.8], P = 0.23). In models including both time outdoors and sunlight-exposure–related vitamin D, there was no independent association between vitamin D and incident myopia (Total, HR = 0.83 [0.66–1.04], P = 0.11; D3, HR = 0.89 [0.72–1.10], P = 0.30), while time outdoors retained the same strong negative association with incident myopia as in unadjusted models (HR = 0.69 [0.55–0.86], P = 0.001). Conclusions.: Total vitamin D and D3 were biomarkers for time spent outdoors, however there was no evidence they were independently associated with future myopia.

It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.

Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (<i>r</i>² ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10⁻⁸) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10⁻⁴⁰). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases.

The etiology of major depressive disorder (MDD) is likely to be heterogeneous, but postpartum depression (PPD) is hypothesized to represent a more homogenous subset of MDD. We use genome-wide SNP data to explore this hypothesis. We assembled a total cohort of 1,420 self-report cases of PPD and 9,473 controls with genome-wide genotypes from Australia, The Netherlands, Sweden and the UK. We estimated the total variance attributable to genotyped variants. We used association results from the Psychiatric Genomics Consortia (PGC) of bipolar disorder (BPD) and MDD to create polygenic scores in PPD and related MDD data sets to estimate the genetic overlap between the disorders. We estimated that the percentage of variance on the liability scale explained by common genetic variants to be 0.22 with a standard error of 0.12, p = 0.02. The proportion of variance (R (2)) from a logistic regression of PPD case/control status in all four cohorts on a SNP profile score weighted by PGC-BPD association results was small (0.1 %) but significant (p = 0.004) indicating a genetic overlap between BPD and PPD. The results were highly significant in the Australian and Dutch cohorts (R (2) > 1.1 %, p < 0.008), where the majority of cases met criteria for MDD. The genetic overlap between BPD and MDD was not significant in larger Australian and Dutch MDD case/control cohorts after excluding PPD cases (R (2) = 0.06 %, p = 0.08), despite the larger MDD group affording more power. Our results suggest an empirical genetic evidence for a more important shared genetic etiology between BPD and PPD than between BPD and MDD.

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.

<h3>Objective:</h3> To apply genetic analysis of genome-wide association data to study the extent and nature of a shared biological basis between migraine and coronary artery disease (CAD). <h3>Methods:</h3> Four separate methods for cross-phenotype genetic analysis were applied on data from 2 large-scale genome-wide association studies of migraine (19,981 cases, 56,667 controls) and CAD (21,076 cases, 63,014 controls). The first 2 methods quantified the extent of overlapping risk variants and assessed the load of CAD risk loci in migraineurs. Genomic regions of shared risk were then identified by analysis of covariance patterns between the 2 phenotypes and by querying known genome-wide significant loci. <h3>Results:</h3> We found a significant overlap of genetic risk loci for migraine and CAD. When stratified by migraine subtype, this was limited to migraine without aura, and the overlap was protective in that patients with migraine had a lower load of CAD risk alleles than controls. Genes indicated by 16 shared risk loci point to mechanisms with potential roles in migraine pathogenesis and CAD, including endothelial dysfunction (<i>PHACTR1</i>) and insulin homeostasis (<i>GIP</i>). <h3>Conclusions:</h3> The results suggest that shared biological processes contribute to risk of migraine and CAD, but surprisingly this commonality is restricted to migraine without aura and the impact is in opposite directions. Understanding the mechanisms underlying these processes and their opposite relationship to migraine and CAD may improve our understanding of both disorders.

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10-06) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10-08), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10-25) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10-07) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10-07). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = 15 661, with replication N = 75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (β = 0.06; P = 0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

Nearly a fifth of the world's population suffer from migraine headache, yet risk factors for this disease are poorly characterized.To further elucidate these factors, we conducted a genetic correlation analysis using cross-trait linkage disequilibrium (LD) score regression between migraine headache and 47 traits from the UK Biobank. We then tested for possible causality between these phenotypes and migraine, using Mendelian randomization. In addition, we attempted replication of our findings in an independent genome-wide association study (GWAS) when available.We report multiple phenotypes with genetic correlation (P < 1.06 × 10-3) with migraine, including heart disease, type 2 diabetes, lipid levels, blood pressure, autoimmune and psychiatric phenotypes. In particular, we find evidence that blood pressure directly contributes to migraine and explains a previously suggested causal relationship between calcium and migraine.This is the largest genetic correlation analysis of migraine headache to date, both in terms of migraine GWAS sample size and the number of phenotypes tested. We find that migraine has a shared genetic basis with a large number of traits, indicating pervasive pleiotropy at migraine-associated loci.

Stature at a particular age can be considered the cumulative result of growth during a number of preceding growth trajectory periods. We investigated whether height and weight growth trajectories from birth to age 10 years were related to refractive error at ages 11 and 15 years, and eye size at age 15 years.Prospective analysis in a birth cohort.Children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) U.K. birth cohort (minimum N = 2676).Growth trajectories between birth and 10 years were modeled from a series of height and weight measurements (N = 6815). Refractive error was assessed by noncycloplegic autorefraction at ages 11 and 15 years (minimum N = 4737). Axial length (AXL) and radius of corneal curvature were measured with an IOLMaster (Carl Zeiss Meditec, Welwyn Garden City, U.K.) at age 15 years (minimum N = 2676). Growth trajectories and an allelic score for 180 genetic variants associated with adult height were tested for association with refractive error and eye size.Noncycloplegic autorefraction at ages 11 and 15 years, and AXL and corneal curvature at age 15 years.Height growth trajectory during the linear phase between 2.5 and 10 years was negatively associated with refractive error at 11 and 15 years (P<0.001), but explained <0.5% of intersubject variation. Height and weight growth trajectories, especially shortly after birth, were positively associated with AXL and corneal curvature (P<0.001), predicting 1% to 5% of trait variation. Height growth after 2.5 years was not associated with corneal curvature, whereas the association with AXL continued up to 10 years. The height allelic score was associated with corneal curvature (P = 0.03) but not with refractive error or AXL.Up to the age of 10 years, shared growth mechanisms contribute to scaling of eye and body size but minimally to the development of myopia.The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes.

Genome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and where educational performance is more routinely and more precisely assessed. Single nucleotide polymorphisms exhibiting genome-wide significant associations with adult educational attainment were combined to derive an unweighted allele score in 5,979 and 6,145 young participants from the Avon Longitudinal Study of Parents and Children with key stage 3 national curriculum test results (SATS results) available at age 13 to 14 years in English and mathematics respectively. Standardised (z-scored) results for English and mathematics showed an expected relationship with sex, with girls exhibiting an advantage over boys in English (0.433 SD (95%CI 0.395, 0.470), p<10(-10)) with more similar results (though in the opposite direction) in mathematics (0.042 SD (95%CI 0.004, 0.080), p = 0.030). Each additional adult educational attainment increasing allele was associated with 0.041 SD (95%CI 0.020, 0.063), p = 1.79×10(-04) and 0.028 SD (95%CI 0.007, 0.050), p = 0.01 increases in standardised SATS score for English and mathematics respectively. Educational attainment is a complex multifactorial behavioural trait which has not had heritable contributions to it fully characterised. We were able to apply the results from a large study of adult educational attainment to a study of child exam performance marking events in the process of learning rather than realised adult end product. Our results support evidence for common, small genetic contributions to educational attainment, but also emphasise the likely lifecourse nature of this genetic effect. Results here also, by an alternative route, suggest that existing methods for child examination are able to recognise early life variation likely to be related to ultimate educational attainment.

Mandel et al recently reported that season of birth and daylight hours (photoperiod) at birth were associated with moderate and high levels of myopia in Israeli conscripts. We sought to investigate whether these associations were evident in subjects from the United Kingdom (UK).Retrospective cross-sectional study.The study population comprised 74,459 subjects aged 18 to 100 years attending UK optometry practices for an eye examination.Data comprising non-cycloplegic spectacle prescription, sex, date of birth, and date of eye examination were collected from UK optometry practices. The average refractive error in fellow eyes was used to classify the degree of myopia in diopters (D) for each subject as follows: absent (>-0.75 D), low (-0.75 to -2.99 D), moderate (-3.00 to -5.99 D), or high (<-6.00 D). The average monthly hours of daylight for London, UK, were classified into 1 of 4 "photoperiod categories," following Mandel et al. The odds ratio (OR) for each level of severity of myopia was calculated using multivariate logistic regression with age, sex, and either season of birth or photoperiod category as risk factors.The OR for season of birth and photoperiod category as potential risk factors for myopia.Season of birth was significantly associated with the presence of high myopia: Subjects born in summer or autumn were more likely to be highly myopic compared with those born in winter (summer OR=1.17; 95% confidence interval [CI], 1.05-1.30; P=0.006; autumn OR=1.16; 95% CI, 1.04-1.30; P=0.007). However, season of birth was not a significant risk factor for low or moderate myopia. Photoperiod category was weakly associated with low myopia (OR=0.94; 95% CI, 0.89-0.99; P=0.019), but with a direction of effect opposite to that observed by Mandel et al.As in Israel, a disproportionate number of UK high myopes were born in summer or autumn rather than in winter. However, unlike the situation in Israel, this association does not seem to be related to daylight hours during the postnatal period, implicating alternative physiologic influences that vary with season, such as birth weight.

Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993–1996 and 2002–2005 and from UK in 1991–1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10−14 for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10−6 > P > 5 × 10−8). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.

Abstract Smoking and caffeine consumption show a strong positive correlation, but the mechanism underlying this association is unclear. Explanations include shared genetic/environmental factors or causal effects. This study employed three methods to investigate the association between smoking and caffeine. First, bivariate genetic models were applied to data of 10 368 twins from the Netherlands Twin Register in order to estimate genetic and environmental correlations between smoking and caffeine use. Second, from the summary statistics of meta‐analyses of genome‐wide association studies on smoking and caffeine, the genetic correlation was calculated by LD‐score regression. Third, causal effects were tested using Mendelian randomization analysis in 6605 Netherlands Twin Register participants and 5714 women from the Avon Longitudinal Study of Parents and Children. Through twin modelling, a genetic correlation of r 0.47 and an environmental correlation of r 0.30 were estimated between current smoking (yes/no) and coffee use (high/low). Between current smoking and total caffeine use, this was r 0.44 and r 0.00, respectively. LD‐score regression also indicated sizeable genetic correlations between smoking and coffee use ( r 0.44 between smoking heaviness and cups of coffee per day, r 0.28 between smoking initiation and coffee use and r 0.25 between smoking persistence and coffee use). Consistent with the relatively high genetic correlations and lower environmental correlations, Mendelian randomization provided no evidence for causal effects of smoking on caffeine or vice versa. Genetic factors thus explain most of the association between smoking and caffeine consumption. These findings suggest that quitting smoking may be more difficult for heavy caffeine consumers, given their genetic susceptibility.

Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 × 10-3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.

Purpose: An association between birth order and reduced unaided vision (a surrogate for myopia) has been observed previously. We examined the association between birth order and myopia directly in four subject groups.Methods: Subject groups were participants in (1) the Avon Longitudinal Study of Parents and Children (ALSPAC; UK; age 15 years; N = 4401), (2) the Singapore Cohort Study of Risk Factors for Myopia (SCORM; Singapore; age 13 years; N = 1959), (3) the Raine Eye Health Study (REHS; Australia; age 20 years; N = 1344), and (4) Israeli Defense Force Pre-recruitment Candidates (IDFC; Israel; age 16–22 years; N = 888,277). The main outcome was odds ratios (OR) for myopia in first-born versus non-first-born individuals after adjusting for potential risk factors.Results: The prevalence of myopia was numerically higher in first-born versus non-first-born individuals in all study groups, but the strength of evidence varied widely. Adjusted ORs (95% confidence intervals, CIs) were: ALSPAC, 1.31 (1.05–1.64); SCORM, 1.25 (0.89–1.77); REHS, 1.18 (0.90–1.55); and IDFC, 1.04 (1.03–1.06). In the large IDFC sample, the effect size was greater (a) for the first-born versus fourth- or higher-born comparison than for the first-born versus second/third-born comparison (p < 0.001) and (b) with increasing myopia severity (p < 0.001).Conclusions: Across all studies, the increased risk of myopia in first-born individuals was low (OR < 1.3). Indeed, only the studies with >4000 participants provided strong statistical support for the association. The available evidence suggested the relationship was independent of established risk factors such as time outdoors/reading, and thus may arise through a different causal mechanism.

Studies in relatives have generally yielded high heritability estimates for refractive error: twins 75-90%, families 15-70%. However, because related individuals often share a common environment, these estimates are inflated (via misallocation of unique/common environment variance). We calculated a lower-bound heritability estimate for refractive error free from such bias.Between the ages 7 and 15 years, participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent non-cycloplegic autorefraction at regular research clinics. At each age, an estimate of the variance in refractive error explained by single nucleotide polymorphism (SNP) genetic variants was calculated using genome-wide complex trait analysis (GCTA) using high-density genome-wide SNP genotype information (minimum N at each age=3,404).The variance in refractive error explained by the SNPs ("SNP heritability") was stable over childhood: Across age 7-15 years, SNP heritability averaged 0.28 (SE=0.08, p<0.001). The genetic correlation for refractive error between visits varied from 0.77 to 1.00 (all p<0.001) demonstrating that a common set of SNPs was responsible for the genetic contribution to refractive error across this period of childhood. Simulations suggested lack of cycloplegia during autorefraction led to a small underestimation of SNP heritability (adjusted SNP heritability=0.35; SE=0.09). To put these results in context, the variance in refractive error explained (or predicted) by the time participants spent outdoors was <0.005 and by the time spent reading was <0.01, based on a parental questionnaire completed when the child was aged 8-9 years old.Genetic variation captured by common SNPs explained approximately 35% of the variation in refractive error between unrelated subjects. This value sets an upper limit for predicting refractive error using existing SNP genotyping arrays, although higher-density genotyping in larger samples and inclusion of interaction effects is expected to raise this figure toward twin- and family-based heritability estimates. The same SNPs influenced refractive error across much of childhood. Notwithstanding the strong evidence of association between time outdoors and myopia, and time reading and myopia, less than 1% of the variance in myopia at age 15 was explained by crude measures of these two risk factors, indicating that their effects may be limited, at least when averaged over the whole population.

Purpose.: To examine the extent to which the two major determinants of refractive error, corneal curvature and axial length, are scaled relative to one another by shared genetic variants, along with their relationship to the genetic scaling of height. Methods.: Corneal curvature, axial length, and height were measured in unrelated 14- to 17-year-old white European participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 1915) and in unrelated 40- to 80-year-old participants of the Singapore Chinese Eye Study (SCES; n = 1642). Univariate and bivariate heritability analyses were performed with methods that avoid confounding by common family environment, using information solely from genome-wide high-density genotypes. Results.: In ALSPAC subjects, axial length, corneal curvature, and height had similar lower-bound heritability estimates: axial length, h2 = 0.46 (SE = 0.16, P = 0.002); corneal curvature, h2 = 0.42 (SE = 0.16, P = 0.004); height, h2 = 0.48 (SE = 0.17, P = 0.002). The corresponding estimates in the SCES were 0.79 (SE = 0.18, P < 0.001), 0.35 (SE = 0.20, P = 0.036), and 0.31 (SE = 0.20, P = 0.061), respectively. The genetic correlation between corneal curvature and axial length was 0.69 (SE = 0.17, P = 0.019) for ALSPAC participants and 0.64 (SE = 0.22, P = 0.003) for SCES participants. In the subset of 1478 emmetropic ALSPAC individuals, the genetic correlation was 0.85 (SE = 0.12, P = 0.008). Conclusions.: These results imply that coordinated scaling of ocular component dimensions is largely achieved by hundreds to thousands of common genetic variants, each with a small pleiotropic effect. Furthermore, genome-wide association studies (GWAS) for either axial length or corneal curvature are likely to identify variants controlling overall eye size when using discovery cohorts dominated by emmetropes, but trait-specific variants in discovery cohorts dominated by ametropes.

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E−8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E−07), TOX (rs7823467, P = 3.47E−07) and LINC00340 (rs12212674, P = 1.49E−06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = −0.59, P = 2.10E−04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

Corneal curvature is a key determinant of the refractive power of the eye. Variants in two genes, FKBP12-rapamycin complex-associated protein 1 (FRAP1) on chromosome 1p36.2 and platelet-derived growth factor receptor alpha (PDGFRA) on chromosome 4q12, have shown genome-wide significant association with normal variation in corneal curvature in a study of subjects of Asian origin. Variants at the PDGFRA locus have also shown genome-wide significant association with corneal astigmatism. Whether these variants influence other ocular parameters such as axial length has yet to be reported. We performed a genome-wide association study for corneal curvature in white European subjects from a population-based birth cohort, with the aim of replicating and extending the above findings.White European children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were examined at age about 15.5 years (95% confidence interval=15.45 to 15.48 years). Radius of corneal curvature and axial eye length were measured with an IOLmaster. DNA samples were genotyped with Illumina HumanHap550 arrays and untyped variants imputed using MACH, with CEU individuals from HapMap release 22, Phase II NCBI B36, Single Nucleotide Polymorphism database 126 as the reference panel. Association between corneal curvature and single nucleotide polymorphism (SNP) genotype was tested, genome-wide, using mach2qtl, with sex as a covariate (n=2023; 46.6% male).The variant exhibiting the strongest evidence for association with corneal curvature (rs6554163; p=2.8×10(-6)) was located in the same linkage disequilibrium block as the previously discovered PDGFRA variants. Meta-analysis of the current and prior findings enhanced the evidence for association (rs17084051, p=4.5×10(-14)). rs6554163 genotype predicted 1.0% of variation in corneal curvature. In addition, these PDGFRA variants were associated with axial eye length, predicting 0.6% of the normal trait variation (p=5.3×10(-4)). Each copy of the minor allele of variants at the locus also increased the risk of corneal astigmatism in this white European cohort (odds ratio [OR]=1.24, 95% confidence interval=1.07-1.45; p=0.006).As in Asians, variants at the PDGFRA locus influence corneal curvature (and corneal astigmatism). However, rather than affecting corneal curvature in isolation, this locus influences the size of the eye while maintaining its scaling.

Aims Alcohol problems (AP) contribute substantially to the global disease burden. Twin and family studies suggest that AP are genetically influenced, although few studies have identified variants or genes that are robustly associated with risk. This study identifies genetic and genomic influences on AP during young adulthood, which is often when drinking habits are established. Design We conducted a genome-wide association study of AP. We further conducted gene-based tests, gene ontology analyses and functional genomic enrichment analyses to assess genomic factors beyond single variants that are relevant to AP. Setting The Avon Longitudinal Study of Parents and Children, a large population-based study of a UK birth cohort. Participants Genetic and phenotypical data were available for 4304 participants. Measurements The AP phenotype was a factor score derived from items from the Alcohol Use Disorders Identification Test, symptoms of DSM-IV alcohol dependence, and three additional problem-related items. Findings One variant met genome-wide significance criteria. Four out of 22 880 genes subjected to gene-based analyses survived a stringent significance threshold (q < 0.05); none of these have been implicated previously in alcohol-related phenotypes. Several biologically plausible gene ontologies were statistically over-represented among implicated single nucleotide polymorphisms (SNPs). SNPs on the Illumina 550 K SNP chip accounted for ~5% of the phenotypical variance in AP. Conclusions Genetic and genomic factors appear to play a role in alcohol problems in young adults. Genes involved in nervous system-related processes, such as signal transduction and neurogenesis, potentially contribute to liability to alcohol problems, as do genes expressed in non-brain tissues.

Nat. Genet.; doi:10.1038/ng.3598; corrected online 18 July 2016 In the version of this article initially published online, the affiliations for Bertram Muller-Myhsok and Patricia Pozo-Rosich were incorrect or incomplete. These errors have been corrected for the print, PDF and HTML versions of this article.

This article describes three creative arts exercises designed to promote belonging, connectedness, and wellness among adolescents with and without disabilities. The scenarios are multifaceted and based on utilization of creative visual and performing arts. Creative outlets may help groups be more effective and meaningful for participants, particularly creative adolescents, adolescents with various learning styles, and those with learning differences.

Classical or transferase-deficient galactosaemia is an inherited metabolic disorder caused by mutation in the human Galactose-1-phosphate uridyl transferase (GALT) gene. Of some 170 causative mutations reported, fewer than 10% are observed in more than one geographic region or ethnic group. To better understand the population history of the common GALT mutations, we have established a haplotyping system for the GALT locus incorporating eight single nucleotide polymorphisms and three short tandem repeat markers. We analysed haplotypes associated with the three most frequent GALT gene mutations, Q188R, K285N and Duarte-2 (D2), and estimated their age. Haplotype diversity, in conjunction with measures of genetic diversity and of linkage disequilibrium, indicated that Q188R and K285N are European mutations. The Q188R mutation arose in central Europe within the last 20 000 years, with its observed east-west cline of increasing relative allele frequency possibly being due to population expansion during the re-colonization of Europe by Homo sapiens in the Mesolithic age. K285N was found to be a younger mutation that originated in Eastern Europe and is probably more geographically restricted as it arose after all major European population expansions. The D2 variant was found to be an ancient mutation that originated before the expansion of Homo sapiens out of Africa.

Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine.We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS).We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases.Our study is based on self-reported migraine.NBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.

Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 m ‘1000 Genomes Reference Panel’ imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (PMale = 2 × 10−49, Beta: ∼0.9 SDs per allele), rs8112524 (PMale = 3 × 10−8, Beta: ∼0.25)] and low-frequency variants [rs2385821 (PMale = 6 × 10−31, Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (PHet 0.0003–6.3 × 10−12), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men.

Albuminuria is an important risk factor for cardiovascular disease (CVD). We have previously identified a missense single-nucleotide polymorphism (rs1801239) in the CUBN gene that is associated with albuminuria. Whether albuminuria is associated with CVD in the presence of the CUBN mutation is unknown.We analyzed participants from the Framingham Heart Study (n=6399, mean age 47 years, 53.4% women) who underwent genotyping of rs1801239. Cox proportional hazards models were used to test the association between microalbuminuria [UACR≥17 mg/g (men) and ≥25 mg/g (women)] and incident CVD stratified by the presence or absence of the CUBN risk allele. We tested whether the association between microalbuminuria and CVD was altered by the presence of the risk allele with interaction testing.Overall, 21.1% of participants carried the risk allele. As expected, carriers of the risk (C) allele had a higher prevalence of microalbuminuria (10.7 versus 8.9%, P=0.04). During a mean follow-up of 10.4 years, 5.6% (n=346) of participants experienced a CVD event. Microalbuminuria was associated with an increased risk of CVD [hazards ratio (HR) 1.46, 95% confidence interval (CI) 1.14-1.88]. When stratified by risk allele carrier status, the HR for CVD was 1.95 (95% CI 1.15-3.29) among those with compared to 1.33 (95% CI 1.00-1.76) among those without the risk allele. There was no interaction between microalbuminuria and rs1801239 on CVD (Pinteraction=0.49).MA is associated with CVD irrespective of the presence of the CUBN risk allele. These results challenge the concept that albuminuria in the setting of this mutation is benign.

Abstract We conducted genome-wide association study (GWAS) meta-analyses of relative caloric intake from fat, protein, carbohydrates and sugar in over 235,000 individuals. We identified 21 approximately independent lead SNPs. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease ( r g ≈ 0.15 – 0.5). Relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood poverty (| r g | ≈ 0.1 – 0.3). Overall, our results show that the relative intake of each macronutrient has a distinct genetic architecture and pattern of genetic correlations suggestive of health implications beyond caloric content.

Whooping cough is currently seeing resurgence in countries despite high vaccine coverage. There is considerable variation in subject-specific response to infection and vaccine efficacy, but little is known about the role of human genetics. We carried out a case-control genome-wide association study of adult or parent-reported history of whooping cough in two cohorts from the UK: the ALSPAC cohort and the 1958 British Birth Cohort (815/758 cases and 6341/4308 controls, respectively). We also imputed HLA alleles using dense SNP data in the MHC region and carried out gene-based and gene-set tests of association and estimated the amount of additive genetic variation explained by common SNPs. We observed a novel association at SNPs in the MHC class II region in both cohorts [lead SNP rs9271768 after meta-analysis, odds ratio [95% confidence intervals (CIs)] 1.47 (1.35, 1.6), P-value 1.21E - 18]. Multiple strong associations were also observed at alleles at the HLA class II loci. The majority of these associations were explained by the lead SNP rs9271768. Gene-based and gene-set tests and estimates of explainable common genetic variation could not establish the presence of additional associations in our sample. Genetic variation at the MHC class II region plays a role in susceptibility to whooping cough. These findings provide additional perspective on mechanisms of whooping cough infection and vaccine efficacy.

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P &lt; 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Three previous studies have tested for an association between high myopia and polymorphisms in the open angle glaucoma gene, myocilin (MYOC), all in subjects of Chinese ethnicity. In two of the studies, a significant association was found while in the third, there was no association. We sought to investigate the association between high myopia and polymorphisms in MYOC in subjects of European ethnicity.Subjects were recruited from two sites, Cardiff University in the UK and Duke University in the United States. The Cardiff University cohort was comprised of 164 families with high myopia (604 subjects) plus 112 unrelated, highly myopic cases and 114 emmetropic controls. The Duke University cohort was comprised of 87 families with high myopia (362 subjects) plus 59 unrelated, highly myopic cases. Subject DNA was genotyped with a panel of MYOC single nucleotide polymorphisms (SNPs) including those found previously associated with high myopia. The Cardiff cohort was also genotyped for two flanking microsatellite markers analyzed in prior studies. Association between high myopia and MYOC polymorphisms was assessed using the Unphased program.Since there was no evidence of heterogeneity in genotype frequencies between families and singleton samples or between cohorts, both subject groups (families and unrelated subjects) from both recruitment sites were analyzed jointly for those SNPs genotyped in common. Two variants showed significant association before correction for multiple testing. These two variants were rs16864720 (p=0.043) and NGA17 (p=0.026). However, there was no significant association after Bonferroni correction. The estimated relative risk (RR) conferred by each of the MYOC variants was low (RR<1.5).Our results suggest that MYOC polymorphisms have a very low, or possibly negligible, influence on high myopia susceptibility in subjects of European ethnicity.

Nat. Genet. 45, 314–318 (2013); doi:10.1038/ng.2554; published online 10 February 2013; corrected after print 9 May 2013 In the version of this article initially published, the affiliations of Daniel W.H. Ho were incorrect, and the spelling of Sarayut Janmahasatian in the author list was incorrect. The errors have been corrected in the HTML and PDF versions of this article.

Schools implementing Positive Behavioral Interventions and Supports (PBIS) with fidelity demonstrate a wealth of student and school benefits. At the same time, there exists limited research from an inclusive innovation perspective: examining whether schools and communities have equitable access to PBIS based on sociodemographic school and community variables. This article presents the results of an ex post facto research design examining PBIS implementation and access across sociodemographic school and community variables from an inclusive innovation lens, examining data from schools ( N = 489) in the state of Georgia. The significant interaction effects revealed that between both PBIS and non-PBIS schools, those located in suburban areas had significantly higher median household incomes compared with rural and urban schools. Additional findings included the following: PBIS rural schools had higher household incomes and lower percentages of free/reduced-price lunch than non-PBIS schools in rural communities, and PBIS schools included significantly higher proportions of students who identified as White compared with non-PBIS schools.

Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10-13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.

Abstract The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P&lt;5×10 −8 ) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.

Nat. Genet. 44, 532–538 (2012); published online 15 April 2012; corrected after print 8 May 2013 In the version of this article initially published, Thorkild I.A. Sørensen was listed incorrectly as a contributing member of the EGG Consortium. The error has been corrected for the HTML and PDF versions of this article.

Files include summary statistics for associations with each phenotype: Drinks per week, Cigarettes per day, Smoking initiation, Smoking cessation, and Age of initiation. Details for each file can be found in the readme file or in the article's Supplementary Text.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Several common fetal genetic variants have been associated with birth weight, but little is known about how maternal genetic variation influences fetal growth through the intra-uterine environment. To identify maternal genetic variants associated with birth weight, we performed a meta-analysis of 11 genome-wide association studies (GWAS; n = 19,626 women of European descent). We selected 18 single nucleotide polymorphisms (SNPs) for replication analysis in up to 13 further studies (n = 18,319 women of European descent). One SNP reached genome-wide significance (rs10830963, P = 2.0 x 10-11) in a combined analysis of discovery and replication results. Rs10830963 is intronic in MTNR1B and is known from previous GWAS to be associated with fasting glucose levels, type 2 diabetes and gestational diabetes. Each copy of rs10830963-G (the allele associated with higher fasting glucose) corresponded to a 31g [95%CI: 22, 41g] higher offspring birth weight. The association between maternal rs10830963 and birth weight was unaltered by adjustment for any potentially confounding effects of fetal genotype in 8716 maternal-fetal pairs. Although no other SNPs reached genome-wide significance, there was an excess of low P-values among SNPs known to be associated with fasting glucose levels. Our study demonstrates that maternal genetic variation at MTNR1B influences offspring birth weight and supports a broader role of genetic variation affecting maternal glucose levels in fetal growth. Our study also highlights that the effect sizes of associations between other maternal genetic variants and birth weight are unlikely to exceed 20g per allele, and therefore much larger sample sizes will be required to detect them.

(Abstracted from JAMA 2016;315(11):1129–1140) Neonates born to overweight or obese women are more likely to be large for gestational age. It has been noted that maternal obesity-related traits are observationally associated with birth weight; however, the causal nature of these associations is uncertain.

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk ( P -8 ) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

textabstractGenome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and where educational performance is more routinely and more precisely assessed. Single nucleotide polymorphisms exhibiting genome-wide significant associations with adult educational attainment were combined to derive an unweighted allele score in 5,979 and 6,145 young participants from the Avon Longitudinal Study of Parents and Children with key stage 3 national curriculum test results (SATS results) available at age 13 to 14 years in English and mathematics respectively. Standardised (z-scored) results for English and mathematics showed an expected relationship with sex, with girls exhibiting an advantage over boys in English (0.433 SD (95%CI 0.395, 0.470), p<10-10) with more similar results (though in the opposite direction) in mathematics (0.042 SD (95%CI 0.004, 0.080), p = 0.030). Each additional adult educational attainment increasing allele was associated with 0.041 SD (95%CI 0.020, 0.063), p = 1.79×10-04 and 0.028 SD (95%CI 0.007, 0.050), p = 0.01 increases in standardised SATS score for English and mathematics respectively. Educational attainment is a complex multifactorial behavioural trait which has not had heritable contributions to it fully characterised. We were able to apply the results from a large study of adult educational attainment to a study of child exam performance marking events in the process of learning rather than realised adult end product. Our results support evidence for common, small genetic contributions to educational attainment, but also emphasise the likely lifecourse nature of this genetic effect. Results here also, by an alternative route, suggest that existing methods for child examination are able to recognise early life variation likely to be related to ultimate educational attainment.

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

An aim of this thesis is to map a genetic factor that is related to myopia progression. A genome-wide association study of myopia, refractive error and two ocular determinants of refractive error, axial length and corneal curvature was undertaken. A number of genetic locations were identified and extra genotyping and replication in an independent cohort is underway. A further aim of this thesis is investigation of an environmental risk factor of myopia. Epidemiological analyses of two myopia risk factors were undertaken; one in the ALSPAC cohort, another in a cohort from Northern England. In both cases, a relationship with myopia was identified and a plausible mechanism for the relationship is discussed.