Maria Arranz

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and -141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (-759-T/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

Inherited variation contributes to autism About one-quarter of genetic variants that are associated with autism spectrum disorder (ASD) are due to de novo mutations in protein-coding genes. Brandler et al. wanted to determine whether changes in noncoding regions of the genome are associated with autism. They applied whole-genome sequencing to ∼2600 families with at least one affected child. Children with ASD had inherited structural variants in noncoding regions from their father. Regulatory regions of some specific genes were disrupted among multiple families, supporting the idea that a component of autism risk involves inherited noncoding variation. Science , this issue p. 327

Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases.We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls).Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15).Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

<h2>Abstract</h2><h3>Background</h3> Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. <h3>Methods</h3> Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (<i>n</i> = 207) and validation (<i>n</i> = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. <h3>Findings</h3> The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. <h3>Interpretation</h3> We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. <h3>Funding</h3> The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.

We did association studies in multiple candidate genes to find the combination of polymorphisms that give the best predictive value of response to clozapine in schizophrenic patients. A combination of six polymorphisms in neurotransmitter-receptor-related genes resulted in 76·7% success in the prediction of clozapine response (p = 0·0001) and a sensitivity of 95% (±0·04) for satisfactory response. These results will form the basis for a simple test to enhance the usefulness of clozapine in psychiatric treatment.

Serotonin (5-HT) neurotransmitter receptors are targeted by atypical antipsychotic drugs. We hypothesized that genetic variation in these receptors may affect clinical response to the drugs targeting them. This hypothesis has been tested by several studies in which the correlation between polymorphic variants in the 5-HT2A receptor gene and clinical response to the atypical antipsychotic clozapine was investigated. The results of these studies either found association between 5-HT2A genetic variants and clozapine response or found differences in the same direction which did not reach statistical significance. Meta-analysis of these studies including 373 patients who responded to the treatment and 360 non-responders showed association between two 5-HT2A polymorphisms, 102-T/C and His452Tyr, and clozapine response. Statistical analysis of extreme responders showed a clearer association of the 102-T/C with clozapine response. These results reinforce the hypothesis and strengthen the candidacy of these receptors as important therapeutic targets.

Clozapine is a potent atypical antipsychotic which binds to a variety of neurotransmitter receptors including serotonin (5-HT) receptors. However, the precise neurochemical site of clozapine's therapeutic action is unknown. We hypothesize that genetic variation in the neurotransmitter receptors to which the drug binds may influence clozapine response. To test this hypothesis we genotyped a novel -1438-G/A polymorphism detected in the promoter region, and a His452Tyr polymorphism described in the coding region of the 5-HT2A receptor gene in two independent samples of clozapine-treated patients including responders and non-responders. Although the strong association between these polymorphisms and clozapine response observed in the first sample (sample I) was not statistically significant in the second sample (sample II), the results in both samples were in the same direction. Homozygosity for the allele G-1438 was higher among non-responders (56% in sample I, 43% in sample II) than in responders (28% in sample I and 32% in sample II) in both samples. Similarly, the frequency of allele Tyr452 was higher in non-responders (11% in sample I, 16% in sample II) than in responders (6% in sample I and 10% in sample II). A combined analysis of both samples showed association between both polymorphisms and clozapine response. These results provide further evidence suggesting that genetic variation at 5-HT2A receptors may influence clozapine response and strengthen the candidacy of these receptors as important therapeutic targets.

The serotonin transporter is a strong candidate for aetiological involvement in affective disorders and psychosis. We analysed a VNTR in intron 2 of the human serotonin transporter gene (hSERT) for allelic association with bipolar affective disorder, unipolar depression and schizophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi 2 p = 0.00048 by allele) but not unipolar depression (n = 86; chi 2 p = 0.18, ns) or schizophrenia (n = 129; chi 2 p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bipolar affective disorder and unipolar depression (p = 0.0087). The relative risk for bipolar affective disorder with respect to allele 12 was 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.07) for homozygotes, with evidence for a gene-dosage effect. Because allele 12 is common in the population, the attributable risk is 50.8% (95% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regulation of expression of hSERT at the transcriptional level or it is in linkage disequilibrium with another functional polymorphism in the gene, and this results in an increased risk for the development of bipolar affective disorder.

In addition to an established role for sociocultural factors, twin studies provide evidence that anorexia nervosa may be heritable1, although this view is balanced by a population study that indicates familial aggregation but not high heritability.2 Factors related to a desire for weight loss and body dissatisfaction in normal subjects have heritabilities of about 40–50%.3 The most likely model of inheritance involves gene-environment interaction, in which the influence of sociocultural factors leads to the development of the disease in genetically susceptible individuals.

A cysteine to serine substitution at amino acid 23 in the 5-HT2C receptor gene alters the pharmacological properties of the protein. We investigated this polymorphism in subjects with schizophrenia resistant to conventional neuroleptic drugs, and analysed our data for allelic association between the disease state or clinical response to the atypical antipsychotic drug, clozapine. Ninety percent of subjects who had one or more 5-HT2Cser alleles (19/21) were classified as clozapine responders compared with 59% (84/141) without this allele (chi 2 = 7.7, p = 0.005), suggesting that this mutation is a predictor of good response to clozapine. There was no association between schizophrenia and the 5-HT2Cser allele, but our results indicate that the 5-HT2C receptor may contain the major site of action through which clozapine mediates its antipsychotic effects.

In response to reported schizophrenia linkage findings on chromosomes 3, 6 and 8, fourteen research groups genotyped 14 microsatellite markers in an unbiased, collaborative (New) sample of 403-567 informative pedigrees per marker, and in the Original sample which produced each finding (the Johns Hopkins University sample of 46-52 informative pedigrees for chromosomes 3 and 8, and the Medical College of Virginia sample of 156-191 informative pedigrees for chromosome 6). Primary planned analyses (New sample) were two-point heterogeneity lod score (lod2) tests (dominant and recessive affected-only models), and multipoint affected sibling pair (ASP) analysis, with a narrow diagnostic model (DSM-IIIR schizophrenia and schizoaffective disorders). Regions with positive results were also analyzed in the Original and Combined samples. There was no evidence for linkage on chromosome 3. For chromosome 6, ASP maximum lod scores (MLS) were 2.19 (New sample, nominal p = 0.001) and 2.68 (Combined sample, p = .0004). For chromosome 8, maximum lod2 scores (tests of linkage with heterogeneity) were 2.22 (New sample, p = .0014) and 3.06 (Combined sample, p = .00018). Results are interpreted as inconclusive but suggestive of linkage in the latter two regions. We discuss possible reasons for failing to achieve a conclusive result in this large sample. Design issues and limitations of this type of collaborative study are discussed, and it is concluded that multicenter follow-up linkage studies of complex disorders can help to direct research efforts toward promising regions.

[(11)C]PK11195 is used in positron emission tomography (PET) studies for imaging brain inflammation in vivo as it binds to the peripheral-type benzodiazepine receptor (PBR) expressed by reactive glia and macrophages. However, features of the cellular reaction required to induce a positive [(11)C]PK11195 signal are not well characterized. We performed [(11)C]PK11195 PET and autoradiography in rats after transient focal cerebral ischemia. We determined [(3)H]PK11195 binding and PBR expression in brain tissue and examined the lesion with several markers. [(11)C]PK11195 standard uptake value increased at day 4 and grew further at day 7 within the ischemic core. Accordingly, ex vivo [(3)H]PK11195 binding increased at day 4, and increases further at day 7. The PET signal also augmented in peripheral regions, but to a lesser extent than in the core. Binding in the region surrounding infarction was supported by [(11)C]PK11195 autoradiography at day 7 showing that the radioactive signal extended beyond the infarcted core. Enhanced binding was preceded by increases in PBR mRNA expression in the ipsilateral hemisphere, and a 18-kDa band corresponding to PBR protein was detected. Peripheral-type benzodiazepine receptor immunohistochemistry showed subsets of ameboid microglia/macrophages within the infarcted core showing a distinctive strong PBR expression from day 4. These cells were often located surrounding microhemorrhages. Reactive astrocytes forming a rim surrounding infarction at day 7 also showed some PBR immunostaining. These results show cellular heterogeneity in the level of PBR expression, supporting that PBR is not a simple marker of inflammation, and that the extent of [(11)C]PK11195 binding depends on intrinsic features of the inflammatory cells.

The hypothalamus-pituitary-adrenal axis (HPA) is essential in the regulation of stress responses. Increased methylation of the promoter region of the glucocorticoid receptor gene (NR3C1) has been described both in subjects with history of childhood trauma and in patients with Borderline Personality Disorder (BPD). However, no data on the possible association between a higher methylation of this gene and clinical severity is available. The aim of this study was to evaluate the association between NR3C1 methylation status, the history of childhood trauma, and current clinical severity in subjects with BPD. A sample of 281 subjects with BPD (diagnosed by SCID-II and DIB-R semi-structured diagnostic interviews) was recruited. Clinical variables included previous hospitalizations, self-injurious behavior, and self-reported history of childhood trauma. DNA was extracted from peripheral blood. The results indicated a significant positive correlation between NR3C1 methylation status and childhood maltreatment (specifically physical abuse). In addition, a positive correlation between methylation status and clinical severity (DIB-R total score and hospitalizations) was observed. These findings suggest that NR3C1 methylation in subjects with BPD may be associated not only with childhood trauma but also with clinical severity, adding new evidence to the involvement of gene-environment interactions in this disorder.

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father’s sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment. Genetic analysis of paternal sperm from families with a child affected by autism reveals that the recurrent risk for transmitting disease-associated de novo mutations to future offspring is near 0% for most couples but is substantially higher for a small fraction of couples.

Abstract Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P &amp;lt; 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (&amp;lt;60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Clozapine is an atypical antipsychotic with affinity for a broad range of receptors, including serotonin (5-HT) and dopamine receptors. It is successful in treating about 60% of patients refractory to other antipsychotic drugs. Since genetic variation in clozapine's neurotransmitter receptor targets may affect clinical response through altering drug binding or receptor expression, we have studied a His452Tyr polymorphism in the 5-HT2A receptor (HTR2A) in a sample of 153 schizophrenic patients undergoing clozapine treatment and 178 normal controls. An association was found between the allele Tyr452 and poor clinical response.

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates catecholamines such as adrenaline, noradrenaline, dopamine, and levodopa. Recently an amino acid change (Val-108-Met) of the COMT protein was found to determine high and low activity alleles of the COMT gene. We genotyped 109 Japanese patients with Parkinson's disease (PD) and 153 controls by using polymerase chain reaction (PCR) amplification and digestion by the restriction enzyme NlaIII. The frequency of low activity allele in the controls was 0.29, which was significantly different from that reported in Caucasians (0.50). When comparison was made between patients with PD and controls, homozygosity for the low activity allele was significantly more common among the patients than among the controls (P=0.017; odds ratio, 2.8, 95% CI 1.2–6.5), suggesting that homozygosity for the low activity allele may increase susceptibility to PD.

Abstract Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10 −10 , OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h 2 SNP = 0.34) when compared to ADHD without DBDs (h 2 SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (r g = 0.81) and anti-social behaviors (r g = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

This study investigated possible associations between selected polymorphisms in the dopamine receptor genes DRD1 and DRD3 with the presence of psychotic phenomena or aggressive behaviour in a community based cohort of 134 patients with late onset Alzheimer's disease. An association was found between the presence of psychotic symptoms and aggressive behaviour and the DRD1 polymorphism and between the presence of psychosis, but not aggression, and the DRD3 polymorphism. Specifically, carriers of the DRD1 B2 allele were more likely to be aggressive or experience hallucinations whereas homozygous carriers of the DRD3 1 allele were more likely to experience delusions.

Catechol-o-methyltransferase (COMT) is an enzyme that inactivates biologically active or toxic catechols. Previous studies have yielded inconsistent results on the relationship between erythrocyte COMT activity and affective disorders. Recently an amino acid change (Val-108-Met) of the COMT protein was shown to determine high- and low-activity alleles of the enzyme. Using polymerase chain reaction and the restriction enzyme NLaIII, we genotyped 107 patients with bipolar disorder, 62 with unipolar depression, and 121 controls. Neither bipolar nor unipolar patients differ significantly in the genotypic or allelic frequency from the control group. Even when the bipolar and unipolar patients were pooled into a single group, the distributions of both the genotypes and the alleles for the patient group were similar to those for the controls. We conclude that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in our sample.

There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (χ2=4.765, df=1, P=0.030 and χ2= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global χ2=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

The involvement of specific pathways mediated through muscarinic receptor activity has been widely implicated in schizophrenia. Extensive pharmacological evidence supports the systems role in mediating antipsychotic drug efficacy, while mounting physiological evidence demonstrates the presence of significant alterations to normal muscarinic receptor integrity in the disorder. The mechanisms that facilitate the systems involvement and their magnitude, however, remain poorly understood. We have proposed that alterations to normal muscarinic receptor expression exist in schizophrenia, and that these significantly influence the physiological changes often reported for the system amongst patients. In this study, we investigate this potential, and have selected to examine the muscarinic 1 receptor, which constitutes a major target for antipsychotic action and plays a conspicuous role in those regions central to the disorders pathophysiology. Using relative gene quantification, we measured post-mortem levels of steady-state cortical muscarinic 1 receptor cDNA in patients (N = 20) and unaffected controls (N = 20), and examined group differences in expression levels. Commensurate with our hypothesis, we observed significant reductions in muscarinic 1 receptor cDNA in our patient sample (F(1,37) = 4.73, P = 0.036) and have estimated this to constitute a 28% decrease compared to the control subjects (95% CI from 2 to 47%). These results provide evidence in support of altered muscarinic 1 receptor expression in schizophrenia, though further work is needed to corroborate these findings.

Catechol-O-methyltransferase catalyses the O-methylation of biologically active or toxic catechols and is a major component of the metabolism of drugs and neurotransmitters such as L-dopa, noradrenaline, adrenaline, and dopamine. Human catechol-O-methyltransferase activity is an autosomal partially dominant trait and is strongly associated with a valine to methionine substitution at codon 158 of the protein. About 25% of Caucasians have low activity, 50% intermediate activity and 25% high activity as determined by either phenotypic or genotypic measurement. In black populations, the low activity allele (Metl 58; COMTL) is less frequent with about 7% being homozygous. Using a PCR based genotyping assay, we report that the Metl 58 allele is also less frequent in normal Han Chinese subjects with about 3% of the population being homozygous. Because of its role in catecholamine metabolism and several lines of evidence pointing to a locus for psychosis near the COMT gene on chromosome 22q 11, we have analysed the COMT Vail 58Met polymorphism as a candidate susceptibility factor for bipolar affective disorder. We report an association between bipolar affective disorder and the Metl 58 allele (p=0.004) and genotype (p=0.01) in 93 affected Chinese subjects and 98 controls. We hypothesize that either the low activity allele of catechol-0- methyltransferase is a risk factor for bipolar affective disorder in Chinese populations or is in linkage disequilibrium with a nearby susceptibility gene or polymorphism.

Abstract Genetics promises to provide one of the most powerful approaches to understanding the functional pathology of the human brain. This book presents a critical review of the evidence for a genetic contribution to common psychiatric conditions and the rarer single-gene disorders that may have psychiatric presentations. The first section of the book introduces the reader to molecular biology and the techniques of molecular genetics. The coverage then moves on to consider the genetics of normal and abnormal development, followed by a look at the genetics of abnormal behaviour in adults. This section includes, amongst others, consideration of personality disorders, schizophrenia and the dementias. The final section considers the applications of the work and covers issues such as counselling and ethics, closing with a look to the future. The editors are internationally renowned figures in this field and they have invited a team of equally eminent chapter authors. This will be essential reading for psychiatrists and geneticists and will be of interest to neurologists, psychologists and neuroscientists.

This article focuses on the first generation of pharmacogenetic tests that are potentially useful in psychiatry. All pharmacogenetic tests currently on the market, or soon to be marketed in psychiatry, for which some information has been published in peer-reviewed journal articles (or abstracts), were selected. Five pharmacogenetic tests are reviewed in detail: the Roche AmpliChip CYP450 Test, the Luminex Tag-It Mutation Detection Kit, the LGC clozapine response test, the PGxPredict: Clozapine test, and the Genomas PhyzioType system. After reviewing these tests, three practical aspects of implementing pharmacogenetic testing in psychiatric clinical practice are briefly reviewed: (1) the evaluation of these tests in clinical practice, (2) cost-effectiveness, and (3) regulatory oversight. Finally, the future of these and other pharmacogenetic tests in psychiatry is discussed.

Childhood maltreatment and temperamental traits play a role in the development of Borderline Personality Disorder (BPD). The aim of the present study was to assess the involvement and the interrelationship of both factors in the clinical severity of BPD. The self-reported history of childhood trauma, psychobiological temperamental traits, and severity of BPD symptoms were evaluated in 130 subjects with BPD. Approximately 70% of the sample reported some form of abuse or neglect. Childhood maltreatment inversely correlated with sociability, but no correlation was observed with the other temperamental traits. The regression model showed that neuroticism–anxiety and aggression–hostility traits, as well as emotional abuse, were risk factors independently associated with the severity of BPD. Sexual abuse was not associated with the severity of the disorder. Finally, the interaction between high neuroticism–anxiety traits and the presence of severe emotional abuse was associated with BPD severity. These results suggest that the interaction between temperamental traits and childhood emotional abuse has an influence not only on the development but also on the severity of BPD. Further studies are needed to identify more biological and environmental factors associated with the severity of the disorder.

Inflammatory and immune response genes have significantly altered expression in schizophrenia

The serotonergic system is targeted by both antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT5A gene might be involved in susceptibility to depression, the major psychoses or in influencing clinical response to treatment. To examine this hypothesis we genotyped two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene in a sample of 269 unrelated schizophrenic patients treated with clozapine, 112 bipolar patients, 75 unipolar patients and 187 controls. After five-fold correction for multiple testing, allelic association was found with the -19G/C polymorphism and bipolar affective disorder, (p = 0.025; OR 0.56), unipolar depression (p = 0.004; OR 0.52) and schizophrenia (p = 0.036; OR 0.67) indicating a potential protective effect of the G19 allele. For the 12A/T polymorphism allelic association was observed with unipolar depression only (p = 0.004). We conclude that allelic variation in the human 5-HT5A receptor gene may be involved in susceptibility to schizophrenia and affective disorders but not in determining response to clozapine.

The serotonin transporter (5-HTT) is an important candidate gene for the genetic transmission of manic depressive illness. Many studies of patients with affective disorders have found abnormalities in serotonin metabolism and dysregulation of the transporter itself. In the present study, we hypothesize that genetic variation in the 5-HTT gene (17q11.1-17q12) may have an effect in the etiology of manic depression.To test this hypothesis, we analyzed allele, genotype, and haplotype frequencies of two polymorphisms recently described in the 5-HTT gene (a variable number of tandem repeats in intron 2 and a deletion/insertion polymorphism in the transcriptional control region) in a sample of 88 patients with manic-depressive illness and 113 controls. Cases and controls were matched for ethnic and geographic origin.No associations were found between any of these polymorphisms, tested individually or as haplotypes, and manic depression. Moreover, the genetic analysis by sex, presence/absence of psychiatric family history, and age of onset did not reveal significant differences in allele or genotype distributions.Our results suggest that the genetic variability of the 5-HTT gene is not a major risk factor for manic depression.

Some patients with idiopathic Parkinson's disease experience hallucinations as a result of treatment with levodopa and dopamine agonists. There is evidence for some heterogeneity in these hallucinating patients based on duration of Parkinson's disease at onset of hallucinations. We compared the frequency of polymorphisms in the dopamine D2 and D3 receptor genes between patients with drug-induced hallucinations and non-hallucinating patients. Two polymorphisms close to DRD2 and one in DRD3 were studied. No association was found with the whole group of hallucinating patients and their controls. However, an association was found with late-onset hallucinations and the C allele of the Taq IA polymorphism, 10.5 kb 3′ to DRD2. This polymorphism may be in linkage disequilibrium with a mutation in DRD2 or a nearby gene that predisposes to drug-induced hallucinations which occur later in the course of idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (IPD) is characterised by the loss of pigmented neurones in the substantia nigra, leading to reduced tyrosine hydroxylase activity and depletion of dopamine. Treatments attempt to correct this deficit by the use of levodopa and inhibitors of dopamine metabolising enzymes such as catechol-O-methytransferase (COMT). A common amino-acid polymorphism in COMT, valine-108-methionine, results in a low activity form of the enzyme which we hypothesised may influence susceptibility to IPD. We examined this polymorphism in 139 Caucasian subjects with IPD and 173 control subjects, using a PCR-RFLP and a novel Amplification Refractory Mutation System (ARMS) assay. Allele and genotype frequencies were similar in the affected and control subjects, indicating that variation of COMT activity is not an aetiological factor in IPD. We have also characterised a new polymorphism, 256C/G, which is not associated with IPD. However it remains possible that allelic variation in COMT influences severity, type of pathology or treatment response to levodopa or COMT inhibitors.

Background: Methotrexate (MTX) is the most used drug for the treatment of rheumatoid arthritis (RA) although outcome differs among patients. Aim: To evaluate whether polymorphisms in pharmacokinetic genes are associated with outcome in RA patients receiving MTX. Patients &amp; methods: We analyzed 28 SNPs in SLC19A1/RFC1, ABCB1, FPGS and GGH genes. Results: We studied 194 RA patients receiving MTX monotherapy. Two FPGS SNPs, rs10987742 and rs10106, were associated with response (p = 0.033 and p = 0.041, respectively). The FPGS rs10106 variant was also associated with MTX survival (p = 0.005) and toxicity (p = 0.021). Three ABCB1 SNPs, rs868755, rs10280623 and rs1858923, were associated with toxicity (p = 0.025, p = 0.048 and p = 0.031, respectively). Conclusion: FPGS and ABCB1 genetic variants can influence the outcome in RA patients receiving MTX monotherapy.

Antipsychotic drugs fail to achieve adequate response in 30-50% of treated patients and about 50% of them develop severe and lasting side effects. Treatment failure results in poorer prognosis with devastating repercussions for the patients, carers and broader society. Our study evaluated the clinical benefits of a pharmacogenetic intervention for the personalisation of antipsychotic treatment. Pharmacogenetic information in key CYP polymorphisms was used to adjust clinical doses in a group of patients who started or switched treatment with antipsychotic drugs (PharmG+, N = 123), and their results were compared with those of a group of patients treated following existing clinical guides (PharmG-, N = 167). There was no evidence of significant differences in side effects between the two arms. Although patients who had their antipsychotic dose adjusted according to CYPs polymorphisms (PharmG+) had a bigger reduction in side effects than those treated as usual (PharmG-), the difference was not statistically significant (p > 0.05 for all comparisons). However, PharmG+ patients treated with CYP2D6 substrates that were carriers of CYP2D6 UMs or PMs variants showed a significantly higher improvement in global, psychic and other UKU side effects than PharmG- patients (p = 0.02, p = 0.05 and p = 0.01, respectively). PharmG+ clozapine treated patients with CYP1A2 or CYP2C19 UM and PMs variants also showed higher reductions in UKU scores than PharmG- clozapine patients in general. However, those differences were not statistically significant. Pharmacogenetic interventions may improve the safety of antipsychotic treatments by reducing associated side effects. This intervention may be particularly useful when considering treatment with antipsychotics with one major metabolic pathway, and therefore more susceptible to be affected by functional variants of CYP enzymes.

Decades of research have produced extensive evidence of the contribution of genetic factors to the efficacy and toxicity of antipsychotics. Numerous genetic variants in genes controlling drug availability or involved in antipsychotic processes have been linked to treatment variability. The complex mechanism of action and multitarget profile of most antipsychotic drugs hinder the identification of pharmacogenetic markers of clinical value. Nevertheless, the validity of associations between variants in CYP1A2, CYP2D6, CYP2C19, ABCB1, DRD2, DRD3, HTR2A, HTR2C, BDNF, COMT, MC4R genes and antipsychotic response has been confirmed in independent candidate gene studies. Genome wide pharmacogenomic studies have proven the role of the glutamatergic pathway in mediating antipsychotic activity and have reported novel associations with antipsychotic response. However, only a limited number of the findings, mainly functional variants of CYP metabolic enzymes, have been shown to be of clinical utility and translated into useful pharmacogenetic markers. Based on the currently available information, actionable pharmacogenetics should be reduced to antipsychotics’ dose adjustment according to the genetically predicted metabolic status (CYPs’ profile) of the patient. Growing evidence suggests that such interventions will reduce antipsychotics’ side-effects and increase treatment safety. Despite this evidence, the use of pharmacogenetics in psychiatric wards is minimal. Hopefully, further evidence on the clinical and economic benefits, the development of clinical protocols based on pharmacogenetic information, and improved and cheaper genetic testing will increase the implementation of pharmacogenetic guided prescription in clinical settings.

Dopamine has long been hypothesised to be involved in the pathogenesis of schizophrenia. The dopamine D2 receptor is a major site of action of neuroleptic agents used in the treatment of schizophrenia. Arinami et al. [1997; Human Mol Genet 6:577–582] have recently sequenced the dopamine receptor 2 (DRD2) gene in Japanese individuals and identified a novel polymorphism: a single cytosine deletion at position −141 disrupting a BstN1 restriction site with a frequency of 0.22 in their control group. They then found a strong association with this polymorphism and schizophrenia (p < 0.001) with an odds ratio of 0.60 in a Japanese population. We have attempted to verify their results by repeating the RFLP analysis on a sample of Scottish schizophrenics and controls. We then combined our data with those from another British sample recruited using similar procedures. The total combined sample size was 439 schizophrenics and 437 controls. We obtained a significant association—p = 0.02 with an odds ratio of 1.41. Schizophrenia is associated with the C insertion in the Japanese, but that association is reversed in Caucasians. Linkage disequilibrium with a causative polymorphism nearby is the most likely explanation for this reverse association. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:407–410, 1999. © 1999 Wiley-Liss, Inc.

We report the identification of four novel histamine 1 (H1-17-C/T, -974-C/A, -1023-A/G and -1536-G/C) and four novel histamine 2 promoter polymorphisms (H2-294-A/G, -592-A/G, -1018-G/A and -1077-G/A) which we have investigated for involvement in susceptibility to schizophrenia, and in clinical response to clozapine treatment. We identified a weak independent association between variants at the H1-1536-G/C locus and schizophrenia, where an excess of the H1-1536-C allele was observed amongst such patients (P=0.036). However upon correction for multiple testing this relationship was no longer statistically significant. Similar investigation of the H2 receptor polymorphisms revealed association between genotype at the H2-1018-G/A locus and clinical response to clozapine treatment (P=0.027), though upon correction for multiple testing this difference was no longer significant. We have concluded that the participation of these variants in the disorder is unlikely, particularly in view of their apparent lack of function and unlikely influence on receptor expression. However their nature alludes to the potential presence of other more important alterations further along these regions, where sequences encoding alternate promoters have recently been identified for each receptor that may yet be found to harbour such polymorphisms.

The adrenergic system plays an important role in psychiatric disorders such as depression and schizophrenia. Antagonism of the adrenergic receptor subtypes alpha1A and alpha2A has been found to have an antipsychotic effect. Genetic mutations in these receptors could be related to the alterations in the adrenergic system observed in psychiatric patients and to failure to respond to drug antagonism. We have studied one polymorphism in the alpha1A-adrenergic receptor (Arg492Cys) and two polymorphisms in the promoter region of the alpha2A-adrenergic receptor (-1291-C/G and -261-G/A) in a sample of clozapine-treated schizophrenic patients and controls. No clear differences were observed between the different groups suggesting that these polymorphisms did not play an important role in the aetiology of the disorder or in determining antipsychotic response.

Catechol O-methyltransferase (COMT) is an enzyme that inactivates catecholamines. Two common COMT alleles determine high and low activity of the enzyme. Previous studies using biochemical methods found lower enzyme activity in patients with major depression and bipolar disorder in comparison with control values, suggesting that a dysfunction in catecholamine metabolism may be related to the etiology of depression.The authors studied two recently described DNA polymorphisms at the COMT gene (a silent C256G mutation and a structural mutation, Val-108-Met) in 88 patients with bipolar disorder and in 113 healthy comparison subjects, all of Spanish origin.The frequency of the C256 allele was 0.58 in the patients and 0.54 in the comparison subjects. The frequency of the Val108 variant was 0.57 for both the patients and the comparison subjects. No allelic or genotypic associations were observed.The lack of association suggests that the COMT gene is not a major risk factor for bipolar disorder.

Abstract This study investigated possible associations between selected polymorphisms in the serotonin receptor genes, 5‐HT2A and 5‐HT2C , with the presence of co‐morbid depressive illness at baseline in a community based cohort of 158 patients with late onset patients with Alzheimer's disease (AD). An association was found between the presence of major depressive illness at baseline and both the 5‐HT2A and 5‐HT2C polymorphisms. Specifically, homozygous carriers of the 5‐HT2A C102 allele were five times more likely to have major depressive illness than heterozygotes. In addition, homozygous or hemizygous carriers of the 5‐HT2C Ser allele were 12 times more likely to have major depressive illness than homozygous or hemizygous carriers of the 5‐HT2C Cys allele. © 2003 Wiley‐Liss, Inc.

We have examined a structural variant of the 5-HT2C receptor (Cys23Ser) for allelic association with bipolar affective disorder in 88 cases and 113 controls. Overall, there was no significant difference in allele frequencies between the two groups, indicating that the 5-HT2C gene is not a major risk factor for bipolar affective disorder. However, when the subjects were analysed according to sex, there was a small excess of the serine ser23 allele in female cases (P = 0.04) and this effect was also seen if the ser23 allele was considered recessive (P = 0.03). A small increase in significance was found if only female cases with a known family history were included (P = 0.01). These results suggest that the ser23 allele may increase susceptibility to bipolar affective disorder in women.

Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and –141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 −141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia.

Weight gain is one of the major adverse effects of antipsychotics. Although mechanisms remain unclear, genetic susceptibility has become increasingly attractive as a potential mechanism that could explain a significant part of interindividual variability. Most investigations have explored genes related with the mechanism of action of antipsychotic drugs. An alternative approach to investigate the role that genetic factors play in weight gain secondary to antipsychotic treatment is to study those genetic variants that have been found associated with obesity. The aim of this study was to determine whether the fat mass and obesity-associated gene (FTO) rs9939609 variant, the single nucleotide polymorphism that has shown the strongest association with common obesity in different populations, influences weight gain during the first year of antipsychotic treatment. We investigated also the genetic variants in other 3 strong candidates genes involved in the leptin-signaling pathway including leptin, leptin receptor, and Src homology 2. We carried out a prospective study on 239 patients with first-episode psychosis. Two hundred five patients completed the follow-up at 1 year (85.8%). Before antipsychotic treatment, the homozygous subjects for the risk allele A of the FTOrs9939609 variant had a higher body mass index at baseline (24.2 T 3.8 kg/m²) than the AT/TT group (22.82 T 3.3 kg/m2; F = 5.744; P = 0.018). After 1 year, the magnitude of weight increase was similar in the 3 genotypes defined by the rs9939609 variant. These results suggest that the pharmacological intervention accompanied by changes in energy intake and expenditure could suppress the genetic susceptibility conferred by the FTO genotype. None of the other single nucleotide polymorphisms evaluated were associated with weight gain during the first 12 months of antipsychotic therapy.

People with schizophrenia have an increased risk of metabolic syndrome, with consequent elevated morbidity and mortality, largely due to cardiovascular disease. Metabolic disorders comprise obesity, dyslipidemia and elevated levels of triglycerides, hypertension, and disturbed insulin and glucose metabolism. The elevated risk of metabolic syndrome in individuals suffering from schizophrenia is believed to be multifactorial, related to a genetic predisposition, lifestyle characteristics and treatment with antipsychotic medications. Relaxin 3 (RLN3, also known as INSL7) is a recently identified member of the insulin/relaxin superfamily that plays a role in the regulation of appetite and body weight control. RLN3 stimulates relaxin-3 receptor 1 (relaxin/insulin-like family peptide receptor 3, RXFP3) and relaxin receptor 2 (relaxin/insulin-like family peptide receptor 4, RXFP4). We have investigated the role of ten polymorphisms in these genes ( RLN3 rs12327666, rs1982632, and rs7249702, RLN3R1 rs42868, rs6861957, rs7702361, and rs35399, and RLN3R2 rs11264422, rs1018730 and rs12124383) in the occurrence of metabolic syndrome phenotypes (obesity, diabetes, hypercholesterolemia, hypertrigyceridemia, and hypertension) in a cross-sectional cohort of 419 US Caucasian patients treated with antipsychotic drugs. We found several associations between relaxin polymorphisms and hypecholesterolemia, obesity and diabetes, suggesting a role for the relaxin/insulin pathway in the development of metabolic disturbance observed in patients treated with antipsychotics.

We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P = 0.03 by allele) and the DRD2 taq1A polymorphism (P = 0.001 by allele) in Chinese bipolar disorder patients. However, this finding was not replicated in the Caucasian subjects, indicating that the significant association we observed in the Chinese population is a false positive finding. An alternative explanation is that these polymorphisms are risk factors in Chinese but not Caucasian populations, a hypothesis which seems unlikely in view of the similarity of the clinical characteristics of bipolar disorder in the two populations. We also report a novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.

The aim of this study was to investigate the possible involvement of genetic variation in serotonin receptors in the aetiology of bipolar affective disorder. The 5-HT2A receptor gene was systematically screened for genetic variants by single strand conformation polymorphism (SSCP) methods in subjects with bipolar affective disorder. Four polymorphisms (two structural changes, Thr25Asn and His452Tyr, and two silent polymorphisms, 102-T/C and 516-C/T) which had previously been found in patients with schizophrenia and control subjects were detected. No novel polymorphisms were found in patients with bipolar affective disorder. These polymorphisms were genotyped in a sample of 129 patients and 252 controls of German origin and 176 patients and 182 controls of British origin. No strong associations were found between any of these polymorphisms and bipolar affective disorder. Genetic variation at the 5-HT2A receptor gene does not play a major role in the pathogenesis of the disorder.

There are several lines of evidence implicating the dopamine D3 receptor in the pathophysiology of schizophrenia. The Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) has been the most extensively investigated DRD3 variant in connection with the disease but results have been inconclusive. Recent reports indicate that the Ser9Gly polymorphism is in linkage disequilibrium with other markers, but association studies between DRD3 haplotypes and schizophrenia have had mixed results. Genetic heterogeneity may be one of the causes of contradicting results. In order to clarify the role of DRD3 alterations in the aetiology of disease, we have investigated three D3 genetic variants (Ser9Gly, -205-G/A, -7685-G/C) in a sample of patients with schizophrenia or schizoaffective disorder (N=118) and controls (N=162) recruited from a human isolate from Navarra (Northern Spain) of Basque origin. Although no association was found between the Ser9Gly or the -205-A/G polymorphisms and disease, an excess of allele -7685-C was observed in patients (p=0.002 after correction for multiple analyses). Haplotype analysis shows the three markers to be in strong linkage disequilibrium (p<0.0001) and strongly associated with disease (p<1x 10(-5)). These results may suggest that these polymorphisms exert a combined or synergistic effect on susceptibility to schizophrenia, or are in linkage with an unknown causative factor. However, further replication in independent samples is required.

The goal of this study was to select some genes that may serve as good candidates for future studies of the direct effects (not explained by obesity) of some antipsychotics on hyperlipidemia. A search for single-nucleotide polymorphisms (SNPs) that may be associated with these direct effects was conducted. From a published cross-sectional sample, 357 patients on antipsychotics were genotyped using a DNA microarray with 384 SNPs. A total of 165 patients were taking olanzapine, quetiapine or chlorpromazine which may directly cause hypertriglyceridemia or hypercholesterolemia. Another 192 patients taking other antipsychotics were controls. A two-stage statistical analysis that included loglinear and logistic models was developed to select SNPs blindly. In a third stage, physiological knowledge was used to select promising SNPs. Known physiological mechanisms were supported for 3 associations found in patients taking olanzapine, quetiapine or chlorpromazine [acetyl-coenzyme A carboxylase α SNP (rs4072032) in the hypertriglyceridemia model, and for the neuropeptide Y (rs1468271) and ACCβ, (rs2241220) in the hypercholesterolemia model]. These genes may be promising candidates for studies of the direct effects of some antipsychotics on hyperlipidemia.

Background Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol- O -methyltransferase ( COMT ), brain-derived neurotrophic factor ( BDNF ) and neuregulin 1 ( NRG1 ) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. Method The possible role of NRG1 , COMT Val 158 Met and BDNF Val 66 Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. Results Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1 , COMT Val 158 Met or BDNF Val 66 Met genotypes and the P50 endophenotype. Conclusions The evidence from our large study suggests that any such association between P50 indices and NRG1 , COMT Val 158 Met or BDNF Val 66 Met genotypes, if present, must be very subtle.

Wolfram syndrome (DIDMOAD syndrome; MIM 222300) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy. Previous linkage analysis of multiply affected families indicated that the gene for Wolfram syndrome is on chromosome 4p, and it produced no evidence for locus heterogeneity. We have investigated 12 U.K. families with Wolfram syndrome, and we report confirmation of linkage to chromosome 4p, with a maximum two-point LOD score of 4.6 with DRD5, assuming homogeneity, and of 5.1, assuming heterogeneity. Overlapping multipoint analysis using six markers at a time produced definite evidence for locus heterogeneity: the maximum multipoint LOD score under homogeneity was <2, whereas when heterogeneity was allowed for an admixture a LOD of 6.2 was obtained in the interval between D4S432 and D4S431, with the peak close to the marker D4S3023. One family with an atypical phenotype was definitely unlinked to the region. Haplotype inspection of the remaining 11 families, which appear linked to chromosome 4p and had typical phenotypes, revealed crossover events during meiosis, which also placed the gene in the interval D4S432 and D4S431. In these families no recombinants were detected with the marker D4S3023, which maps within the same interval.

There is substantial evidence suggesting that individual variability in antipsychotic treatment response could be genetically determined. Variations in several serotonin transporter (5-HTT) gene polymorphisms have been associated with antipsychotic response among chronic patients with schizophrenia, although their implication in early response among first-episode patients remains unclear. Two polymorphisms in the 5-HTT gene (a 44 bp insertion/deletion in the promoter region and the functional polymorphism rs25531) were genotyped in a sample of 147 drug-naïve patients experiencing a first episode of a non-affective psychosis. Early (6 weeks) response to antipsychotic treatment with haloperidol, olanzapine or risperidone was assessed with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. No clear association was found between the rs25531 variant and treatment response. However, significant associations were observed between 5-HTT-LPR variants and early negative symptom response among first-episode patients with psychosis. Our results suggest a minor contribution to antipsychotic drug response of genetic alterations in the 5-HTT gene.

The products of the serotonin receptor genes are important targets for conventional and atypical antipsychotics, and may be relevant for antipsychotic activity and associated adverse reactions. It has been shown that the high potency at 5-HT2 receptors may also be associated with the production of moderate extrapyramidal side effects (EPS). In addition, serotonin neurotransmitter systems in the central nervous system play an important role in eating behaviours, and are involved in the symptomatology related to the metabolic syndrome, including obesity, diabetes and hyperlipidemia.This study was designed to investigate the hypothesis that serotonin pathway genes play a part in mediating antipsychotic-induced adverse reactions, including EPS, tardive dyskinesia, obesity and diabetes. Polymorphisms in the 5-HT2A (102 (T/C), His452Tyr), 5-HT2C (Cys23Ser, -759 (C/T), -995 (G/A), TPH2 (-366 (C/T), -8933 (A/G) and 5-HTT (LPR, -15370 (A/G)) genes were investigated in a cohort of 427 US Caucasian patients undergoing antipsychotic treatment, using automated genotyping techniques.5-HTT (LPR) and 5-HT2A (102 (T/C) polymorphisms were found to be associated with BMI (P=0.05 and 0.005, respectively). The genotype distribution of the TPH2-366 (T/C) polymorphism was found to be significantly associated with the presence of diabetes (P=0.01). A trend towards an association (P=0.07) between the 5-HT2C Cys23Ser polymorphism and tardive dyskinesia was found when age, duration of treatment, dose and sex were considered. Genotype distributions of the 5-HT2C -995 (G/A), 5-HT2C -759 (C/T) and 5-HT2A His452Tyr polymorphisms differed among patients presenting EPS and those without (P=0.08, 0.06 and 0.08, respectively). No other statistically significant associations were observed.Serotonergic polymorphism may play a moderate role in the development of side effects associated with antipsychotic treatment.

Although pharmacogenetics for major depressive disorder (MDD) is gaining momentum, the role of genetics in differences in response to antidepressant treatment is controversial, as they depend on multifactorial and polygenic phenotypes. Previous studies focused on the genes of the serotonergic system, leaving apart other pathological factors such as the inflammatory pathway. The main objective of the study was to assess whether treatment response might be associated with specific inflammation-related genetic variants or their methylation status.41 SNPs in 8 inflammatory genes: interleukin (IL) 1-β, IL2, IL6, IL6R, IL10, IL18, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were genotyped in 153 patients with MDD, who were evaluated with the Mausdley Staging Method to determine treatment response profiles. Pyrosequencing reactions and methylation quantification were performed in a PyroMark Q24 in 5 selected CpG islands of IL1- β, IL6 and IL6R. Linear and logistic regression analyses were conducted, including age and gender as covariates using PLINK 1.07.Allelic distribution of IL1- β rs1143643 was significantly associated with MSM scores (FDR corrected p = 0.04). Allelic distribution of IL6R rs57569414 showed a trend towards significance with MSM scores (p = 0.002; FDR corrected p = 0.07). Haplotype analyses showed associations between allelic combinations of IL1-β and IL10 with treatment response (FDR corrected p < 0.01). Methylation percentage of treatment responders was only higher in an IL6R CpG island (p < 0.05).These exploratory findings suggest that IL1-β and, marginally, IL6R polymorphisms may affect treatment response in major depression. If confirmed, these results may account for the heterogeneous phenotypes of major depression that underlie differences in treatment response.

Abstract The genetic etiology of autism spectrum disorder (ASD) is multifactorial with contributions from rare variants, polygenic risk, and sex. How combinations of factors determine risk for ASD is unclear. In 11,313 ASD families (N = 37,375 subjects), we investigated the effects rare and polygenic risk individually and in combination. We show that genetic liability for ASD differs by sex, with females having a greater polygenic load, and males having a lower liability threshold as evident by a negative correlation of rare and polygenic risk. Multiple genetic factors were associated with differing sets of behavioral traits with effects that differed by sex. Furthermore, the correlation of parental age with genetic risk for ASD was attributable to de novo mutations and sex-biased effects of inherited risk in parents. Our results demonstrate that a phenotypic spectrum of ASD is attributable to the relative loadings and gene-by-sex effects of rare and common variation.

Los trastornos del espectro del autismo (TEA) afectan la comunicación social con una presencia de intereses, conductas o lenguaje estereotipado y de anomalías sensoriales que comienzan en la primera infancia y continúan a lo largo de la vida. La prevalencia de TEA es del 1-2%, siendo la ratio chicos/chicas de 3:1. El 50-70% de los pacientes con TEA presentan comorbilidad con TDAH, 40% con trastornos de ansiedad, 11% con tics y un 10% con trastornos depresivos. Es fundamental considerar la posibilidad de que una persona con TEA sufra un cuadro depresivo y estar alerta ante los síntomas que puedan englobarse dentro de dicho trastorno, teniendo en cuenta que las personas con TEA tienen dificultades para detectar y expresar sus emociones. Es fundamental no considerar que todo lo que expresa conductual y cognitivamente está directamente relacionado al autismo. La depresión puede no manifestarse de la misma manera que en las personas con desarrollo típico. Los tics son movimientos repetitivos, no rítmicos y estereotipados, que resultan de las contracciones musculares súbitas, abruptas, involuntarias y no propositivas. El DSM-5 engloba los trastornos de tics dentro de los trastornos del neurodesarrollo y los integra dentro de los trastornos motores. La presencia de tics crónicos se ha descrito en el 9% de niños con TEA mientras que su asociación con el Síndrome de Tourette (ST) se daría en el 4.8% de los casos. En muchos casos, los tics coexisten con otros movimientos o comportamientos involuntarios y repetitivos como las estereotipias. Los pacientes con TEA y tics pueden cumplir los criterios diagnósticos de ST, lo que puede dificultar considerablemente su diagnóstico diferencial.

A dysfunctional glutamatergic system has been implicated in the pathophysiology of schizophrenia. The group III metabotropic glutamate receptor (mGluR) types 7 and 8 presynaptically inhibit glutamate release, thereby modulating glutamatergic transmission in the brain. We conducted association studies to investigate the novel Tyr433Phe (mGluR7) variant and the 2846-C/T (mGluR8) polymorphism in schizophrenia. Both variants, present at high frequencies, failed to demonstrate any significant association with schizophrenia (mGluR7 [Tyr433Phe] allele: P=0.33; genotype: P=0.63; mGluR8 [2846-C/T] allele: P=0.72; genotype: P=0.63).

The dopamine system has long been suspected of aetiological involvement in schizophrenia because of a number of lines of evidence pointing to excess dopaminergic activity in the illness. Recently, negative allelic association was reported between a single base deletion in the promoter region of the DRD2 gene, -141 delta C, and schizophrenia, with an odds ratio of 0.60. This was of particular interest since the deletion, which occurs in about 22% of the Japanese population, is functional in that it results in reduced (20-40% of wild-type) basal levels of receptor expression. We have examined this polymorphism in 229 family trios from SW China, consisting of both parents and a single offspring affected by schizophrenia, and 151 Caucasian cases with schizophrenia and 145 Caucasian normal controls from the UK. Using the haplotype-based haplotype relative risk method (HHRR), the frequency of the -141 delta C allele was 6.9% in the affected Chinese subjects compared to an estimated frequency of 9.0% in this population (chi 2 = 1.21, 1 df, ns), with an odds ratio of 0.76 (95% CI 0.46-1.25). Using the transmission disequilibrium test, we likewise found no evidence for linkage or linkage disequilibrium with this polymorphism (chi 2 = 0.94, 1 df, ns). In the Caucasian cases, the frequency of the -141 delta C was 13% compared to 10% in controls (chi 2 = 1.57, p = 0.21) with an odds ratio of 1.39 (95% CI 0.81-2.40). We thus conclude that the DRD2 -141 delta C polymorphism is less frequent in Chinese and Caucasian populations (9%) than in Japan (22%) and is not a significant risk factor for schizophrenia in our populations. The -141 delta C allele remains a strong candidate for a variety of other traits and diseases, including reward-related behaviours such as drug abuse, which have been associated with the dopamine system.

Clozapine is an atypical antipsychotic drug known as being more effective compared with traditional antipsychotics for patients with poor response or resistance to treatment. It has been demonstrated that clozapine modulates hypothalamic–pituitary–adrenal activity and affects central brain-derived neurotrophic factor levels, which could explain part of its therapeutic efficacy. In this study, we investigated the role of genes related to the hypothalamic–pituitary–adrenal axis (FKBP5 and NR3C1) and neurotrophic factors (BDNF and NTRK2) in clinical response to clozapine in 591 schizophrenia patients. We found significant allelic and genotype associations between FKBP5-rs1360780, NTRK2-rs1778929 and NTRK2-rs10465180 polymorphisms and clozapine response. The haplotypes composed of rs1360780-rs3777747-rs17542466-rs2766533 (FKBP5) and rs1619120-rs1778929-rs10465180 (NTRK2) were also nominally significant. Our results suggest that genetic variability in FKBP5 and NTRK2 genes may partially explain clinical response to clozapine. Further studies are needed to clarify the involvement of these genes in clinical response to atypical antipsychotics.

Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (P-gp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan.

Background Antipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment. Methods We conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups (poor, intermediate, normal/extensive, and ultra-rapid metabolizers, UMs). Results Twelve studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associations. Seventeen studies were included in the meta-analysis with clinical data of 2,041 patients, including 93 poor metabolizers (PMs), 633 intermediate metabolizers (IMs), 1,272 normal metabolizers (NMs), and 30 UMs. Overall, we did not find associations in any of the comparisons made. The estimated pooled standardized differences for the following comparisons were (i) PM versus NM; weight = –0.07 (95%CI: –0.49 to 0.35, p = 0.74), BMI = 0.40 (95%CI: –0.19 to 0.99, p = 0.19). (ii) IM versus NM; weight = 0.09 (95% CI: –0.04 to 0.22, p = 0.16) and BMI = 0.09 (95% CI: –0.24 to 0.41, p = 0.60). (iii) UM versus EM; weight = 0.01 (95% CI: –0.37 to 0.40, p = 0.94) and BMI = –0.08 (95%CI: –0.57 to 0.42, p = 0.77). Conclusion Our systematic review of cohort studies suggested that CYP2D6 poor metabolizers have higher BMI than normal metabolizers, but the data of cross-sectional studies and the meta-analysis did not show this association. Although our review and meta-analysis constitutes one of the largest studies with comprehensively genotyped samples, the literature is still limited by small numbers of participants with genetic variants resulting in poor or UMs status. We need further studies with larger numbers of extreme metabolizers to establish its clinical utility in antipsychotic treatment. CYP2D6 is a key gene for personalized prescribing in mental health.

Decades of pharmacogenetic research have revealed genetic biomarkers of clinical response to antipsychotics. Genetic variants in antipsychotic targets, dopamine and serotonin receptors in particular, and in metabolic enzymes have been associated with the efficacy and toxicity of antipsychotic treatments. However, genetic prediction of antipsychotic response based on these biomarkers is far from accurate. Despite the clinical validity of these findings, the clinical utility remains unclear. Nevertheless, genetic information on CYP metabolic enzymes responsible for the biotransformation of most commercially available antipsychotics has proven to be effective for the personalisation of clinical dosing, resulting in a reduction of induced side effects and in an increase in efficacy. However, pharmacogenetic information is rarely used in psychiatric settings as a prescription aid. Lack of studies on cost-effectiveness, absence of clinical guidelines based on pharmacogenetic biomarkers for several commonly used antipsychotics, the cost of genetic testing and the delay in results delivery hamper the implementation of pharmacogenetic interventions in clinical settings. This narrative review will comment on the existing pharmacogenetic information, the clinical utility of pharmacogenetic findings, and their current and future implementations.

The genetic basis of severe COVID-19 has been thoroughly studied and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we have conducted the largest GWAS meta-analysis for COVID-19 hospitalization in admixed Americans, comprising a total of 4,702 hospitalized cases recruited by SCOURGE and other seven participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and first discovered in Latin-American populations ( BAZ2B and DDIAS ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort.

The genetic basis of severe COVID-19 has been thoroughly studied and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we have conducted the largest GWAS meta-analysis for COVID-19 hospitalization in admixed Americans, comprising a total of 4,702 hospitalized cases recruited by SCOURGE and other seven participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and first discovered in Latin-American populations ( BAZ2B and DDIAS ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.

Abstract There is strong biological evidence relating alterations in the serotonergic system with mental disorders. These alterations may be originated at the DNA level by sequence mutations that alter the functioning of serotonin receptors and transporter. To test this hypothesis we investigated three genetic variants of the 5‐HT2A receptor (−1438G/A, 102T/C and His452Tyr) and two variants of the serotonin transporter (a VNTR in the second intron and a 44 bp insertion/delition in the promoter region of the gene) in a clinical sample recruited in a human isolate and in surrounding areas in Northern Spain (N = 257) and in ethnically matched controls (N = 334). No clear association was found between 5‐HT2A variants and psychosis. However, marginal associations were observed between the 5‐HTT LPR and VNTR variants and psychosis ( P ≤ 0.05) indicating a minor contribution to psychosis of genetic alterations in this gene. © 2003 Wiley‐Liss, Inc.

Abstract Choline acetyltransferase (ChAt) is extensively distributed throughout the CNS where, by catalyzing acetylcholine synthesis, it participates in modulating wide‐ranging cholinergic‐dependent functions including cognitive performance, sleep, arousal, movement, and visual information processing. Recently, compelling evidence has mounted implicating ChAt in schizophrenia. In particular, studies have identified significant reductions in ChAt activity in the nucleus accumbens and pontine tegmentum of such patients, which furthermore correlate significantly with measures of cognitive performance in the disorder. Similarly, elevated levels of choline, the acetylcholine precursor, have been identified among patients, implicating altered ChAt activity in these individuals. We sought to investigate the potential contribution of three ChAt gene polymorphisms in schizophrenia, and uncovered evidence for significant association between one of these, rs1880676G/A, and disease susceptibility among Basque individuals (genotypewise χ 2 = 20.7, P = 0.00003; allelewise χ 2 = 10.1, P = 0.002). A similar trend for association with susceptibility was observed for a second SNP, rs3810950G/A, (genotypwise χ 2 = 6.4, P = 0.05; allelewise χ 2 = 3.75, P = 0.05). Evidence was also uncovered for a potential influence of these polymorphisms on olanzapine treatment outcome among Spanish patients (F‐statistic = 5.02, P = 0.03; F‐statistic = 6.53, P = 0.02 respectively), and on improvements in positive symptoms in the case of rs3810950 (F‐statistic = 5.3, P = 0.03) and general psychopathology in the case of rs1880676 and rs3810950 (F‐statistic = 5.24, P = 0.03; F‐statistic = 5.31, P = 0.03 respectively) during therapy. While more comprehensive studies are warranted to determine the precise contribution of ChAt mediated mechanisms in schizophrenia, our findings tentatively implicate a genetic influence of ChAt in the disorder's susceptibility and treatment. © 2007 Wiley‐Liss, Inc.

Abstract Antipsychotic treatment is hampered by the induction of side‐effects such as tardive dyskinesia (TD), weight gain, sedation and extrapyramidal side‐effects (EPS). Identification of the factors related to their development would facilitate their avoidance and the improvement of antipsychotic treatment. It has been hypothesised that genetic variants in drug targeted receptors may contribute to the development of side‐effects. In this study, we have investigated the possible influence of genetic variants (‐563‐C/T, ‐4155‐G/C and ‐4884‐A/G) of the α 1A ‐adrenergic receptor, an important target of atypical antipsychotic drugs, and development of side‐effects after antipsychotic medication in a sample of N = 427 US Caucasian patients. We found several marginal associations ( p &lt; 0.05) between α 1A ‐adrenergic genetic variants and antipsychotic‐induced side‐effects which did not reach statistical significance after corrections for multiple analyses. These results do not support a major role of α 1A ‐adrenergic genetic variants in obesity and other side‐effects observed after prolonged treatment with antipsychotic medications. Copyright © 2007 John Wiley &amp; Sons, Ltd.

Catechol-O-methyltransferase (COMT) Val158Met polymorphism has been identified as a potential etiologic factor in schizophrenia. It has been proposed that this polymorphism could be associated with specific clinical markers. The aim of the study was to evaluate the influence of COMT Val158Met polymorphism genotype in the phenotypic expression of first episode psychosis at onset. Age of onset, DUP, SANS, and SAPS (positive, disorganized, and negative dimensions) were studied in 169 Caucasian drug-naïve patients with a first-episode of non-affective psychosis. The COMT Val158Met polymorphism was typed using PCR amplification of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with COMT and gender as independent variables. Patients with Val/Val genotype had significantly higher levels of SANS negative dimension scores (F: 3.539; P = 0.031) and had a younger age of onset (F: 4.649; P = 0.011) than Met carriers. Our findings suggest that the Val allele is associated with onset phenotypic features related to a poor prognosis of the illness. These data would indicate that COMT genotype may have a role in the etiological model for schizophrenia and other psychotic disorders.

Abstract Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of apoE found in specific areas of post-mortem schizophrenic brains. This study investigated whether apoE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalence of diabetes and possibly overweight in psychiatric patients. Unfortunately, due to the cross sectional nature of this study, the contribution of antipsychotic treatment was not determined. These associations warrant prospective study to assess interaction between APOE gene variants and the propensity of antipsychotics to induce cardiovascular risk factors.

Introduction: Abnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-Schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia. Methods: We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis. Results: Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies. Discussion: The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.

Abstract Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with ( N = 49) and without ( N = 47) childhood traumas and in a control group ( N = 44). Results were confirmed in a replication cohort ( N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome ( PQBP1 , ZNF41 , RPL10 , cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes ( POU5F1 , GGT6 , TNFRSF13C and FAM113B ), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.

Autistic spectrum disorders (ASD) are severe neurodevelopmental alterations characterised by deficits in social communication and repetitive and restricted behaviours. About a third of patients receive pharmacological treatment for comorbid symptoms. However, 30-50% do not respond adequately and/or present severe and long-lasting side effects.Genetic variants in CYP1A2, CYP2C19, CYP2D6 and SLC6A4 were investigated in N = 42 ASD sufferers resistant to pharmacological treatment. Clinical recommendations based on their pharmacogenetic profiles were provided within 24-48 h of receiving a biological sample.A total of 39 participants (93%) improved after the pharmacogenetic intervention according to their CGI scores (difference in basal-final scores: 2.26, SD 1.55) and 37 participants (88%) according to their CGAS scores (average improvement of 20.29, SD 11.85). Twenty-three of them (55%) achieved symptom stability (CGI ≤ 3 and CGAS improvement ≥ 20 points), requiring less frequent visits to their clinicians and hospital stays. Furthermore, the clinical improvement was higher than that observed in a control group (N = 62) with no pharmacogenetic interventions, in which 66% responded to treatment (difference in CGI scores: -0.87, SD 9.4, p = 1 × 10-5; difference in CGAS scores: 6.59, SD 7.76, p = 5 × 10-8).The implementation of pharmacogenetic interventions has the potential to significantly improve the clinical outcomes in severe comorbid ASD populations with drug treatment resistance and poor prognosis.

Background Animal models have implicated the α1-adrenergic subtypes in cognitive functions relevant to schizophrenia, but no consensus exists with regard to the status of noradrenergic receptor populations in psychiatric patients. We focused on one α1-adrenergic subtype, the α1A-adrenergic receptor, and proposed that genetic variants within the regulatory region of this gene (ADRA1A) alter the expression of this receptor, influencing susceptibility toward schizophrenia. Methods This study examined this proposal by testing the hypothesis that single nucleotide polymorphisms (SNPs) in the promoter region of the α1A-adrenergic gene were associated with schizophrenia by performing case–control association analysis on SNPs found in a 5′ upstream region, which included the putative promoter region and 5′ untranslated region. Our sample consisted of 103 schizophrenia and 14 schizoaffective disorder patients and 176 control subjects. All recruits were from a Spanish population isolate of Basque origin that is characterized by low heterogeneity, which was selected with the intent that it might facilitate the identification of disease-related polymorphisms. Results A total of eight SNPs (−9625 G/A, −7255 A/G, −6274 C/T, −4884 A/G, −4155 C/G, −2760 A/C, −1873 G/A, and −563 C/T) were confirmed at a rare allele frequency of >5%. Association with schizophrenia and schizoaffective disorder was found for the −563 C/T SNP (p = .0005 for allele and p = .007 for genotype, Bonferroni corrected) and −9625 G/A SNP (p = .02 for allele and p = .03 for genotype, Bonferroni corrected). Significant differences in the 54 haplotypes formed by these eight SNPs were also found between patients and control subjects (p = .008, Bonferroni corrected). Conclusions Because of the strength of these results and the location of these SNPs in the regulatory region of this gene, functional studies investigating the possible influence of these SNPs on receptor expression levels in schizophrenia are warranted. Animal models have implicated the α1-adrenergic subtypes in cognitive functions relevant to schizophrenia, but no consensus exists with regard to the status of noradrenergic receptor populations in psychiatric patients. We focused on one α1-adrenergic subtype, the α1A-adrenergic receptor, and proposed that genetic variants within the regulatory region of this gene (ADRA1A) alter the expression of this receptor, influencing susceptibility toward schizophrenia. This study examined this proposal by testing the hypothesis that single nucleotide polymorphisms (SNPs) in the promoter region of the α1A-adrenergic gene were associated with schizophrenia by performing case–control association analysis on SNPs found in a 5′ upstream region, which included the putative promoter region and 5′ untranslated region. Our sample consisted of 103 schizophrenia and 14 schizoaffective disorder patients and 176 control subjects. All recruits were from a Spanish population isolate of Basque origin that is characterized by low heterogeneity, which was selected with the intent that it might facilitate the identification of disease-related polymorphisms. A total of eight SNPs (−9625 G/A, −7255 A/G, −6274 C/T, −4884 A/G, −4155 C/G, −2760 A/C, −1873 G/A, and −563 C/T) were confirmed at a rare allele frequency of >5%. Association with schizophrenia and schizoaffective disorder was found for the −563 C/T SNP (p = .0005 for allele and p = .007 for genotype, Bonferroni corrected) and −9625 G/A SNP (p = .02 for allele and p = .03 for genotype, Bonferroni corrected). Significant differences in the 54 haplotypes formed by these eight SNPs were also found between patients and control subjects (p = .008, Bonferroni corrected). Because of the strength of these results and the location of these SNPs in the regulatory region of this gene, functional studies investigating the possible influence of these SNPs on receptor expression levels in schizophrenia are warranted.

The objective of this study was to examine whether the functional genetic polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene influences cognitive deterioration in a sample of patients with psychosis under treatment with atypical antipsychotics. Eighty-seven patients with psychosis were genotyped for this polymorphism and were assessed with three Wechsler Adult Intelligence Scale (WAIS)-III subtests (Vocabulary, Information, and Digit Symbol-Coding). Performance on these three subtests was used to compute a 'cognitive deterioration index', and the effect of COMT genotype on this cognitive deterioration index was examined. A linear relationship between the number of Val alleles and the score on the cognitive deterioration index (i.e. the more Val alleles, the more cognitive deterioration) was observed. These results confirm the role of COMT genotype in the cognition of patients under treatment for psychosis, suggesting that it influences the extent of their cognitive deterioration.

Johannes Schumacher and colleagues (Aug 5, p 506),1Schumacher J Schulze TG Wienker TF Rietschel M, Nöthen MM. Pharmacogenetics of clozapine response.Lancet. 2000; 356: 506-507Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar with the genetic markers reported in our study (May 6, p 1615)2Arranz MJ Munro K Birkett J et al.Pharmacogenetic prediction of clozapine response.Lancet. 2000; 355: 1615-1616Summary Full Text Full Text PDF PubMed Scopus (310) Google Scholar cannot predict clinical response to the antipsychotic drug clozapine. They conclude that their inability to repoduce our results is due to false-positives or false-negative results or to unnoticed phenotypic differences. Replication of findings of association studies is frequently difficult because of a false-positive finding in the initial study. In some cases, however, such a result can be attributed to phenotypic differences in the replicating samples. We have reported an association between a 5-HT2A 102-T/C genetic variant and clozapine response. Workers in several studies, including one from Schumacher's study, could not replicate this finding. However, a meta-analysis of published studies showed a strong association between the 102-T/C polymorphism and clozapine response.3Arranz MJ Munro J Sham P et al.Meta-analysis of studies on genetic variation in 5-HTA receptors and clozapine response.Schiz Res. 1998; 32: 93-99Summary Full Text Full Text PDF PubMed Scopus (237) Google Scholar Important sample differences (ie, method of response assessment, duration of treatment, ethnic origin) can lead to discrepancies between studies. Schumacher and colleagues' sample of patients include those who had been taking clozapine for 28 days. Only 35–50% of patients who finally respond to clozapine improve in the first 4 weeks.4Miller DD Fleming F Holman TL Perry PJ Plasma clozapine concentrations as a predictor of clinical response: a follow-up study.J Clin Psychiatry. 1994; 55: 117-121PubMed Google Scholar, 5Leiberman JA Safferman AZ Pollack S et al.Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome.Am J Psychiatry. 1994; 151: 1744-1752PubMed Google Scholar Later assessment of patients might lead to the reclassification of some non-responders as responders. By contrast, we assessed patients on long-term clozapine treatment (mean duration >1 year). Schumacher and colleagues' conclusion that our prediction model should be replicated and validated is correct. Replication should however, be done in a clinically similar sample. A strategy to clarify disagreement between studies could be the comparison of extreme phenotypes (ie, very good versus very bad responders), which clarifies apparent discrepancies between association studies.3Arranz MJ Munro J Sham P et al.Meta-analysis of studies on genetic variation in 5-HTA receptors and clozapine response.Schiz Res. 1998; 32: 93-99Summary Full Text Full Text PDF PubMed Scopus (237) Google Scholar

Antipsychotic treatment response is highly heterogeneous and unpredictable in terms of both efficacy and side effects. A combination of factors influences treatment outcome, including clinical, demographic, environmental and genetic factors. No comprehensive studies have quantified the relative contributions of these factors to date. Two decades of pharmacogenetic and pharmacogenomic studies have attempted to identify key gene variants associated with antipsychotic response, with a dual goal of better understanding the mechanisms underlying drug response and guiding prescribing decisions in clinical care. Pharmacogenetic studies have succeeded in identifying several genes that are associated with antipsychotic treatment efficacy or side effects. However, the strength of these associations is modest and they are of limited clinical value. Genome-wide association studies, moving beyond hypothesis-based discovery, have greater potential to identify novel gene associations, although only a few genome-wide association studies have been conducted and they have not revealed clearly significant findings. The first pharmacogenetic tests to guide the selection or dosing of antipsychotic drugs are now commercially available. Their uptake has been limited by the modest level of prediction they offer, compounded by the lack of data supporting their clinical or economic benefits. Advances in genomic analysis techniques, the better characterization of larger subject cohorts and an improved understanding of the role of environmental factors and gene–environment interactions are renewing hope that future research will identify genetic variants with stronger associations with treatment outcome. Tests incorporating such genetic data, with environmental and clinical variables, may offer the potential to personalize medicine and significantly improve the efficacy and tolerability of antipsychotic treatment.

Genetic studies on human personality have provided little satisfactory results to date mainly because of the complexity of this trait. Neonatal temperament using observational measures is an alternative phenotype to approach genetics to human behavior. An association study was conducted on 117 Caucasian newborns. Their temperament was evaluated using the Neonatal Behavior Assessment Scale 48 h after birth. Thirteen polymorphisms in the SLC6A4, DRD4 and TFAP2B genes were genotyped. Linear regression was performed to analyze data, and Bonferroni correction was applied. To check the functional effect of the TFAP2B Indel Intron 2 polymorphism, reporter gene luciferase assays using a mouse cortical neural progenitor cell line and quantitative polymerase chain reaction (qPCR) studies in human post-mortem brain samples were performed. A significant association was found between 5-HTTLPR, 5-HTTLPR + rs25531 and TFAP2B Indel Intron 2 with Range of State cluster as well as an interaction between rs25531 and TFAP2B Indel Intron 2 with Range of State. DRD4 variable number tandem repeat exon 3 was associated with orientation. A 30% increase in the luciferase levels of the TFAP2B 5-repeat alleles compared with the 6-repeat alleles (P-value = 0.03) was found using the pGL3 promoter vector. The qPCR experiments showed the same trend as the in vitro studies, although no significant results were obtained. This study supports a role of the SLC6A4, DRD4 and TFAP2B genes in the temperament, including a gene-gene interaction between SLC6A4 and TFAP2B. It also provides evidence about an effect of the TFAP2B polymorphism in TFAP2B gene transcription.

Pharmacogenetic research into neurotransmitter-related genes is helping to unravel genetic factors that determine antipsychotic response. Several genetic mutations in neurotransmitter receptors targeted by antipsychotic drugs have been found to be related to clinical response. Modern molecular genetic techniques will facilitate the identification of those mutations that determine treatment response. Future psychiatric prescription will include the genetic characterization of neurotransmitter receptors for the selection of the most beneficial drug according to the individual's pharmacogenetic profile.

Abstract The contribution of immune system to schizophrenia has been an important area of focus in schizophrenia research. Several genetic variants in the cytokine system have been associated with the pathogenesis of schizophrenia. The purpose of this study was to determine whether a pharmacogenetic relationship exists between a variable number of tandem repeats (VNTR) polymorphism in the interleukin‐1 receptor antagonist gene ( IL‐1RN ) and clinical improvement during antipsychotic treatment in patients with a first non‐affective psychotic episode. One hundred and fifty‐four subjects presenting with a first non‐affective psychotic episode were randomly assigned to treatment with haloperidol, risperidone, or olanzapine and rated with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) both at baseline and after 6 weeks of treatment. A control sample of 336 blood bank donors was also included. No differences in genotype or allele distributions were found between patients and controls. However, after controlling for baseline SANS scores, the genotype in the VNTR polymorphism in the IL‐1RN gene significantly predicted negative symptom improvement, accounting for approximately 7% of the variance (F = 5.23, df = 2, P = 0.006). The mean decrease in SANS scores was 58% for the IL‐1RN* 2 / 2 , 44% for the IL‐1RN* 1 / 2 , and 14% for the IL‐1RN* 1 / 1 subjects, respectively. These results suggest that the VNTR polymorphism in the IL‐1RN gene may be a useful predictor of negative symptom improvement in schizophrenic patients treated with antipsychotic drugs. © 2006 Wiley‐Liss, Inc.

Acetyl-coenzyme A carboxylase alpha (ACACA) single-nucleotide polymorphism (SNP) (rs2229416) was significantly associated with hypertriglyceridemia, during exploration of antipsychotic direct effects on lipids. Neuropeptide Y (NPY) gene (rs1468271) and ACACB gene (rs2241220) SNPs were significantly associated with severe hypercholesterolemia. In the same sample (173 patients on olanzapine, quetiapine, chlorpromazine or mirtazapine [increasing the risk of hyperlipidemia] and 184 controls taking other antipsychotics), three (rs1266175, rs12453407 and rs9906543) of eight additional ACACA SNPs were significantly associated with hypertriglyceridemia in those taking drugs of interest, but not in controls. Five other ACACA SNPs, three additional NPY SNPs, and seven additional ACACB SNPs were not significant.

This study investigated the possible association of 40 polymorphisms within 4 noradrenergic genes with BPD risk and the modulating effect of childhood trauma on these associations in 481 BPD subjects and 442 controls. COMT rs5993882, DBH rs77905 and SLC6A2 rs1814270 showed associations with BPD, which were modulated by childhood trauma. However, none of these findings survived Bonferroni correction. Further investigation is needed to clarify the involvement of these genes in BPD pathogenesis.

The pathogenesis of IPD remains unknown, especially among middle-aged individuals without risk factors (WRF). The aim of the present study was to investigate the role of single nucleotide polymorphisms (SNP) within key genes involved in innate immune response on IPD susceptibility. Forty-three SNPs within 10 immunological genes were investigated in a cohort of 144 Caucasian IPD patients and 280 ethnically matched controls. The allele distribution of the NFKBIA rs1050851 and NFKBIE rs2282151 variants were associated with IPD susceptibility (χ2 = 4.23, p = 0.04 and χ2 = 5.13, p = 0.02, respectively). Additionally, the genotype distribution of NFKBIZ rs645781 (χ2 = 8.25, p = 0.02) and IL1R1 rs3917254 (χ2 = 6.70, p = 0.04) were also associated with IPD risk. When only IPD-WRF patients were considered; the allele distribution of IL1R1 rs2160227 (χ2 = 5.62, p = 0.03), rs13020778 (χ2 = 5.73, p = 0.02), rs3917267 (χ2 = 3.72, p = 0.05) and IL4 rs2227284 (χ2 = 3.76, p = 0.05) and the genotype distribution of IL10 rs3024509 (χ2 = 7.70, p = 0.02), IL1R1 rs3917254 (χ2 = 13.40, p = 0.001), NFKBIZ rs645781 (χ2 = 13.86, p = 0.001) and rs677011 (χ2 = 9.06, p = 0.01) variants were associated with IPD risk. We found several associations between variants in the IL1R1, IL4, IL10, NFKBIE, NFKBIA, and NFKBIZ genes and risk of IPD. If validated, these biomarkers may help to identify people with higher risk of IPD.

Psychiatric patients demonstrate varied responses to treatment. Consequently, treatment strategies are trial-and-error, which has a negative effect on prognosis and compliance. The aim of pharmacogenomic research is to enable customised drug treatment by identifying variations within multiple candidate genes (those encoding drug-targeted neurotransmitter receptors, transporters and metabolic enzymes) that are likely to confer the inter-individual differences in drug response and development of drug-induced side effects. Pharmacogenetic and pharmacogenomic research to date has identified genetic polymorphisms of dopamine (DA) and serotonin (5-HT) receptor subtypes, the serotonin transporter (5-HTT) and metabolic enzymes (cytochrome P450 [CYP] family) as important contributors to the variability in response to psychiatric drugs and the development of drug-induced side effects such as tardive dyskinesia and weight gain. It is anticipated that technological and methodological advances will provide further candidate genes and refine association analyses of existing candidates, enabling pharmacogenomic research to move towards future treatment regimes that are catered to the individual.

Preterm birth is associated with a range of neurodevelopmental deficits, including corpus callosum (CC) abnormalities, which persist into late adolescence and early adulthood. A common single-nucleotide polymorphism in the catechol-o-methyl transferase (COMT) gene (Val158Met) is associated with cognition and brain structure and may play a role in neurodevelopment. It is not known whether this polymorphism is associated with CC morphometry in individuals born preterm.Structural MRI scans were acquired in 33 adults born very preterm (before 33 weeks' gestation) and 29 healthy controls. DNA was collected and COMT Val158Met polymorphism status determined using standard available assays. The mid-sagittal area of four antero-posterior subdivisions of the CC was measured. The effect of COMT Val158Met polymorphism on cross-sectional CC areas was studied using multivariate analysis and generalised linear models, adjusted for the effects of the clinical sample group (preterm vs. control), age and sex.The COMT Val/Val homozygous genotype was observed to be significantly associated with reduced size of the total corpus callosum, and this relationship was present for the anterior, midposterior and posterior quarters of the CC.The COMT Val158Met polymorphism possibly influences the morphometry of the corpus callosum associated with very preterm births. Further studies with larger sample sizes are warranted to conclusively establish the effects of individual genotypes of the COMT gene on corpus callosum in preterm born adults.

Background Higher prevalence of atherosclerosis and higher cardiovascular risk is observed in HIV-infected individuals. The biological mechanisms underlying these processes are unclear. Several studies have implicated genetic variants in the inflammatory genes in cardiovascular disease and in HIV natural course infection. Methods & Findings In this study we have tested the possible association between genetic variants in several inflammatory genes and asymptomatic cardiovascular disease measured by carotid intima media thickness (cIMT) and atherosclerotic plaque presence as dependent variables in 213 HIV-infected individuals. A total of 101 genetic variants in 25 candidate genes have been genotyped. Results were analyzed using Plink and SPSS statistical packages. We have found several polymorphisms in the genes ALOX5 (rs2115819 p = 0.009), ALOX5AP (rs9578196 p = 0.007; rs4769873 p = 0.004 and rs9315051 p = 0.0004), CX3CL1 (rs4151117 p = 0.040 and rs614230 p = 0.015) and CCL5 (rs3817655 p = 0.018 and rs2107538 p = 0.018) associated with atherosclerotic plaque. cIMT mean has been associated with CRP (1130864 p = 0.0003 and rs1800947 p = 0.008), IL1RN (rs380092 p = 0.002) and ALOX5AP (rs3885907 p = 0.02) genetic variants. Conclusions In this study we have found modest associations between genetic variants in several inflammatory genes and atherosclerotic plaque or cIMT. Nevertheless, our study adds evidence to the association between inflammatory pathway genetic variants and the atherosclerotic disease in HIV-infected individuals.

In spite of the lack of epidemiological information, pharmacogenetic research has produced evidence of the relationship between genes and treatment response. Genetic variants of metabolic enzymes are related to toxic reactions; polymorphisms in genes coding for drug-targeted neurotransmitter receptors influence therapeutic efficacy. Also, recent studies have shown that response to antipsychotic drugs can be predicted by looking at the individual’s pharmacogenetic profile. In addition to providing the first evidence that treatment response can be predicted by looking at a core of key genes, these studies illustrate the feasibility of individualisation of psychiatric treatment.