Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

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

Three genetic-environmental networks for human personality.

Phylogenetic, developmental, and brain-imaging studies suggest that human personality is the integrated expression of three major systems of learning and memory that regulate (1) associative conditioning, (2) intentionality, and (3) self-awareness. We have uncovered largely disjoint sets of genes regulating these dissociable learning processes in different clusters of people with (1) unregulated temperament profiles (i.e., associatively conditioned habits and emotional reactivity), (2) organized character profiles (i.e., intentional self-control of emotional conflicts and goals), and (3) creative character profiles (i.e., self-aware appraisal of values and theories), respectively. However, little is known about how these temperament and character components of personality are jointly organized and develop in an integrated manner. In three large independent genome-wide association studies from Finland, Germany, and Korea, we used a data-driven machine learning method to uncover joint phenotypic networks of temperament and character and also the genetic networks with which they are associated. We found three clusters of similar numbers of people with distinct combinations of temperament and character profiles. Their associated genetic and environmental networks were largely disjoint, and differentially related to distinct forms of learning and memory. Of the 972 genes that mapped to the three phenotypic networks, 72% were unique to a single network. The findings in the Finnish discovery sample were blindly and independently replicated in samples of Germans and Koreans. We conclude that temperament and character are integrated within three disjoint networks that regulate healthy longevity and dissociable systems of learning and memory by nearly disjoint sets of genetic and environmental influences.

Uncovering the complex genetics of human temperament.

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37-53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.

Uncovering the complex genetics of human character.

Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.

A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study.

Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10-8) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10-05) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

Kynurenine and Tryptophan Levels in Patients With Schizophrenia and Elevated Antigliadin Immunoglobulin G Antibodies.

OBJECTIVE: Several studies have reported an association between nonceliac gluten sensitivity and schizophrenia. Immune and kynurenine (KYN) pathways have also been implicated in the pathophysiology of schizophrenia, and certain proinflammatory immune mediators may increase KYN and reduce tryptophan (TRP) levels. METHODS: We measured serum antigliadin immunoglobulin G (IgG), KYN, and TRP in 950 patients with schizophrenia. Patients with antibody level at the 90th percentile or higher of control participants (21.9% of all patients) were classified as having elevated antigliadin IgG. Independent t tests and linear regression models were used to compare TRP, KYN, and KYN-TRP ratio (indicator of TRP metabolism) between patients with and those without elevated antigliadin IgG. The correlation between antigliadin IgG and TRP, KYN, and the ratio was also evaluated in the patients. RESULTS: KYN and KYN-TRP ratio were higher in patients with elevated antigliadin IgG (geometric mean [standard deviation {SD}] = 2.65 [0.25] µmol/L versus 2.25 [0.23] µmol/L [p < .001] and 0.05 [0.26] versus 0.04 [0.25; p = .001] respectively), findings robust to adjustment for potential demographic and clinical confounders. Antigliadin IgG positively correlated with KYN and KYN-TRP ratio (r = 0.12, p < .001; r = 0.11, p = .002). TRP did not differ between the two groups and did not correlate with antigliadin IgG. CONCLUSIONS: Our results connect nonceliac gluten sensitivity with the KYN pathway of TRP metabolism in psychotic illness and hint toward potential individualized treatment targets.

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium.

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.

Reciprocal moderation by Toxoplasma gondii seropositivity and blood phenylalanine - tyrosine ratio of their associations with trait aggression.

We previously reported that trait aggression, proposed as an endophenotype for suicidal behavior, is positively associated with Toxoplasma gondii (T. gondii) seropositivity in females, but not in males. Additionally, older males seropositive for T. gondii had lower scores on measures of trait aggression, including self-aggression. Trait aggression may be influenced by dopaminergic signaling, which is known to be moderated by gender and age, and potentially enhanced in T. gondii positives through the intrinsic production of dopamine by the microorganism. Therefore, we investigated associations between trait aggression and interactions between T. gondii enzyme-linked immunoabsorbant assay (ELISA) IgG titer-determined seropositivity and high-performance liquid chromatography- (HPLC-) measured blood levels of dopamine precursors phenylalanine (Phe), tyrosine (Tyr), and their ratio in a sample of 1000 psychiatrically healthy participants. Aggressive traits were assessed using the questionnaire for measuring factors of aggression (FAF), the German version of the Buss-Durkee hostility questionnaire. We found that 1) the decrease in trait aggression scores in T. gondii-positive older males was only present in individuals with a low Phe:Tyr ratio, and 2) that there was a positive correlation between Phe:Tyr ratio and total aggression and selected subscales of aggression in T. gondii-positive males, but not in T. gondii-negative males. These findings point toward a gender-specific reciprocal moderation by Phe:Tyr ratio and T. gondii seropositivity of their associations with aggression scores, and lead to experimental interventions geared to manipulating levels of dopamine precursors in selected T. gondii positive individuals with increased propensity for aggression.

Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.

Genome-wide association study supports the role of the immunological system and of the neurodevelopmental processes in response to haloperidol treatment.

AIM: The aim of the study was to detect the genetic predictors of reseponse to haloperidol. BACKGROUND: Haloperidol is a benchmark drug for the pharmacological treatment of schizophrenia, but the genetics of its efficacy is yet to be elucidated. METHODS: A genome-wide association analysis was carried out in a small sample of patients treated with haloperidol (n=96) and the results were replicated in a larger sample of patients treated with second-generation antipsychotics or perphenazine (final n=169, available from the Clinical Antipsychotic Trials for Intervention Effectiveness study). The Positive and Negative Symptom Scale % score decrease was the outcome in both samples. The period of observation was restricted to 1 month in the replication sample and the most severe cases were included to best balance the replication. The quality control (QC) for the investigation and replication sample included a minor allele frequency at least 0.01, call rate at least 0.95, and Hardy-Weinberg equilibrium P at least 0.0001. The source for imputation was the 1000 Genomes Pilot+HapMap 3 dataset. In total 1 080 870 single nucleotide polymorphisms (SNPs) were available after imputation and QC in the investigation sample. After QC of real genotypes, locus-targeted imputations were restricted to windows of 10 kb on either side of the sentinel SNP in the replication sample. Sentinel SNPs were the most significant findings in the investigation sample. Analysis of variance was the test of choice, PLINK, SNPTEST, and GTOOL were used in the analysis. RESULTS: Two SNPs (rs7912580 and rs2412459) were associated with response in both samples, respectively, located in an intergenic region between the AT-rich interactive domain 5B (ARID5B, MRF1-like) gene and rhotekin 2 (RTKN2) gene, an intronic region located in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene (P=1.358e-06 and 0.015 for the Positive and Negative Symptom Scale % total score decrease in the investigation and replication samples, respectively). The direction of association was opposite in the two samples, a finding that is sometimes reported as a flip-flop association. CONCLUSION: Heterozygosis for the ancestral allele was associated with the best improvement in the investigation sample and with poorer outcome in the replication sample. This discrepancy can be because of differences in the replication and investigation sample including the drugs used and the severity at baseline. Nevertheless, this finding is in line with two relevant hypothesis of schizophrenia, related to alterations in the immunological system (RTKN2) and in the neurodevelopment of the central nervous system (EIF2AK4). More studies are warranted to further investigate these associations.

Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory.

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

Influence of differentially expressed genes from suicide post-mortem study on personality traits as endophenotypes on healthy subjects and suicide attempters.

Although a genetic contribution to the complex aetiology of suicidal behaviour has been suggested since many years, the attempt to identify specific genes related to suicide has led to contrasting results. In a post-mortem study on suicide, we previously detected several differentially expressed genes which, however, have not been subsequently associated with suicidal behaviour, or only nominally. Therefore, personality traits may represent good intermediate endophenotypes. Our primary aim was to investigate the potential modulation of several single-nucleotide polymorphisms (SNPs) of the same previously investigated genes (S100A13, EFEMP1, PCDHB5, PDGFRB, CDCA7L, SCN2B, PTPRR, MLC1 and ZFP36) on personality traits, as measured with the Temperament and Character Inventory (TCI), in a German sample composed of 287 healthy subjects (males: 123, 42.9 %; mean age: 45.2 ± 14.9 years) and in 111 psychiatric patients who attempted suicide (males: 43, 38.6 %; mean age: 39.2 ± 13.6 years). Multivariate analysis of covariance was used to test possible influence of single SNPs on TCI scores. Genotypic, allelic and haplotypic analyses have been performed. Controlling for sex, age and educational level, genotypic analyses showed a modulation of EFEMP1 rs960993 and rs2903838 polymorphisms on both harm avoidance and self-directedness in healthy subjects. Interestingly, we could replicate these associations in haploblocks within controls (p < 0.0001) and in the independent sample of suicide attempters for harm avoidance (p < 0.00001), a phenotype highly associated with suicidal behaviour. This study suggests that EFEMP1 SNPs, never investigated in association with suicidal behaviour and related personality, could be involved in its modulation in healthy subjects as well as in suicide attempters.

MAOA and MAOB polymorphisms and anger-related traits in suicidal participants and controls.

MAOA and, to a lesser extent, MAOB polymorphisms have been related to aggression traits and suicidality. We aimed to investigate the role of MAOA and MAOB in suicidal versus non-suicidal participants and interactions between genetic variation and suicidal status on aggression and anger-related traits. The sample was composed of three groups: one group of suicide attempters (n = 171, males 35.1 %), one group of suicide completers (n = 90, males 57.8 %) and a healthy control group (n = 317, males 43.8 %). We examined the following markers: MAOA rs909525, rs6323, and rs2064070, and MAOB rs1799836. Anger traits were measured with the state-trait anger expression inventory (STAXI) and aggression traits with the questionnaire for measuring factors of aggression (FAF). Associations were separately examined for males and females. Variation in the three MAOA variants was associated with higher levels of anger expressed outwards (STAXI "anger-out" subscale) in male suicidal patients compared to controls (p < 0.001). In females, the C allele of rs6323 showed higher scores on the same subscale ("anger out") (p = 0.002). Allele frequencies of the MAOA rs909525 were associated with suicidality (p < 0.007). Our findings show an association between genetic variation in three polymorphisms of the MAOA and anger traits in suicidal males and one replication for the functional variant rs6323 in females. This relationship was stronger than a direct genetic association with suicide status. Future studies incorporating endophenotypic measures of anger and aggression in suicidal participants are warranted.

Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol.

The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation.

Lack of association of the 5-HT(3A) receptor with schizophrenia.

The serotonin type 3 (5-HT(3) ) receptor (R) belongs to the family of ligand-gated ion channels. It is supposed to play an important role in the pathogenesis of schizophrenia and might also represent an interesting target for the pharmacological treatment of this disorder. In this study, we searched for variations within the 5-HT(3A) receptor gene which might be specifically associated to schizophrenia. Twenty-nine single nucleotide polymorphisms (SNPs) of 943 schizophrenic patients compared to 2,343 healthy individuals were analyzed. SNPs were selected taking into account previous results on a 5-HT(3A) receptor domain involved in neuroleptic binding. Dominant logistic and linear regression models were calculated for the phenotypes number of hospitalizations, duration of hospitalization, age at onset and case-control. The data did not show significant associations of any SNP under investigation specific for schizophrenic patients. In conclusion, our study does not support the hypothesis that the 5-HT(3A) receptor plays a major role in the pathogenesis of schizophrenia.

Genome-wide association uncovers shared genetic effects among personality traits and mood states.

Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome-wide SNP (~2.5 million) and gene-based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of mood states using genetic polygenic scores for personality. Measures of neuroticism, extraversion, and symptoms of anxiety, depression, and general psychological distress were collected in eight European cohorts (n ranged 546-1,338; maximum total n = 6,268) whose mean age ranged from 55 to 79 years. Meta-analysis of the cohort results was performed, with follow-up associations of the top SNPs and genes investigated in independent cohorts (n = 527-6,032). Suggestive association (P = 8 × 10(-8)) of rs1079196 in the FHIT gene was observed with symptoms of anxiety. Other notable associations (P < 6.09 × 10(-6)) included SNPs in five genes for neuroticism (LCE3C, POLR3A, LMAN1L, ULK3, SCAMP2), KIAA0802 for extraversion, and NOS1 for general psychological distress. An association between symptoms of depression and rs7582472 (near to MGAT5 and NCKAP5) was replicated in two independent samples, but other replication findings were less consistent. Gene-based tests identified a significant locus on chromosome 15 (spanning five genes) associated with neuroticism which replicated (P < 0.05) in an independent cohort. Support for common genetic effects among personality and mood (particularly neuroticism and depressive symptoms) was found in terms of SNP association overlap and polygenic score prediction. The variance explained by individual SNPs was very small (up to 1%) confirming that there are no moderate/large effects of common SNPs on personality and related traits.

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.