Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia

We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r(2)>0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P=1.10 × 10(-3) and rs2274736, P=1.21 × 10(-3)). In a meta-analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR=0.92, 95% CI: 0.86-0.97, P=5.45 × 10(-3) and rs2401751, OR=0.92, 95% CI: 0.86-0.97, P=5.29 × 10(-3)). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR=1.08, 95% CI: 1.02-1.14, P=6.43 × 10(-3)). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.     

Meta-analysis of genome-wide association studies for personality

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

5-HT2A SNPs and the Temperament and Character Inventory

Temperamental traits, the most basic part of personality, have been largely correlated with neurotransmitter systems and are under genetic control. Among serotonin candidates, the 2A receptor (5-HT(2A)) received considerable attention. We analyzed four SNPs (rs643627, rs594242, rs6311 and rs6313) in the 5-HT(2A) gene and their association with personality traits, as measured with the Temperament and Character Inventory (TCI). The sample was composed of three sub-groups: two German sub-samples, consisting of a healthy group of 289 subjects (42.6% males, mean age: 45.2+/-14.9) and a psychiatric patient group of 111 suicide attempters (38.7% males, mean age: 39.2+/-13.6), and an Italian sub-sample, composed of 60 mood disorder patients (35.0% males, mean age: 44.0+/-14.8). Controlling for sex, age and educational level, the SNPs were not strongly associated with personality dimensions. Only the rs594242 showed an association with Self-Directedness (p=0.003) in the German sample, while rs6313 was marginally associated with Novelty Seeking (p=0.01) in the Italian sample. We conclude that 5-HT(2A) SNPs may marginally modulate personality traits but further studies are required.     

Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500?kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.     

The role of parental psychopathology and personality in adolescent non-suicidal self-injury

Adolescent non-suicidal self-injury (NSSI), a significant risk factor for suicidal behavior, is strongly associated with adolescent psychopathology and personality traits, particularly those characterized by poor self-regulation. Some parental psychopathology and personality traits have also been identified as risk factors for adolescent NSSI, but specific parental characteristics and mechanisms involved in this association have not been systematically examined. The current study comprehensively investigated the contribution of parental psychopathology and personality to adolescent NSSI using data from the baseline wave of the Adolescent Development of Emotion and Personality Traits (ADEPT) study of 550 adolescent girls (mean age = 14.39 years, SD = 0.63) and their biological parents. We first investigated whether parental lifetime psychiatric diagnoses, and personality and clinical (rumination, self-criticism, emotional reliance) traits were associated with adolescent NSSI. We also tested whether adolescent history of psychiatric illness, personality, and clinical traits mediated the associations between parental characteristics and adolescent NSSI. Parental substance use disorder, adult-ADHD symptoms, self-criticism, and lower agreeableness and conscientiousness were associated with offspring's NSSI. These associations were mediated through adolescent characteristics. In contrast, parental mood and anxiety disorders and neuroticism were unrelated to adolescent NSSI. The results suggest that parental traits and disorders characterized by self-regulatory difficulties and lack of support constitute risk factors for self-injury in adolescent girls, acting via adolescent traits. This demonstrates that parental influences play a significant role in the etiology of adolescent NSSI.     

Low novelty seeking and high self directedness scores in alcohol-dependent patients without comorbid psychiatric disorders homozygous for the A10 allele of the dopamine transporter gene

The gene for the human dopamine transporter DAT1 displays several polymorphisms, including a 40-bp variable number of tandem repeats (VNTR) ranging from 3 to 13 copies in the 3′-untranslated region (UTR) of the gene. Some hints for an association of certain VNTR with psychiatric disorders, behavioural problems and temperament traits have been found. This study explored possible associations between the most frequent DAT1 polymorphism, namely the A10 VNTR, and personality traits as measured by the Temperament and Character Inventory (TCI) and the NEO Five Factor Inventory (NEO-FFI) in alcohol-dependent patients (ADP). One hundred and forty-four ADP and 144 age-, educational level- and sex-matched controls (CO) were genotyped and interviewed with the TCI and NEO-FFI. ADP showed higher neuroticism, lower extraversion, lower openness, lower agreeableness and lower conscientiousness than CO on the NEO-FFI and higher scores in harm avoidance, reward dependence and self transcendence and lower scores in self directedness and cooperativeness on the TCI than controls. There were no genetic links regarding those personality traits, the diagnosis of alcohol dependence and the VNTR. Only in a subgroup of ADP, those without psychiatric co-diagnoses and homozygous for A10, significantly lower scores in novelty seeking and higher scores in self directedness than in all the other ADP and CO could be detected. Summarizing, the 40-bp VNTR did not help to differentiate between ADP and CO, but might contribute to some personality dimensions in certain ADP subgroups.     

Analysis of Four Genes Involved in the Neurodevelopment Shows Association of rs4307059 Polymorphism in the Cadherin 9/10 Region with Completed Suicide

Background: We hypothesized that DNA variants affecting neurodevelopment such as rs4307059 (CDH10/CDH9), rs930752 (NRXN1), rs6265 (BDNF) or rs10868235 (NTRK2) may predispose to completed suicide. Methodology: We used a case-control two-stage approach based on a discovery cohort (557 cases and ～550 controls) and replication cohort (159 cases and 186 controls). The suicides were ascertained as consecutive cases autopsied at the Department of Forensic Medicine, Medical University of Warsaw, Poland. Results: In the discovery cohort we found an association between suicide and the CC genotype in the rs4307059 polymorphism (OR 1.64, p = 0.012). The trend for an overrepresentation of the CC homozygotes among suicides was replicated in the second cohort (OR 1.97, p = 0.056). Analysis in the pooled cohorts showed that rs4307059 CC was associated with completed suicide (OR 1.71, p = 0.002) also after Bonferroni correction (p(cor.) = 0.024). In an exploratory search for genotype-phenotype correlation we found that males with the rs4307059 CC genotype committed suicide earlier than those with CT/TT genotypes (p = 0.049). Conclusions: The CC genotype of rs4307059 located in the region between CDH9 and CDH10 is associated with completed suicide in a Polish cohort.     

散发性肌萎缩侧索硬化单核苷酸多态位点质谱分型及疾病易患性关联分析

目的 肌萎缩侧索硬化(amyotrophic lateral sclerosis,ALS)是由上、下运动神经元进行性丢失引起的一种致死性疾病,散发性ALS(SALS)近90%,目前认为是一种复杂性疾病.已有数个ALS全基因组关联分析研究先后报道了若干与增加ALS发病风险相关的单核苷酸多态(SNP)位点,但亚洲人资料较少.我们将筛查与增加中国人SALS致病风险相关的SNP.方法 提取样本外周血基因组DNA,进行病例组和对照组年龄、性别匹配,质谱法分型筛选出的SNP位点并进行关联分析.结果 完成86例SALS患者与94名对照者rs6700125、rs10260404、rs1942239、rs2279812、rs2405657、rs558889、rs6922711、rs9351470等8个SNP位点的基因分型,统计分析后两组差异无统计学意义.合并Cronin等研究数据后rs1942239(邻近基因GALNT1)的P值减小(由1.48×10-4减少为9.07×10-5),关联性增强.rs558889的病例组基因频率偏离Hardy-Weinberg平衡,可能存在关联.结论 rs1942239和rs558889两个SNP可能与增加中国人SALS致病风险相关,与rs1942239邻近的GALNT1基因和rs558889附近的ANK1基因值得进一步研究.     

DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder

Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73+/-95% confidence interval (CI) 1.42-5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64+/-95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27+/-95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.     

Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression.

BACKGROUND: Suicide and depressive disorders are strongly associated, yet not all depressed patients commit suicide. Genetic factors may partly explain this difference. We investigated whether variation at the tryptophan hydroxylase-2 (TPH2) gene and its 5' upstream region may predispose to suicide in major depressive disorder (MDD) and whether this predisposition is mediated by impulsive-aggressive behaviors (IABs). METHODS: We genotyped 14 single nucleotide polymorphisms (SNPs) in 259 depressed subjects, 114 of which committed suicide while depressed. Phenotypic assessments were carried out by means of proxy-based interviews. Single-marker and haplotype association analyses were conducted. Differences in behavioral and personality traits according to genotypic variation were investigated, as well as genetic and clinical predictors of suicide. RESULTS: We found two upstream and two intronic SNPs associated with suicide. No direct effect of these variants was observed on IABs. However, a slight association with reward dependence scores was found. Controlling for suicide risk factors, two SNPs (rs4448731 and rs4641527) significantly predicted suicide, along with cluster B personality disorders and family history of suicide. CONCLUSIONS: The TPH2 gene and its 5' upstream region variants may be involved in the predisposition to suicide in MDD; however, our findings do not support the role of IABs as mediators.     

COMT genetic variation confers risk for psychotic and affective disorders: a case control study

Background  

Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. We hypothesized that COMT variation may confer a general risk for psychiatric disorders and have genotyped four COMT variants (Val158Met, rs737865, rs165599, and a SNP in the P2 promoter [-278A/G; rs2097603]) in 394 Caucasian cases and 467 controls. Cases included patients with schizophrenia (n = 196), schizoaffective disorder (n = 62), bipolar disorder (n = 82), major depression (n = 30), and patients diagnosed with either psychotic disorder NOS or depressive disorder NOS (n = 24).     

Genetic polymorphisms and personality in healthy adults: a systematic review and meta-analysis

A meta-analysis was conducted on studies reporting data on associations between candidate genes and human personality. Studies reporting data for psychiatric populations (including organic disease and substance abuse) were excluded. A total of 46 studies contributed to the analysis. Pooled data using a fixed-effects model suggested significant associations between the 5HTT LPR, DRD4 c>t, DRD4 length, DRD2 A1/A2, DRD3 A1/A2 polymorphisms and personality traits. A multivariate analysis using a mixed-effects model and including age, sex and predominant ethnicity as covariates was applied to the analyses of 5HTT LPR and DRD4 length polymorphism data. Only the association between the 5HTT LPR polymorphism and avoidance traits remained significant (P=0.038). However, sensitivity analyses excluding data from studies reporting allele frequencies not in Hardy-Weinberg equilibrium and unpublished data resulted in this association no longer being significant. Implications for the design of future association studies of human personality are discussed, including the likely sample sizes that will be required to achieve sufficient power and the potential role of moderating variables such as sex.     

Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism

Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory γ-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI). In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two single-nucleotide polymorphisms (SNPs) and haplotypes were more likely to have alcohol dependence symptoms (rs279858, P=0.01; rs279826, P=0.05; haplotype, P=0.02) and higher NEO Personality Inventory-Revised (NEO-PI-R) Impulsiveness scores (rs279858, P=0.016; rs279826, P=0.012; haplotype, P=0.032) with a stronger effect in women (rs279858, P=0.011; rs279826, P=0.002; haplotype, P=0.006), all P-values are corrected for family history and age. A subset of offspring from these families (n=44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r(2)=0.4; P=0.026) and loss (r(2)=0.38; P=0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (P's<0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.     

Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia

Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ～1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P=7.6 × 10(-11)) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P<0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P=2.0 × 10(-4)), excitability (P=9.0 × 10(-4)) and cell adhesion and trans-synaptic signaling (P=2.4 × 10(-3)). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.     

Catechol-o-methyltransferase gene modulation on suicidal behavior and personality traits: review, meta-analysis and association study

Suicide is one of the leading causes of death among young adults. Both genetic and personality factors plausibly have a role on suicidal behavior. We focused on the catechol-O-methyltransferase gene (COMT) and we performed: a review of studies investigating the association between COMT and both suicidal behavior and personality; a meta-analysis of studies investigating the association between suicidal behavior and COMT rs4680 polymorphism; an association study investigating the link between seven COMT polymorphisms (rs737865, rs5844402, rs5993883, rs4680, rs4633, rs165599 and rs9332377) and both personality traits and suicidal behavior. For the review and the meta-analysis we performed an electronic search to identify studies focused on the association between COMT and both suicidal behavior and personality. The sample of the association study was composed of three groups: 289 German healthy controls, 111 German suicide attempters and 70 Italian mood disorder patients. From the review, the meta-analysis and the association study no relationship emerged between COMT and suicidal behavior. Nevertheless, from both review and association study several links were found between COMT and personality traits. In particular, in the association study we found a significant correlation between rs4633 and Reward Dependence (Temperament and Character Inventory). As secondary results we found an association between rs737865 and Angry Reaction (State-Trait Anger Expression Inventory) and between rs9332377 and Irritability (Questionnaire for Measuring Factors of Aggression). Our findings suggested that COMT variants may not be directly implicated in suicidal behavior, however evidence of a COMT role in the modulation of personality traits has been found.     

Association between corticotropin-releasing hormone receptor 2 (CRHR2) gene polymorphism and personality traits

Corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of anxiety disorders and depression. Corticotropin-releasing hormone receptor 2 (CRHR2) is one of the receptors that mediate CRH signal. The purpose of the present study was to investigate the association between the CRHR2 gene and personality traits, evaluated using the Revised NEO Personality Inventory (NEO PI-R), in 243 healthy Japanese subjects. As a result, significant association was observed between the polymorphism in intron 2 (rs2267717) and Openness (P = 0.004, uncorrected, anova), while no relationship was observed concerning Neuroticism. The present result suggests an association between CRHR2 and the personality trait of Openness.     

Human leukocyte antigen variation and Parkinson's disease

A role for the immune system in the pathogenesis of Parkinson's Disease (PD) has previously been suggested. A recent genome-wide association (GWA) study identified an association between one single nucleotide polymorphism (SNP) in the human leucocyte antigen (HLA) region (HLA-DRA rs3129882) and PD in a population of American patients with European ancestry. In that study, the minor rs3129882 allele (G) was associated with an increased risk of PD under an additive model. Due to the increased likelihood of obtaining false positive results in GWA studies compared to studies conducted based on a hypothesis-driven approach, repeated validation of findings from GWA studies are necessary. Herein, we evaluated the association between rs3129882 and PD in three different Caucasian patient-control series (combined 1313 patients and 1305 controls) from the US, Ireland, and Poland. We observed no association (OR: 0.96, P = 0.50) between rs3129882 and PD when analyzing our data under an additive or dominant model. In contrast, when examined under a recessive model, the GG genotype was observed to be protective in the Irish (OR: 0.55, P = 0.008), Polish (OR: 0.67, P = 0.040) and combined (OR: 0.75, P = 0.006) patient-control series. In view of these diverging results, the exact role of genetic variation at the HLA region and susceptibility to PD remains to be resolved.