Modeling prior information of common genetic variants improves gene discovery for neuroticism.

Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remain unclear. Inconsistent genetic variants identified by different genome-wide association studies (GWAS) may be attributable to low statistical power. We proposed a novel framework to improve the power for gene discovery by incorporating prior information of single nucleotide polymorphisms (SNPs) and combining two relevant existing tools, relative enrichment score (RES) and conditional false discovery rate (FDR). Here, SNP's conditional FDR was estimated given its RES based on SNP prior information including linkage disequilibrium (LD)-weighted genic annotation scores, total LD scores and heterozygosity. A known significant locus in chromosome 8p was excluded before estimating FDR due to long-range LD structure. Only one significant LD-independent SNP was detected by analyses of unconditional FDR and traditional GWAS in the discovery sample (N = 59 225), and notably four additional SNPs by conditional FDR. Three of the five SNPs, all identified by conditional FDR, were replicated (P < 0.05) in an independent sample (N = 170 911). These three SNPs are located in intronic regions of CADM2, LINGO2 and EP300 which have been reported to be associated with autism, Parkinson's disease and schizophrenia, respectively. Our approach using a combination of RES and conditional FDR improved power of traditional GWAS for gene discovery providing a useful framework for the analysis of GWAS summary statistics by utilizing SNP prior information, and helping to elucidate the links between neuroticism and complex diseases from a genetic perspective.

Shared and specific genetic risk factors for lifetime major depression, depressive symptoms and neuroticism in three population-based twin samples.

BACKGROUND: Vulnerability to depression can be measured in different ways. We here examine how genetic risk factors are inter-related for lifetime major depression (MD), self-report current depressive symptoms and the personality trait Neuroticism. METHOD: We obtained data from three population-based adult twin samples (Virginia n = 4672, Australia #1 n = 3598 and Australia #2 n = 1878) to which we fitted a common factor model where risk for 'broadly defined depression' was indexed by (i) lifetime MD assessed at personal interview, (ii) depressive symptoms, and (iii) neuroticism. We examined the proportion of genetic risk for MD deriving from the common factor v. specific to MD in each sample and then analyzed them jointly. Structural equation modeling was conducted in Mx. RESULTS: The best fit models in all samples included additive genetic and unique environmental effects. The proportion of genetic effects unique to lifetime MD and not shared with the broad depression common factor in the three samples were estimated as 77, 61, and 65%, respectively. A cross-sample mega-analysis model fit well and estimated that 65% of the genetic risk for MD was unique. CONCLUSION: A large proportion of genetic risk factors for lifetime MD was not, in the samples studied, captured by a common factor for broadly defined depression utilizing MD and self-report measures of current depressive symptoms and Neuroticism. The genetic substrate for MD may reflect neurobiological processes underlying the episodic nature of its cognitive, motor and neurovegetative manifestations, which are not well indexed by current depressive symptom and neuroticism.

Is there an association between NPY and neuroticism?

Psychiatric genetics has been hampered by the fact that initially exciting findings from underpowered studies are so often not replicated in larger, more powerful, data sets. Here we show that the claims of Zhou et al. that neuropeptide Y (NPY) diplotype-predicted expression is correlated with trait anxiety (neuroticism) is not replicated in a data set consisting of phenotypically extreme individuals drawn from a large (n = 88,142) non-clinical population. We found no association between NPY diplotype or diplotype-predicted expression and neuroticism. Our reply to Zhou and colleagues forms part of a larger debate (see, for example, http://www.nature.com/news/2008/080709/full/454154a.html) about the efficacy and replicability of candidate driven versus genome wide approaches to psychiatric genetics.

What can we learn from twin studies? A comprehensive evaluation of the equal environments assumption.

Twin studies are a major source of information about genetic effects on behavior, but they depend on a controversial assumption known as the equal environments assumption (EEA): that similarity in co-twins' environments is not predictive of similarity in co-twin outcomes. Although evidence has largely supported the EEA, critics have claimed that environmental similarity has not been measured well, and most studies of the EEA have focused on outcomes related to health and psychology. This article addresses these limitations through (1) a reanalysis of data from the most cited study of the EEA, Loehlin and Nichols (1976), using better measures, and through (2) an analysis of nationally representative twin data from MIDUS using more comprehensive controls on a wider variety of outcomes than previous studies. Results support a middle ground position; it is likely that the EEA is not strictly valid for most outcomes, but the resulting bias is likely modest.

Genetic co-morbidity between neuroticism, anxiety/depression and somatic distress in a population sample of adolescent and young adult twins.

BACKGROUND: Genetic studies in adults indicate that genes influencing the personality trait of neuroticism account for substantial genetic variance in anxiety and depression and in somatic health. Here, we examine for the first time the factors underlying the relationship between neuroticism and anxiety/depressive and somatic symptoms during adolescence. METHOD: The Somatic and Psychological Health Report (SPHERE) assessed symptoms of anxiety/depression (PSYCH-14) and somatic distress (SOMA-10) in 2459 adolescent and young adult twins [1168 complete pairs (35.4% monozygotic, 53% female)] aged 12-25 years (mean=15.5 ± 2.9). Differences between boys and girls across adolescence were explored for neuroticism, SPHERE-34, and the subscales PSYCH-14 and SOMA-10. Trivariate analyses partitioned sources of covariance in neuroticism, PSYCH-14 and SOMA-10. RESULTS: Girls scored higher than boys on both neuroticism and SPHERE, with SPHERE scores for girls increasing slightly over time, whereas scores for boys decreased or were unchanged. Neuroticism and SPHERE scores were strongly influenced by genetic factors [heritability (h(2)) = 40-52%]. A common genetic source influenced neuroticism, PSYCH-14 and SOMA-10 (impacting PSYCH-14 more than SOMA-10). A further genetic source, independent of neuroticism, accounted for covariation specific to PSYCH-14 and SOMA-10. Environmental influences were largely specific to each measure. CONCLUSIONS: In adolescence, genetic risk factors indexed by neuroticism contribute substantially to anxiety/depression and, to a lesser extent, perceived somatic health. Additional genetic covariation between anxiety/depressive and somatic symptoms, independent of neuroticism, had greatest influence on somatic distress, where it was equal in influence to the factor shared with neuroticism.

Substantial genetic overlap between schizotypy and neuroticism: a twin study.

Schizotypy is phenotypically associated with neuroticism. To reveal the origin of this association, we assessed 3,349 (1,449 monozygotic, 1,105 dizygotic [DZ] same-sex and 795 DZ opposite-sex) twins on a 12-item version of Chapman's Psychosis-Proneness Scales and the short form of the Eysenck Personality Questionnaire-Revised as measures of schizotypy and neuroticism. A substantial proportion (0.51 with 95 % CI from 0.38 to 0.64) of the phenotypic correlation of 0.37 between neuroticism and the perceptual and ideational components of schizotypy was accounted for by shared genetic influences on these two traits. Moreover, a Cholesky decomposition including anhedonia, hypomania and impulsivity fully accounted for the heritable variance in perceptual and ideational components of schizotypy. These findings suggest a shared genetic etiology between neuroticism and perceptual and ideational components of schizotypy and affect future investigations on the etiology of these phenotypically overlapping traits and affective and psychotic disorders.

Gene by neuroticism interaction and cognitive function among older adults.

OBJECTIVES: Both apolipoprotein E (ApoE) ε-4 allele(s) and elevated trait neuroticism, the tendency to experience distress, are associated with cognitive function among older adults. We predicted that neuroticism moderates the association between ApoE and cognitive function and also explored whether other personality dimensions (openness to experience, agreeableness, extraversion, and conscientiousness) affect the association between ApoE status and cognitive function. METHOD: Five-hundred and ninety-seven older adults (mean age of 78 years) enrolled in the Ginkgo Evaluation of Memory study completed the NEO five-factor inventory of personality. Cognitive function was assessed via the cognitive portion of the Alzheimer's Disease Assessment Scale, and a blood sample for ApoE genotyping was drawn. RESULTS: As hypothesized, regression analysis indicated that neuroticism moderated the relationship between the presence of ApoE ε-4 and cognitive function. Individuals with high neuroticism scores had significantly lower scores on the cognitive portion of the Alzheimer's Disease Assessment Scale compared with individuals with low neuroticism scores, but this was true only among carriers of ApoE ε-4 (interaction effect ß = 0.124, p = 0.028). There was scant evidence that other personality dimensions moderate the association between ApoE ε-4 and cognitive function. CONCLUSIONS: Cognitive function may be affected by ApoE and neuroticism acting in tandem. Research on the underlying physiological mechanisms by which neuroticism amplifies the effect of ApoE ε-4 is warranted. The study of genotype by phenotype interactions provides an important and useful direction for the study of cognitive function among older adults and for the development of novel prevention programs.

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.

Genetic variants in the catechol-o-methyltransferase gene are associated with impulsivity and executive function: relevance for major depression.

The catechol-o-methyltransferase (COMT) gene has been extensively investigated in depression with somewhat contradictory results but the role of impulsivity, as a possible intermediate phenotype in this disorder, has not been considered yet. In our study, four tagging SNPs in the COMT gene (rs933271, rs740603, rs4680, rs4646316) were genotyped in two independent population cohorts: Manchester (n = 1267) and Budapest (n = 942). First, we investigated the association between COMT genotypes, impulsivity, neuroticism and depression using haplotype trend regression, and constructed a model using structural equation modeling to investigate the interaction between these factors. Secondly, we tested the effect of executive function on this model in a smaller interviewed sample (n = 207). Our results demonstrated that COMT haplotypes were significantly associated with impulsivity in the combined cohort, showing the same direction of effects in both populations. The COMT effect on depressive symptoms (in subjects without history of depression) and on executive function (interviewed sample) showed the opposite pattern to impulsivity. Structural equation models demonstrated that COMT and impulsivity acted, both together (through neuroticism) and independently, to increase the risk of depression. In addition, better executive function also operated as a risk factor for depression, possibly though reduced ability to flexibly disengage negative emotions. In conclusion, variations in the COMT gene exert complex effects on susceptibility to depression involving various intermediate phenotypes, such as impulsivity and executive function. These findings emphasise that modeling of disease pathways at phenotypic level are valuable for identifying genetic risk factors.

Genetic and environmental influences on internalizing psychopathology vary as a function of economic status.

BACKGROUND: Different theories of the link between socio-economic status (SES) and mental illness have been postulated. In particular, two theories of this association, social causation and social selection, differ in the implied causal pathway. The authors employ behavior genetic modeling to consider evidence for both social selection and social causation in the relationship between income variation and internalizing disorders. METHOD: Behavior genetic modeling was used to estimate the presence of gene-environment interaction (GxE, social causation) in the presence of gene-environment correlation (rGE, social selection). Participants were members of a sample of 719 twin pairs from the Midlife in the United States study. Four internalizing (INT) syndromes were assessed: major depression (MD); generalized anxiety disorder (GAD); panic attacks (PA); neuroticism (N). SES was measured with total family household income. RESULTS: One factor best accounted for the variance shared between MD, GAD, PA and N. The etiology of variation in INT changed from high to low levels of income, with unique environmental factors playing a larger role in INT variation at lower levels of income. Across levels of income, rGE between income and INT was modest (low income ra=0.39 to high income ra=0.54), implying a selection process operating through genetic effects linking lower income with INT psychopathology. CONCLUSIONS: Findings support social causation by suggesting that low income contributes significantly to environmental variation in INT. Modest support was found for social selection, but should be extended using longitudinal designs. Effective interventions for internalizing psychopathology may differ depending on income.

Effects of acute psychosocial stress exposure on endocrine and affective reactivity in college students differing in the 5-HTTLPR genotype and trait neuroticism.

Enhanced stress vulnerability has been implicated in the pathogenesis of affective disorders. Although both genetic (5-HTTLPR) and cognitive (neuroticism) factors are known to increase stress vulnerability, no experimental study has investigated the interaction between these two factors on psychobiological reactivity following acute stress exposure. This study used a balanced experimental design to examine the interaction between the 5-HTTLPR genotype and trait neuroticism in neuroendocrine and affective stress responses. From a large group of 771 students, 48 carriers of the short/short (S/S) allele and 48 carriers of the long/long (L/L) allele with the lowest and the highest neuroticism scores (77 females, 19 males; mean age ± SD: 20.6 ± 2 years) were selected and exposed to an acute psychosocial stressor. Mood was assessed before and after the stressor, and salivary cortisol concentrations were measured before and at 20, 30, and 60 min after stressor onset. Acute stress increased salivary cortisol concentration regardless of either 5-HTTLPR genotype or neuroticism, but it caused a less profound negative mood change in L/L compared to S/S-allele carriers with the lowest neuroticism scores. The 5-HTTLPR genotype influences affective reactivity to acute stress conditional upon neuroticism, improving resilience to acute stress in L/L-allele carriers if they do not already possess high cognitive-affective (neuroticism) vulnerability.

Moderation of the association between childhood maltreatment and neuroticism by the corticotropin-releasing hormone receptor 1 gene.

BACKGROUND: Neuroticism is a personality trait reflecting the tendency to experience negative affect. It is a major risk for psychopathology, especially depression and anxiety disorders. Childhood maltreatment is another major risk factor for psychopathology and may influence personality. Maltreatment may interact with genotype to predict developmental outcomes. Variation in three polymorphisms of the CRHR1 gene has been found to moderate the association of childhood maltreatment with depression, and we hypothesized that it would also be linked to neuroticism. METHODS: Variation in three CRHR1 SNPs (rs110402, rs242924, rs7209436) was assessed in 339 maltreated and 275 demographically similar nonmaltreated children, who participated in a day camp research program. Maltreated children were further categorized based on the number of types of maltreatment they had experienced and the most severe form of maltreatment experienced. Genotype and maltreatment status were used to predict the Big Five personality traits, as assessed by camp counselors following a week of interaction with children. RESULTS: CRHR1 genotype significantly moderated the association of maltreatment with neuroticism but none of the other traits. Having two copies of the TAT haplotype of CRHR1 was associated with higher levels of neuroticism among maltreated children relative to nonmaltreated children, with the exception of sexually abused children and children who had experienced 3 or 4 types of abuse. Effects sizes of these interactions ranged from η2=.01 (p=.02) to η2=.03 (p=.006). CONCLUSIONS: Variation in CRHR1 moderates the association of maltreatment with neuroticism. The effects of specific types of maltreatment on neuroticism are differentially moderated by CRHR1 genotype, as are the effects of experiencing more or fewer types of maltreatment.

A role for the DRD4 exon III VNTR in modifying the association between nicotine dependence and neuroticism.

INTRODUCTION: Neurotic psychopathology has been extensively examined as a risk factor for nicotine dependence (ND). Genetic stratification may partially explain variability in risk estimates. Genetic variants that compromise dopaminergic neurotransmission may motivate exposure to dopamine-stimulating agents, including nicotine. The 7-repeat allele of a Variable Number Tandem Repeat (VNTR) polymorphism in DRD4 (and evolutionary derivatives 5, 6, and 8 repeats; 7R+) is associated with reduced dopamine receptor function. The purpose of this study was to examine association between both smoking initiation (SI) and progression to ND by young adulthood and (a) history of neuroticism during adolescence, (b) DRD4 7R+, and (c) interaction between neuroticism and DRD4 7R+. METHODS: Participants were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of young Australians across 8 waves (14-24 years). Neuroticism was measured at Waves 3 and 6 (mean 15.9 and 17.4 years). SI was defined as any smoking at any wave. ND was measured at Wave 8 (mean 24.1 years). Genotype data for the DRD4 VNTR were available for 839 participants. RESULTS: While adolescent neuroticism was associated with SI, evidence for association with progression to ND was weak. However, there was evidence of interaction between neuroticism and DRD4 7R+: The odds of progression to ND among those with a history of neuroticism were more than 3.5-fold higher among 7R+ carriers. CONCLUSIONS: Without considering stratification by 7R+, the association between progression to ND and neuroticism would have been assumed barely significant. However, among those carrying DRD4 7R+, risk of progression was considerably intensified.

Neuroticism explained? From a non-informative vulnerability marker to informative person-context interactions in the realm of daily life.

OBJECTIVES: Despite the well-replicated finding that neuroticism is associated with increased susceptibility for psychopathology, it remains unclear what 'vulnerability as indexed by neuroticism' represents in terms of everyday life emotional processes. This study examined the association between neuroticism and six phenotypes of daily life emotional responses: positive affect (PA), negative affect (NA), PA variability, NA variability, stress sensitivity, and reward experience, and investigated the contribution of genetic and environmental factors to these associations. DESIGN: A prospective cohort study in a population-based sample of 416 adult female twins. METHOD: A momentary assessment approach (experience sampling method) was used to collect multiple assessments of affect in daily life. Neuroticism was assessed with the Eysenck Personality Scale. Multi-level regression analyses were carried out to examine the association between neuroticism and the phenotypes of daily life emotional responses. Cross-twin, cross-trait analyses, and bivariate structural equation modelling (SEM) were performed in order to investigate the nature of these associations. RESULTS: A high neuroticism score was associated with lower momentary PA levels and increased NA variability, independent of momentary NA, PA variability, stress sensitivity, and reward experience. Both the cross-twin, cross-trait analyses, and the bivariate SEM showed that unique, non-shared environmental factors drive the association between neuroticism and PA and that the association between neuroticism and increased NA variability is based on shared genetic factors as well as individual-specific environmental factors. CONCLUSIONS: Neuroticism as measured by Eysenck questionnaire may index an environmental risk for decreased daily life PA levels and a genetic as well as an environmental risk for increased NA variability. Decomposing the broad measure of neuroticism into measurable persons-context interactions increases its 'informative' value in explaining psychopathology.

The genetic and environmental relationship between major depression and the five-factor model of personality.

BACKGROUND: Certain personality traits have long been suspected to reflect an enduring vulnerability to major depression (MD) in part because of shared genetic risk factors. Although many have agreed that normative personality is well captured by the 'Big-Five' personality traits of Openness (O), Conscientiousness (C), Extraversion (E), Agreeableness (A) and Neuroticism (N), to date genetically informative studies have only examined the relationship between MD and N and E. METHOD: Questionnaires were completed on a website, yielding a sample of 44 112 subjects including both members of 542 same-sex twin pairs. Personality was measured by the Big Five Inventory. Structural modeling was performed by Mx. RESULTS: Three of the big-five personality traits--O, E and A--had small phenotypic associations with risk for MD and small genetic correlations. Two traits--N and C--had stronger phenotypic associations (positive for N and negative for C) with the following estimates of the genetic correlation with MD: +0.43 for N and -0.36 for C. N and C were moderately negatively correlated. Controlling for N reduced the genetic correlation between C and MD more than controlling for C reduced the genetic correlation between N and MD. CONCLUSIONS: A large proportion of the genetic risk for MD that is expressed via personality is captured by N, with a modest amount due to C, and small amounts from O, E and A.

Genetic contribution to the relationship between personality and depressive symptoms among older women.

BACKGROUND: Prior studies suggest that certain types of personality are at higher risk for developing depressive disorders. This study examined the relationship between old age depressive symptoms and two middle-age personality dimensions, neuroticism and extraversion. METHOD: The present study is part of the Finnish Twin Study on Aging, where altogether 409 female twins who had completed the Eysenck Personality Inventory at the age of 38-51 years were studied for depressive symptoms 28 years later using Center for the Epidemiologic Studies Depression Scale. Logistic regression analysis suitable for dependent data and univariate and Cholesky models for decomposing the genetic and environmental factor were used. RESULTS: Middle age extraversion protected from later depressive symptoms while neuroticism increased the risk. Twin modeling indicated that the association between neuroticism and depressive symptoms resulted from shared genetic risk factors common to both traits. However, a substantial proportion of the genetic vulnerability was specific to old age depressive symptoms and was not shared with neuroticism. Middle age extraversion had no genetic relationship with old age depressive symptoms. CONCLUSIONS: The relationship between middle age neuroticism and old age depressive symptoms is strong but only partly the result of genetic factors that predispose to both neuroticism and depressive symptoms. Extraversion, by contrast, has no genetic relationship with depressive symptoms experienced in old age.

The serotonin transporter gene length polymorphism (5-HTTLPR) and life events: no evidence for an interaction effect on neuroticism and anxious depressive symptoms.

The finding of a significant gene by environment interaction effect on depression of the serotonin transporter length polymorphism (5-HTTLPR) and the Number of experienced Life Events (NLE) was not replicated in two large meta-analyses (Munafo et al., 2009; Risch et al., 2009). These meta-analyses have been criticized on the grounds that large studies that get most weight in meta-analyses have the poorest measurement quality of life events and, as a consequence, do not find an effect. Another issue is the time frame across which the NLE are measured. Proximal life events appear to be better predictors of depression than more distal events. We present the results of analyses of the 5-HTTLPR × NLE effect on anxious depression and neuroticism scores in a sample of 1,155 twins and their parents and siblings from 438 families. The interaction effect was tested separately for NLE experienced across the life span and NLE experienced in the past year. There was a significant main effect of NLE on anxious depression and neuroticism, especially when these were experienced in the past year. No interaction with 5-HTTLPR was found for NLE either experienced across the life span or across the past year. Our results support the two recent meta-analyses. Given recent insights from genome wide association studies, it seems more useful to focus on the joint effect of several genes, that are, for example, part of the same biological pathway, in interaction with the environment, than on one candidate gene.

Neuroticism-related personality traits are related to symptom severity in patients with premenstrual dysphoric disorder and to the serotonin transporter gene-linked polymorphism 5-HTTPLPR.

Neuroticism has been linked to a functional polymorphism in the serotonin transporter gene (5-HTTLPR), with short-allele carriers being overrepresented among high-scorers on neuroticism. Studies evaluating neuroticism-related personality traits in relation to the 5-HTTLPR polymorphism among patients with premenstrual dysphoric disorder (PMDD) and are lacking. The primary aim of this study was to evaluate the relationship between PMDD and neuroticism-related personality traits, and secondly, to relate the personality trait scores of PMDD patients to experienced symptom severity and to the 5-HTTLPR short allele. Thirty PMDD patients and 55 asymptomatic healthy controls were included in the study. The Swedish Universities Scale of Personality was used to evaluate personality traits. Genotype analyses were available in 27 PMDD patients and 18 healthy controls. Women with PMDD displayed higher levels of neuroticism-related personality traits (psychic trait anxiety, somatic trait anxiety, embitterment, stress susceptibility and mistrust) than healthy controls, and these effects were most prominent in women with more severe luteal phase symptoms. Furthermore, PMDD patients with at least one copy of the short allele of the 5-HTTLPR polymorphism scored higher on psychic trait anxiety and lack of assertiveness than PMDD patients who were homozygous for the long allele. PMDD patients who suffer from more severe luteal phase symptoms also display increased scores of neuroticism-related personality traits in comparison with healthy controls. Within the group of PMDD patients, differences in certain personality trait scores are associated with the short allele of the 5-HTTLPR polymorphism.

A whole genome association study of neuroticism using DNA pooling.

We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from approximately 2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had approximately 80% power to identify neuroticism loci in the genome with odds ratio (OR)>2, and approximately 50% power to identify small effects (OR=1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex.

Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.

Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.