Genome-wide association study identifies 74 loci associated with educational attainment.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Interpreting Behavior Genetic Models: Seven Developmental Processes to Understand.

Behavior genetic findings figure in debates ranging from urgent public policy matters to perennial questions about the nature of human agency. Despite a common set of methodological tools, behavior genetic studies approach scientific questions with potentially divergent goals. Some studies may be interested in identifying a complete model of how individual differences come to be (e.g., identifying causal pathways among genotypes, environments, and phenotypes across development). Other studies place primary importance on developing models with predictive utility, in which case understanding of underlying causal processes is not necessarily required. Although certainly not mutually exclusive, these two goals often represent tradeoffs in terms of costs and benefits associated with various methodological approaches. In particular, given that most empirical behavior genetic research assumes that variance can be neatly decomposed into independent genetic and environmental components, violations of model assumptions have different consequences for interpretation, depending on the particular goals. Developmental behavior genetic theories postulate complex transactions between genetic variation and environmental experiences over time, meaning assumptions are routinely violated. Here, we consider two primary questions: (1) How might the simultaneous operation of several mechanisms of gene-environment (GE)-interplay affect behavioral genetic model estimates? (2) At what level of GE-interplay does the 'gloomy prospect' of unsystematic and non-replicable genetic associations with a phenotype become an unavoidable certainty?

Predicting Cognitive Executive Functioning with Polygenic Risk Scores for Psychiatric Disorders.

Executive functions (EFs) have been proposed as an endophenotype for psychopathology because EF deficits are associated with most psychiatric disorders. To examine this hypothesis, we derived polygenic risk scores for autism, attention-deficit/hyperactive disorder (ADHD), bipolar disorder, major depression (MDD), and schizophrenia, using genome-wide data from the Psychiatric Genomics Consortium as discovery samples. We then examined the relationships between these polygenic risk scores and three separable EF components measured with a latent variable model. We also examined the relationship between genetic risk for ADHD and MDD and their respective symptom counts and lifetime diagnoses. We found no evidence for larger effect sizes for EFs as endophenotypes for psychiatric disorders. However, larger sample sizes will be important in examining this relationship further.

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method.

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

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.

Genome-Wide Association Study of Behavioral Disinhibition in a Selected Adolescent Sample.

Behavioral disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs (p = 0.06). Gene-based tests identified seven genes associated with BD (p ≤ 2.0 × 10(-6)). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD.

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.

Basic or Adaptation: The Assessment and Heritability of a Brief Measure of Agency.

The interpersonal circumplex describes two major axes of personality that guide much of social behavior. Agency, one half of the interpersonal circumplex, refers to relatively stable behavioral patterns that center on self-focused dominance and assertiveness. Past empirical work on agency tends to treat the dimension as a characteristic adaptation, rather than a basic component of personality, in part due to the relatively large gender difference in agency with masculine individuals tending to behave more agentic. However, the psychometric overlap between agency and the most closely linked big five dimension, extraversion, is not well-established, and no behavior genetic work has documented evidence concerning the role of genetic and environmental influences. It is unclear whether agency is more similar to a personality trait, with no evidence of shared environmental influence and moderate heritability, or a characteristic adaptation, with some evidence for shared environmental influence and possibly lower heritability. We used the Midlife Development in the United States study to examine agency, big five, and generativity with replication and robustness check (Nnon-twins = 5,194; Ntwins = 1,914; NMilwaukee = 592). Results indicated that agency was higher in men (d = -.24), moderately heritable (44.4%), strongly correlated with extraversion (r = .51), moderately correlated with generativity (r = .36), and that approximately 40% of the variance in agency was shared with the big five. Agency also changed strongly with extraversion and openness, but less so generativity. Altogether, these results indicate that agency functions similar to other basic personality dimensions but is not clearly a dispositional trait.

The aggregate effect of dopamine genes on dependence symptoms among cocaine users: cross-validation of a candidate system scoring approach.

Genome-wide studies of psychiatric conditions frequently fail to explain a substantial proportion of variance, and replication of individual SNP effects is rare. We demonstrate a selective scoring approach, in which variants from several genes known to directly affect the dopamine system are considered concurrently to explain individual differences in cocaine dependence symptoms. 273 SNPs from eight dopamine-related genes were tested for association with cocaine dependence symptoms in an initial training sample. We identified a four-SNP score that accounted for 0.55% of the variance in a separate testing sample (p = 0.037). These findings suggest that (1) limiting investigated SNPs to those located in genes of theoretical importance improves the chances of identifying replicable effects by reducing statistical penalties for multiple testing, and (2) considering top-associated SNPs in the aggregate can reveal replicable effects that are too small to be identified at the level of individual SNPs.

Longevity candidate genes and their association with personality traits in the elderly.

Human longevity and personality traits are both heritable and are consistently linked at the phenotypic level. We test the hypothesis that candidate genes influencing longevity in lower organisms are associated with variance in the five major dimensions of human personality (measured by the NEO-FFI and IPIP inventories) plus related mood states of anxiety and depression. Seventy single nucleotide polymorphisms (SNPs) in six brain expressed, longevity candidate genes (AFG3L2, FRAP1, MAT1A, MAT2A, SYNJ1, and SYNJ2) were typed in over 1,000 70-year old participants from the Lothian Birth Cohort of 1936 (LBC1936). No SNPs were associated with the personality and psychological distress traits at a Bonferroni corrected level of significance (P < 0.0002), but there was an over-representation of nominally significant (P < 0.05) SNPs in the synaptojanin-2 (SYNJ2) gene associated with agreeableness and symptoms of depression. Eight SNPs which showed nominally significant association across personality measurement instruments were tested in an extremely large replication sample of 17,106 participants. SNP rs350292, in SYNJ2, was significant: the minor allele was associated with an average decrease in NEO agreeableness scale scores of 0.25 points, and 0.67 points in the restricted analysis of elderly cohorts (most aged >60 years). Because we selected a specific set of longevity genes based on functional genomics findings, further research on other longevity gene candidates is warranted to discover whether they are relevant candidates for personality and psychological distress traits.

Exploring the utility of current polygenic scores in capturing resilience.

Although resilience has been identified to be moderately heritable, little is known about the genetic variants involved. While there has not yet been a robust genome-wide association study (GWAS) of resilience, existing GWAS of related phenotypes may provide a starting point for developing our understanding of the heritability of resilience. In a sample of older, US adults (N = 9480), we examined the extent to which proxy polygenic scores (PGS) explained the variance in resilience. Four of the 32 PGS assessed (subjective wellbeing, neuroticism, depressive symptoms and educational attainment) reached significance among participants with European ancestries, but with relatively small effects (= 0.002-0.09). Notably, PGSs derived from GWAS of PTSD among participants with either European or African ancestries were uncorrelated with resilience. Even aggregated across all available proxy PGSs, existing PGSs are not sufficient to inform our understanding of the genetics underlying the heritability of resilience. A large-scale GWAS of resilience is needed as it would provide greater insight into the genetic mechanisms underlying the heritability of resilience.

The structure of DSM-IV ADHD, ODD, and CD criteria in adolescent boys: a hierarchical approach.

Numerous studies have examined the structure of the childhood externalizing disorder symptoms of Attention Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD), both separately as well as simultaneously. The present study expanded on previous findings by implementing a multi-level hierarchical approach to investigating the component structure of ADHD, ODD, and CD criteria in 487 14-year-old boys from the Minnesota Twin Family Study (MTFS). We found support for a hierarchical conceptualization of externalizing behavior criteria in early adolescent boys by specifying how one-, two-, three-, four-, five- and six-factor models of externalizing criteria can be integrated. These results suggest that it may be more beneficial to conceptualize different levels of this hierarchy as relevant to different issues in case conceptualization and research design, from the broad level of an overall externalizing spectrum, to the level of finer-grained subtypes within specific disorders.

Personality in DSM-5: helping delineate personality disorder content and framing the metastructure.

The transition from the Diagnostic and Statistical Model of Mental Disorders (4th ed., text revision [DSM-IV-TR]; American Psychiatric Association, 2000 ) to the fifth edition (DSM-5) represents an unprecedented opportunity to integrate dimensional personality trait models into the official nosology. Not surprisingly, a variety of issues have arisen in contemplating this challenging integration. In this article, we address how a dimensional personality trait model could be a helpful component of DSM-5, from the perspective of our roles as work group members and advisors involved in the creation of a trait model and corresponding assessment instrument. We focus in particular on two potential roles for a trait model in DSM-5 that are under official consideration. First, a dimensional personality trait model might be helpful in delineating the content of personality disorders. Second, a trait model might assist in organizing the "metastructure" of DSM-5 (i.e., the arrangement of chapters and other broader classificatory rubrics).

Predicting sensation seeking from dopamine genes. A candidate-system approach.

Sensation seeking is a heritable personality trait that has been reliably linked to behavioral disorders. The dopamine system has been hypothesized to contribute to variations in sensation seeking between different individuals, and both experimental and observational studies in humans and nonhuman animals provide evidence for the involvement of the dopamine system in sensation-seeking behavior. In this study, we took a candidate-system approach to genetic association analysis of sensation-seeking behavior. We analyzed single-nucleotide polymorphisms (SNPs) from a number of dopaminergic genes. Using 273 SNPs from eight dopamine genes in a sample of 635 unrelated individuals, we examined the aggregate effect of SNPs that were significantly associated with sensation-seeking behavior. Multiple SNPs in four dopamine genes accounted for significant variance in sensation-seeking behavior between individuals. These results suggest that multiple SNPs, aggregated within genes that are relevant to a specific neurobiological system, form a genetic-risk score that may explain a significant proportion of observed variance in human traits such as sensation-seeking behavior.

Harsh discipline, childhood sexual assault, and MAOA genotype: an investigation of main and interactive effects on diverse clinical externalizing outcomes.

We studied the impact of MAOA genotype, childhood sexual assault, and harsh discipline on clinical externalizing symptoms (substance problems, adult antisocial behavior, and conduct disorder). Participants were 841 individual twins from the Minnesota Twin Family Study assessed through age 25. MAOA genotype was not associated with differences in any phenotype, nor was there a significant interaction between MAOA and harsh discipline for any phenotype or a significant interaction between MAOA and childhood sexual assault for substance problems. We found evidence that childhood sexual assault interacted with MAOA genotype to predict antisocial behavior and conduct disorder symptoms. Individuals with the low MAOA activity genotype who reported childhood sexual assault had more symptoms than individuals with either the high MAOA activity genotype and/or no history of childhood sexual assault. These findings suggest that the previously reported interaction between MAOA and childhood maltreatment may be specific to the antisocial subset of externalizing disorders.

Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes.

Nicotine dependence is moderately heritable, but identified genetic associations explain only modest portions of this heritability. We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence. Specifically, we incorporated the interaction between allele count and age at onset of regular smoking (AOS) into association analyses of nicotine dependence. Subjects were from the Collaborative Genetic Study of Nicotine Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non-nicotine-dependent smokers as controls, all of European descent. Compared with main effect models, SNP x AOS interaction models resulted in higher numbers of nominally significant tests, increased predictive utility at individual SNPs and higher predictive utility in a multi-locus model. Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis, including rs16969968 from CHRNA5 and rs2314379 from MAP3K4. CHRNA5 exhibited larger effects in later-onset smokers, in contrast with a previous report that suggested the opposite interaction (Weiss et al. 2008). However, a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses. These include SNPs located in GRIN2B (P = 1.5 x 10(-5)), which encodes a subunit of the N-methyl-D-aspartate receptor channel, a key molecule in mediating age-dependent synaptic plasticity. Incorporation of logically chosen interaction parameters, such as AOS, into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery.

You have to follow through: Attaining behavioral change goals predicts volitional personality change.

Prior research has found that people's desires to change their personality traits predict corresponding subsequent trait growth over time. However, few studies have examined the processes through which people can volitionally change their personality traits. Thus, it remains unclear whether merely desiring change predicts trait growth or whether actively pursuing change is necessary. The present study was a 15-week intensive longitudinal design that tested whether engaging in trait-typical behaviors predicted trait change. Participants provided self-report ratings of their personality traits and were able to freely accept and complete weekly "challenges"-prewritten behavioral goals that would pull their thoughts, feelings, and behaviors in line with their desired traits. Results indicated that merely accepting behavioral challenges did not predict trait changes. Rather, only actually completing challenges (i.e., performing trait-typical behaviors) predicted trait change over time. Thus, merely wanting to change does not appear to be sufficient to evoke trait growth; successfully changing one's personality traits may require actively and successfully implementing behaviors to change oneself. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Imputation of behavioral candidate gene repeat variants in 486,551 publicly-available UK Biobank individuals.

Some of the most widely studied variants in psychiatric genetics include variable number tandem repeat variants (VNTRs) in SLC6A3, DRD4, SLC6A4, and MAOA. While initial findings suggested large effects, their importance with respect to psychiatric phenotypes is the subject of much debate with broadly conflicting results. Despite broad interest, these loci remain absent from the largest available samples, such as the UK Biobank, limiting researchers' ability to test these contentious hypotheses rigorously in large samples. Here, using two independent reference datasets, we report out-of-sample imputation accuracy estimates of >0.96 for all four VNTR variants and one modifying SNP, depending on the reference and target dataset. We describe the imputation procedures of these candidate variants in 486,551 UK Biobank individuals, and have made the imputed variant data available to UK Biobank researchers. This resource, provided to the scientific community, will allow the most rigorous tests to-date of the roles of these variants in behavioral and psychiatric phenotypes.

Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability.

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

Do infants possess an evolved spider-detection mechanism?

Previous studies with various non-human animals have revealed that they possess an evolved predator recognition mechanism that specifies the appearance of recurring threats. We used the preferential looking and habituation paradigms in three experiments to investigate whether 5-month-old human infants have a perceptual template for spiders that generalizes to real-world images of spiders. A fourth experiment assessed whether 5-month-olds have a perceptual template for a non-threatening biological stimulus (i.e., a flower). The results supported the hypothesis that humans, like other species, may possess a cognitive mechanism for detecting specific animals that were potentially harmful throughout evolutionary history.