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.

Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking.

The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 × 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed α-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders.

The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data.

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

Plasma BDNF concentration, Val66Met genetic variant and depression-related personality traits.

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression.

Genome-wide association scan for five major dimensions of personality.

Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome-wide association (GWA) scan of 3972 individuals from a genetically isolated population within Sardinia, Italy. On the basis of the analyses of 362 129 single-nucleotide polymorphisms we found several strong signals within or near genes previously implicated in psychiatric disorders. They include the association of neuroticism with SNAP25 (rs362584, P=5 x 10(-5)), extraversion with BDNF and two cadherin genes (CDH13 and CDH23; Ps<5 x 10(-5)), openness with CNTNAP2 (rs10251794, P=3 x 10(-5)), agreeableness with CLOCK (rs6832769, P=9 x 10(-6)) and conscientiousness with DYRK1A (rs2835731, P=3 x 10(-5)). Effect sizes were small (less than 1% of variance), and most failed to replicate in the follow-up independent samples (N up to 3903), though the association between agreeableness and CLOCK was supported in two of three replication samples (overall P=2 x 10(-5)). We infer that a large number of loci may influence personality traits and disorders, requiring larger sample sizes for the GWA approach to confidently identify associated genetic variants.

High neuroticism and low conscientiousness are associated with interleukin-6.

BACKGROUND: High Neuroticism and low Conscientiousness are frequently implicated in health-risk behaviors, such as smoking and overeating, as well as health outcomes, including mortality. Their associations with physiological markers of morbidity and mortality, such as inflammation, are less well documented. The present research examines the association between the five major dimensions of personality and interleukin-6 (IL-6), a pro-inflammatory cytokine often elevated in patients with chronic morbidity and frailty. METHOD: A population-based sample (n=4923) from four towns in Sardinia, Italy, had their levels of IL-6 measured and completed a comprehensive personality questionnaire, the NEO-PI-R. Analyses controlled for factors known to have an effect on IL-6: age; sex; smoking; weight; aspirin use; disease burden. RESULTS: High Neuroticism and low Conscientiousness were both associated with higher levels of IL-6. The findings remained significant after controlling for the relevant covariates. Similar results were found for C-reactive protein, a related marker of chronic inflammation. Further, smoking and weight partially mediated the association between impulsivity-related traits and higher IL-6 levels. Finally, logistic regressions revealed that participants either in the top 10% of the distribution of Neuroticism or the bottom 10% of conscientiousness had an approximately 40% greater risk of exceeding clinically relevant thresholds of IL-6. CONCLUSIONS: Consistent with the literature on personality and self-reported health, individuals high on Neuroticism or low on Conscientiousness show elevated levels of this inflammatory cytokine. Identifying critical medical biomarkers associated with personality may help to elucidate the physiological mechanisms responsible for the observed connections between personality traits and physical health.

Adult antisocial personality traits are associated with experiences of low parental care and maternal overprotection.

OBJECTIVE: To investigate the role of parenting in the development of adult antisocial personality traits. METHOD: A total of 742 community-based subjects were assessed for adult DSM-IV antisocial personality disorder traits and for measures of parental behavior experienced as children, including by the Parental Bonding Instrument (PBI). RESULTS: Three fundamental dimensions of parental behavior - care, behavioral restrictiveness and denial of psychological autonomy - were derived by factor analysis from the PBI. These dimensions significantly correlated with measures of parental behavior considered influential in later antisocial behavior. Adult antisocial traits in males were associated with low maternal care and high maternal behavioral restrictiveness, and in females, antisocial traits were associated with low paternal care and high maternal denial of psychological autonomy. These dimensions did not, however, explain all variance parental behavior has on adult antisocial personality traits. CONCLUSION: Adult antisocial personality traits are associated with experiences of low parental care and maternal overprotection.

Short-term stability of NEO-PI-R personality trait scores in opioid-dependent outpatients.

The present study examined the short-term stability of personality trait scores from the Revised NEO Personality Inventory (NEO-PI-R) among 230 opioid-dependent outpatients. The NEO-PI-R is a 240-item empirically developed measure of the five-factor model of personality (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). Participants completed the NEO-PI-R at admission and again approximately 19 weeks later. Results indicated fair to good stability for all NEO-PI-R factor domain scores, with coefficients ranging from .68 to .74. Stability of NEO-PI-R scores was decreased among potentially invalid response patterns but was not significantly affected by drug-positive versus drug-negative status at follow-up.

Normal personality traits and comorbidity among phobic, panic and major depressive disorders.

High comorbidity among anxiety and depressive conditions is a consistent but not well-understood finding. The current study examines how normal personality traits relate to this comorbidity. In the Baltimore Epidemiologic Catchment Area Follow-up Study, psychiatrists administered the full Schedules for Clinical Assessment in Neuropsychiatry to 320 subjects, all of whom completed the Revised NEO Personality Inventory. The disorders of interest were simple phobia, social phobia, agoraphobia, panic disorder, and major depression. Analyses were carried out with second-order generalized estimating equations. The unadjusted summary odds ratio (SOR - or weighted mean odds ratio) for all five disorders was 1.72 (95% confidence interval=1.21-2.46). Neuroticism, introversion, younger age, and female gender were all significant predictors of prevalence of disorders. After adjustment for the relationships between these personality and demographic predictors and prevalence, the association among disorders was much weaker (SOR=1.11, 95% CI=0.79-1.56). However, subjects with high extraversion had a SOR 213% as high (95% CI=102-444%) as those with low extraversion (1.60 vs. 0.75). Therefore, neuroticism and introversion are associated with increased comorbidity due to relationships in common with the prevalence of the different disorders. In contrast, extraversion is associated with increased comorbidity per se.

Personality profiles and the prediction of categorical personality disorders.

Personality disorders (PDs) are usually construed as psychiatric categories characterized by a unique configuration of traits and behaviors. To generate clinical hypotheses from normal personality trait scores, profile agreement statistics can be calculated using a prototypical personality profile for each PD. Multimethod data from 1,909 psychiatric patients in the People's Republic of China were used to examine the accuracy of such hypotheses in the Interpretive Report of the Revised NEO Personality Inventory. Profile agreement indices from both self-reports and spouse ratings were significantly related to PD symptom scores derived from questionnaires and clinical interviews. However, accuracy of diagnostic classification was only modest to moderate, probably because PDs are not discrete categorical entities. Together with other literature, these data suggest that the current categorical system should be replaced by a more comprehensive system of personality traits and personality-related problems.

Phobic, panic, and major depressive disorders and the five-factor model of personality.

This study investigated five-factor model personality traits in anxiety (simple phobia, social phobia, agoraphobia, and panic disorder) and major depressive disorders in a population-based sample. In the Baltimore Epidemiologic Catchment Area Follow-up Study, psychiatrists administered the Schedules for Clinical Assessment in Neuropsychiatry to 333 adult subjects who also completed the Revised NEO Personality Inventory. All of the disorders except simple phobia were associated with high neuroticism. Social phobia and agoraphobia were associated with low extraversion. In addition, lower-order facets of extraversion, agreeableness, and conscientiousness were associated with certain disorders (i.e., low positive emotions in panic disorder; low trust and compliance in certain phobias; and low competence, achievement striving, and self-discipline in several disorders). This study emphasizes the utility of lower-order personality assessments and underscores the need for further research on personality/psychopathology etiologic relationships.

Personality psychology and problem behaviors: HIV risk and the five-factor model.

Studies of personality and problem behaviors may begin with analyses of the problem and develop hypotheses about personality traits that might be relevant; or they may begin with models of personality and explore links to behavior. Because it is well validated and relatively comprehensive, the Five-Factor Model (FFM) of personality lends itself to systematic exploratory studies that may sometimes lead to unanticipated findings. In this article, we review a program of research in a high-risk, disadvantaged population that illustrates the utility of the FFM in understanding health risk behavior. Previous analyses showed that behavior associated with the risk of HIV infection can be predicted from the personality dispositions of Neuroticism and (low) Conscientiousness.

Personality disorders and normal personality dimensions in obsessive-compulsive disorder.

BACKGROUND: Little is known about personality disorders and normal personality dimensions in relatives of patients with obsessive-compulsive disorder (OCD). AIMS: To determine whether specific personality characteristics are part of a familial spectrum of OCD. METHOD: Clinicians evaluated personality disorders in 72 OCD case and 72 control probands and 198 case and 207 control first-degree relatives. The selfcompleted Revised NEO Personality Inventory was used for assessment of normal personality dimensions. The prevalence of personality disorders and scores on normal personality dimensions were compared between case and control probands and between case and control relatives. RESULTS: Case probands and case relatives had a high prevalence of obsessive-compulsive personality disorder (OCPD) and high neuroticism scores. Neuroticism was associated with OCPD in case but not control relatives. CONCLUSIONS: Neuroticism and OCPD may share a common familial aetiology with OCD.

The cross-cultural generalizability of Axis-II constructs: an evaluation of two personality disorder assessment instruments in the People's Republic of China.

We examined the reliability, cross-instrument validity, and factor structure of Chinese adaptations of the Personality Diagnostic Questionnaire (PDQ-4+; N = 1,926) and Personality Disorders Interview (PDI-IV; N = 525) in psychiatric patients. Comparisons with data from Western countries suggest that the psychometric properties of these two instruments are comparable across cultures. Low to modest agreement between the PDQ-4+ and PDI-IV was observed for both dimensional and categorical personality disorder evaluations. When the PDI-IV was used as the diagnostic standard, the PDQ-4+ showed higher sensitivity than specificity, and higher negative predictive power than positive predictive power. Factor analyses of both instruments replicated the four-factor structure O'Connor and Dyce (1998) found in Western samples. Results suggested that conceptions and measures of DSM-IV personality disorders are cross-culturally generalizable to Chinese psychiatric populations.

Personality predictors of injury-related posttraumatic stress disorder.

This longitudinal, cohort study examined the effect of personality traits on the emergence of posttraumatic stress disorder (PTSD) in a recently traumatized, civilian, mixed-gender sample with significant injuries. Burn survivors (N = 70) were administered the NEO-Personality Inventory (NEO-PI) and the Structured Clinical Interview for DSM III-R (SCID) at hospital discharge and readministered the SCID 4 and 12 months later. Overall, the sample of burn survivors scored significantly higher on neuroticism and extraversion and lower on openness, agreeableness, and conscientiousness relative to a normative national sample. Furthermore, multivariate analysis of variance revealed that PTSD symptom severity groups (i.e., single symptom, multiple symptoms, subthreshold PTSD, PTSD) were differentially related to neuroticism and extraversion. Planned comparisons indicated that neuroticism was higher and extraversion was lower in those who developed PTSD compared with those who did not develop PTSD.

Do the dimensions of the temperament and character inventory map a simple genetic architecture? Evidence from molecular genetics and factor analysis.

OBJECTIVE: It has been reported that the human temperament dimensions of novelty seeking and harm avoidance are associated with polymorphisms in the D(4) dopamine receptor gene (D4DR) and the serotonin-transporter-linked promoter region (5-HTTLPR), respectively. Although these findings are consistent with Cloninger's hypothesized psychobiological model of temperament and character, many studies failed to replicate these findings. In the present study the authors tested whether the psychobiological model taps the genetic architecture of personality by exploring associations between these candidate genes and the dimensions of the Temperament and Character Inventory and by examining its phenotypic structure. METHOD: Of the 946 male and female participants in the Baltimore Longitudinal Study of Aging to whom the Temperament and Character Inventory was administered, 587 were genotyped for a polymorphism with a 48-base-pair repeat in the D4DR gene and 425 were genotyped for a 44-base-pair insertion or deletion in the 5-HTTLPR polymorphism. RESULTS: There was no significant association between D4DR polymorphisms and novelty seeking. The authors also failed to find an association between 5-HTTLPR polymorphisms and harm avoidance. The factor structure of the Temperament and Character Inventory did not reveal the hypothesized phenotypic structure. CONCLUSIONS: This investigation produced no support for the temperament-character model at either the biological or psychological level.

Nature over nurture: temperament, personality, and life span development.

Temperaments are often regarded as biologically based psychological tendencies with intrinsic paths of development. It is argued that this definition applies to the personality traits of the five-factor model. Evidence for the endogenous nature of traits is summarized from studies of behavior genetics, parent-child relations, personality structure, animal personality, and the longitudinal stability of individual differences. New evidence for intrinsic maturation is offered from analyses of NEO Five-Factor Inventory scores for men and women age 14 and over in German, British, Spanish, Czech, and Turkish samples (N = 5,085). These data support strong conceptual links to child temperament despite modest empirical associations. The intrinsic maturation of personality is complemented by the culturally conditioned development of characteristic adaptations that express personality; interventions in human development are best addressed to these.

Personality at midlife: stability, intrinsic maturation, and response to life events.

Although developmental theories and popular accounts suggest that midlife is a time of turmoil and change, longitudinal studies of personality traits have generally found stability of rank order and little or no change in mean levels. Using data from 2,274 men and women in their 40s retested after 6 to 9 years, the present study examined two hypotheses: (a) that retest correlations should be no higher than about .60 and (b) that there should be small decreases in Neuroticism, Extraversion, and Openness, and small increases in Agreeableness and Conscientiousness. The study also explored the effects of recalled life events on subsequent personality scores. Results did not support the first hypothesis; uncorrected retest correlations uniformly exceeded .60. This was true for all personality traits, including facets of Agreeableness and Conscientiousness not previously included in longitudinal studies. The hypothesized decreases in Neuroticism, Extraversion, and Openness were found, but Conscientiousness showed a small decrease instead of the predicted increase. Life events in general showed very little influence on the levels of personality traits, although some effects were seen for changes in job and marital status that warrant further research.

Self-perceptions of stability and change in personality at midlife: the UNC Alumni Heart Study.

The finding of personality stability in adulthood may be counterintuitive to people who perceive a great deal of change in their own personality. The purpose of this study is to determine whether self-reported perceived changes in personality are associated with actual changes based on a 6- to 9-year follow-up of 2,242 middle-aged male and female participants of the UNC Alumni Heart Study (UNCAHS). Respondents completed the Revised NEO Personality Inventory on two occasions and were asked to reflect back over a 6-year period and assess changes in their personality. The majority of respondents (n = 1,177; 52.5%) reported they had "stayed the same," while 863 (38.5%) reported they had "changed a little" and 202 (9%) reported they had "changed a good deal." Coefficients of personality profile agreement computed to evaluate global personality change for the three perceived change groups were essentially equivalent. Further, directional analyses of domain-specific changes in personality showed that perceived changes were weak predictors of residual gain scores. In an absolute sense, perceptions of stability or change were discordant in 8 of 15 (53%) comparisons. Self-perceptions of change are not an adequate substitute for objective assessments.