M.H.M. de Moor

Meta-analysis of genome-wide association studies for personality

Personality can be thought of as a set of characteristics that influence peoples 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 Genetics of Alcohol Dependence: Twin and SNP-Based Heritability, and Genome-Wide Association Study Based on AUDIT Scores

Alcohol dependence (AD) is among the most common and costly public health problems contributing to morbidity and mortality throughout the world. In this study, we investigate the genetic basis of AD in a Dutch population using data from the Netherlands Twin Register (NTR) and the Netherlands Study of Depression and Anxiety (NESDA). The presence of AD was ascertained via the Alcohol Use Disorders Identification Test (AUDIT) applying cut‐offs with good specificity and sensitivity in identifying those at risk for AD. Twin‐based heritability of AD‐AUDIT was estimated using structural equation modeling of data in 7,694 MZ and DZ twin pairs. Variance in AD‐AUDIT explained by all SNPs was estimated with genome‐wide complex trait analysis (GCTA). A genome‐wide association study (GWAS) was performed in 7,842 subjects. GWAS SNP effect concordance analysis was performed between our GWAS and a recent AD GWAS using DSM‐IV diagnosis. The twin‐based heritability of AD‐AUDIT was estimated at 60% (55–69%). GCTA showed that common SNPs jointly capture 33% (SE = 0.12, P = 0.002) of this heritability. In the GWAS, the top hits were positioned within four regions (4q31.1, 2p16.1, 6q25.1, 7p14.1) with the strongest association detected for rs55768019 (P = 7.58 × 10−7). This first GWAS of AD using the AUDIT measure found results consistent with previous genetic studies using DSM diagnosis: concordance in heritability estimates and direction of SNPs effect and overlap with top hits from previous GWAS. Thus, the use of appropriate questionnaires may represent cost‐effective strategies to phenotype samples in large‐scale biobanks or other population‐based datasets.

Associations between ADH glene variants and alcohol phenotypes in Dutch adults

Recently, Macgregor et al. (2009) demonstrated significant associations of ADH polymorphisms with reactions to alcohol and alcohol consumption measures in an Australian sample. The aim of the present study was to replicate these findings in a Dutch sample. Survey data on alcohol phenotypes came from 1,754 unrelated individuals registered with the Netherlands Twin Register. SNPs in the ADH gene cluster located on chromosome 4q (n = 491) were subdivided in seven gene sets: ADH5, ADH4, ADH6, ADH1A, ADH1B, ADH1C and ADH7. Within these sets associations of SNPs with alcohol consumption measures, age at onset variables, reactions to alcohol and problem drinking liability were examined. Of the original 38 SNPs studied by Macgregor et al. (2009), six SNPs were not available in our dataset, because one of them had a minor allele frequency < .01 (rs1229984) and five could not be imputed. The remaining SNP associations with alcohol phenotypes as identified by Macgregor et al. (2009) were not replicated in the Dutch sample, after correcting for multiple genotype and phenotype testing. Significant associations were found however, for reactions to alcohol with a SNP in ADH5 (rs6827292, p = .001) and a SNP just upstream of ADH5 (rs6819724, p = .0007) that is in strong LD with rs6827292. Furthermore, an association between age at onset of regular alcohol use and a SNP just upstream of ADH7 (rs2654849, p = .003) was observed. No significant associations were found for alcohol consumption and problem drinking liability. Although these findings do not replicate the earlier findings at the SNP level, the results confirm the role of the ADH gene cluster in alcohol phenotypes.

Effects of video-feedback intervention on harmonious parent–child interaction and sensitive discipline of parents with intellectual disabilities: A randomized controlled trial

BACKGROUND This study tested whether video-feedback intervention based on attachment and coercion theory increased harmonious parent-child interaction and sensitive discipline of parents with mild intellectual disabilities or borderline intellectual functioning. METHODS Observer ratings of video-recorded structured interaction tasks at home formed pretest, post-test, and 3-month follow-up outcome data in a randomized controlled trial with 85 families. Repeated measures analyses of variance and covariance were conducted to test for the intervention effect and possible moderation by IQ and adaptive functioning. RESULTS The intervention effect on harmonious parent-child interaction was conditional on parental social adaptive behaviour at pretest, with lower adaptive functioning associated with stronger intervention benefit at post-test and follow-up compared to care as usual. Intervention effects were not conditional on parental IQ. Intervention effects for sensitive discipline were not found. CONCLUSION Although the video-feedback intervention did not affect observed parenting for the average parent, it may benefit interaction between children and parents with lower parental adaptive functioning.

A genome-wide association study for subjective wellbeing

with significantly increased rates of anhedonia (58%) in individuals who also experienced childhood physical abuse. While our results are highly consistent with the rodent literature, we cannot determine (as the function of rs1049353 is not well understood) whether this interaction reflects the action of the minor allele in buffering the effects of abuse on anhedonia or whether the presence of the major allele confers risk for anhedonia in the presence of abuse.

Increasing GWAS sample size using item response theory: A pilot study of the personality consortium

with significantly increased rates of anhedonia (58%) in individuals who also experienced childhood physical abuse. While our results are highly consistent with the rodent literature, we cannot determine (as the function of rs1049353 is not well understood) whether this interaction reflects the action of the minor allele in buffering the effects of abuse on anhedonia or whether the presence of the major allele confers risk for anhedonia in the presence of abuse.

Qualitative and quantitative sex differences in genetic architecture for human phenotypes

with significantly increased rates of anhedonia (58%) in individuals who also experienced childhood physical abuse. While our results are highly consistent with the rodent literature, we cannot determine (as the function of rs1049353 is not well understood) whether this interaction reflects the action of the minor allele in buffering the effects of abuse on anhedonia or whether the presence of the major allele confers risk for anhedonia in the presence of abuse.