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

Abstract

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.

Figure 1

(a) Quantile–quantile (Q–Q) plots of the meta-analyses of genome-wide association studies (GWAS) results for excitement-seeking. (b) Manhattan plot summarizing the meta-analysis results for excitement-seeking in six samples. Notes: Each dot represents a single-nucleotide polymorphism (SNP), with the chromosomal position on the x axis and the P-value on the y axis.

Figure 2

Regional plot of the association between catenin cadherin-associated protein, alpha 2 (CTNNA2) single-nucleotide polymorphisms (SNPs) and excitement-seeking. Notes: Each dot represents an SNP, with the chromosomal position on the x axis and the P-value on the y axis. The color of the dots depicts the HapMap CEU derived r² between the SNP with the strongest signal (rs7600563) and the other SNPs in the region. Plot was generated using LocusZoom, http://www.csg.sph.umich.edu/locuszoom.

Figure 3

Association of rs7600563 and excitement-seeking in six samples and the meta-analysis. Notes: N=sample size; MAF=major allele frequency (T); IMP=imputation quality. The single-nucleotide polymorphism (SNP) was genotyped and not imputed in the Baltimore Longitudinal Study of Aging (BLSA). Plot drawn with the program Comprehensive Meta-Analysis V.2.

Figure 4

Association of rs7600563 genotypes and excitement-seeking in the Baltimore Longitudinal Study of Aging (BLSA). Notes: N=840. Estimated means controlling for age and sex. Hardy–Weinberg Equilibrium (HWE) χ²=0.95, P>0.05.