zed by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders and clear heritable components. Identifying the genetic variants associated with personality traits remains challenging. In recent years, attention has turned to genome wide association studies (GWAS), which search across the entire genome for common variants that contribute to quantitative traits and diseases. The results from these studies suggest that a large number of genes contribute to complex traits, and each common variant explains only a small fraction of the trait heritability. To increase power, current research meta-analytically combines the GWAS results from multiple samples to identify the genetic variants associated with the five major dimensions of personality (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness) and the facets that compose each factor. In 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 of European ancestry), we examined scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness based on the NEO Five-Factor Inventory. In the discovery samples, meta-analysis 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. In an earlier meta-analysis of Openness, based on six samples of European ancestry (N=7860), 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). These studies highlight the complexity of the genetics of personality and the importance of replication studies across multiple samples.
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