Genome-wide association study of personality traits in the long life family study

Abstract

Personality traits have been shown to be associated with longevity and healthy aging. In order to discover novel genetic modifiers associated with personality traits as related with longevity, we performed a genome-wide association study (GWAS) on personality factors assessed by NEO-five-factor inventory in individuals enrolled in the Long Life Family Study (LLFS), a study of 583 families (N up to 4595) with clustering for longevity in the United States and Denmark. Three SNPs, in almost perfect LD, associated with agreeableness reached genome-wide significance (p < 10(-8)) and replicated in an additional sample of 1279 LLFS subjects, although one (rs9650241) failed to replicate and the other two were not available in two independent replication cohorts, the Baltimore Longitudinal Study of Aging and the New England Centenarian Study. Based on 10,000,000 permutations, the empirical p-value of 2 × 10(-7) was observed for the genome-wide significant SNPs. Seventeen SNPs that reached marginal statistical significance in the two previous GWASs (p-value <10(-4) and 10(-5)), were also marginally significantly associated in this study (p-value <0.05), although none of the associations passed the Bonferroni correction. In addition, we tested age-by-SNP interactions and found some significant associations. Since scores of personality traits in LLFS subjects change in the oldest ages, and genetic factors outweigh environmental factors to achieve extreme ages, these age-by-SNP interactions could be a proxy for complex gene-gene interactions affecting personality traits and longevity.

Keywords: GWAS; family study; gene-environment interaction; longevity; neo scores.

Figure 1

(A) Q-Q plots for five domains of NEO-FFI. The y-axis is the quantiles of observed p-values and the x-axis is the quantiles from the expected distribution; (B) Manahattan plots for five domains of NEO-FFI. The y-axis is the -log(p) and the x-axis is the genomic locations for each SNP ordered by chromosome and base pair positions.

Figure 2

Graphical representation of hypothesis on gene-gene interactions. Attributes inside the large rectangular box are the variables included in the statistical model. Age, which is associated with NEO scores, is reflective of both genetic and environmental factors associated with aging. As genetics factors outweigh the environmental factors in individuals enriched for longevity, SNP-by-age interaction term in the model may imply gene-gene interaction which plays important roles in personality traits, as related to longevity.