39 - GENETICS OF THE RESEARCH DOMAIN CRITERIA (RDoC): GENOME-WIDE ASSOCIATION STUDY OF DELAY DISCOUNTING

Abstract

Background Delay-discounting has been proposed as a potential endophenotype for various neuropsychiatric diseases, including drug and alcohol abuse. Although this trait is heritable, it remains unclear which genes/loci influence delay-discounting. Methods In collaboration with the genetics company 23andMe, Inc., we performed a genome-wide association (GWAS) study of delay-discounting, using the self-reported Monetary Choice Questionnaire (MCQ). Our sample consisted of 23,217 male and female adult research participants of European descent. Results We estimated chip-heritability, and demonstrated that 12% of the variation in delay-discounting could be explained by SNPs. We detected one genome-wide significant hit on the X-chromosome (2.4 × 10^−8; rs6528024), centered on the gene GPM6B, which is known to regulate internalization of the serotonin transporter; and a suggestive loci (1.4 × 10^−7; rs2665993) that was also associated with the expression of several nearby genes. Next, to identify the top cortically associated genes mediating the role of common variants, we used MetaXcan, a gene-based association analysis that estimates the genetically determined component of gene expression, and correlates the predicted expression levels with the phenotype of interest. This analysis identified the gene CDK3, which showed higher predicted gene expression in the hippocampus (FDR 0.05). We used polygenic methods to examine co-heritability between delay-discounting and several personality and psychiatric traits. We identified strong genetic correlations between delay-discounting, smoking behavior, educational attainment, obesity and other neuropsychiatric conditions, including ADHD. Discussion This study is the first to demonstrate a role for common genetic contribution to individual differences in delay-discounting, and genetic overlap with human psychopathology.