Genome-wide association meta-analysis of cocaine dependence: shared genetics with comorbid conditions

Abstract

Cocaine dependence is a complex psychiatric disorder that is highly comorbid with other psychiatric traits. Twin and adoption studies suggest that genetic variants contribute substantially to cocaine dependence susceptibility, which has an estimated heritability of 65-79%. Here we performed a meta-analysis of genome-wide association studies of cocaine dependence using four datasets from the dbGaP repository (2085 cases and 4293 controls, all of them selected by their European ancestry). Although no genome-wide significant hits were found in the SNP-based analysis, the gene-based analysis identified HIST1H2BD as associated with cocaine-dependence (10% FDR). This gene is located in a region on chromosome 6 enriched in histone-related genes, previously associated with schizophrenia (SCZ). Furthermore, we performed LD Score regression analysis with comorbid conditions and found significant genetic correlations between cocaine dependence and SCZ, ADHD, major depressive disorder (MDD) and risk taking. We also found, through polygenic risk score analysis, that all tested phenotypes are significantly associated with cocaine dependence status: SCZ (R2 = 2.28%; P = 1.21e-26), ADHD (R2 = 1.39%; P = 4.5e-17), risk taking (R2 = 0.60%; P = 2.7e-08), MDD (R2 = 1.21%; P = 4.35e-15), children's aggressive behavior (R2 = 0.3%; P = 8.8e-05) and antisocial behavior (R2 = 1.33%; P = 2.2e-16). To our knowledge, this is the largest reported cocaine dependence GWAS meta-analysis in European-ancestry individuals. We identified suggestive associations in regions that may be related to cocaine dependence and found evidence for shared genetic risk factors between cocaine dependence and several comorbid psychiatric traits. However, the sample size is limited and further studies are needed to confirm these results.