A large-scale genome-wide association study of cocaine use disorder

Genome-wide association studies (GWAS) of cocaine use disorder (CocUD) have been small by current standards, with most analyses having relied on data from the Yale-Penn sample. GWAS discovery for other substance use disorders (SUDs) has been foundational in understanding the genetic and biological components of SUD risk. Although cocaine is one of the most used and addictive illicit drugs in the United States, our biological understanding of CocUD is limited, and not well informed from genetics data. We address this by conducting the largest GWAS of CocUD to date in individuals of African (AFR) and European (EUR) ancestry. The meta-analysis included only new GWAS analyses, and included cohorts from the Million Veteran Program, Yale-Penn, iPSYCH, and BioVU. The AFR meta-analysis included 117,627 individuals (Ncase=22,163) and the EUR meta-analysis consisted of 441,591 subjects (Ncase=14,909) yielding a total sample of 574,127 subjects (Total Ncase=37,072). GWAS were combined using an effective sample-size weighted meta-analysis. Ancestry-specific and cross-ancestry meta-analyses were performed followed by in silico analyses. In the EUR meta-analysis, 27 variants reached genome-wide significance (GWS; p=5.00e-08) mapping to a single locus at DRD2 on chromosome 11 (lead SNP: rs11214607; p=1.02e-11). The AFR meta-analysis resulted in 3 GWS loci; the top AFR association was with rs10467348 (p=7.58e-09) in HS6ST3 on chromosome 13. The cross-ancestry meta-analysis yielded 11 GWS loci; the top cross-ancestry association was with rs2471851 (p=2.65e-12) in DRD2. Gene-set and tissue expression analyses identified processes involved in neurosynaptic functioning and showed enrichment in brain tissue. We conducted the largest GWAS of CocUD to date, substantially advancing CocUD genetic discovery and identifying multiple novel findings including DRD2 that has now been identified across multiple SUDs. This effort advances our understanding of the genetic architecture of CocUD and holds promise for understanding the neurobiology of CocUD and its relationship with other traits.