Genome-wide association study of stimulant dependence

Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls). An independent cohort from the family-based Collaborative Study on the Genetics of Alcoholism (532 EA cases, 7635 EA controls; 53 AA cases, AA 3352 controls) was used for replication. One variant in SLC25A16 (rs2394476, p=3.42x10(-10), odds ratio [OR]=3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p=2.99x10(-7), OR=2.31) which encodes one of the potassium voltage-gated channel protein that has been linked to several other substance use disorders, and CPVL in the combined population groups (rs1176440, p=3.05x10(-7), OR=1.35), whose expression was previously shown to be upregulated in the prefrontal cortex from users of cocaine, cannabis, and phencyclidine. Analysis of the top GWAS signals revealed a significant enrichment with nicotinic acetylcholine receptor genes (adjusted p=0.04) and significant pleiotropy between stimulant dependence and alcohol dependence in EAs (p(adj)=3.6x10(-3)), an anxiety disorder in EAs (p(adj)=2.1x10(-4)), and ADHD in both AAs (p(adj)=3.0x10(-33)) and EAs (p(adj)=6.7x10(-35)). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.