Genome-wide association study of stimulant dependence

• Published in: Translational psychiatry 2021-06, Vol.11 (1), p.363-363, Article 363
• Main Authors: Cox, Jiayi, Sherva, Richard, Wetherill, Leah, Foroud, Tatiana, Edenberg, Howard J., Kranzler, Henry R., Gelernter, Joel, Farrer, Lindsay A.
• Format: Article
• Language: English
• Subjects: 45/43; 631/208/2489; 692/699/476/5; Behavioral Sciences; Biological Psychology; Cocaine; Genomes; Medicine; Medicine & Public Health; Neurosciences; Pharmacotherapy; Psychiatry
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-021-01440-5

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  = 3.42 × 10 −10 , odds ratio [OR] = 3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p  = 2.99 × 10 −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  = 3.05 × 10 −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  = 3.6 × 10 −3 ), an anxiety disorder in EAs ( p adj  = 2.1 × 10 −4 ), and ADHD in both AAs ( p adj  = 3.0 × 10 −33 ) and EAs ( p adj  = 6.7 × 10 −35 ). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.