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. 2021 Jun 29;11(1):363.
doi: 10.1038/s41398-021-01440-5.

Genome-wide association study of stimulant dependence

Jiayi Cox  1 , Richard Sherva  1 , Leah Wetherill  2 , Tatiana Foroud  2 , Howard J Edenberg  2   3 , Henry R Kranzler  4 , Joel Gelernter  5   6 , Lindsay A Farrer  7   8   9   10   11
Affiliations

Genome-wide association study of stimulant dependence

Jiayi Cox et al. Transl Psychiatry. .

Abstract

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 (padj = 3.6 × 10-3), an anxiety disorder in EAs (padj = 2.1 × 10-4), and ADHD in both AAs (padj = 3.0 × 10-33) and EAs (padj = 6.7 × 10-35). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.

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Conflict of interest statement

R.K. is a member of an advisory board for Dicerna Pharmaceuticals and of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which in the past 3 years was sponsored by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. R.K. and J.G. are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. Other authors do not report any conflicts of interest.

Figures

Fig. 1
Fig. 1. Association of stimulant dependence with SNPs located between LRP1B and KYNU in the African American discovery sample.
SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes African reference panel with the top-ranked SNP, rs6721393. Rs6721393 was nearly genome-wide significant (P = 3.13 × 10−7) after meta-analysis with the replication sample.
Fig. 2
Fig. 2. Association of stimulant dependence with SNPs located in the SLC25A16 region in the African American discovery sample.
SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes African reference panel with the top-ranked SNP, rs2394476. Rs2394476 was genome-wide significant (P = 1.22 × 10−9) after meta-analysis with the replication sample.
Fig. 3
Fig. 3. Association of stimulant dependence with SNPs located in the KCNA4 region in the African American discovery sample.
SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes African reference panel with the top-ranked SNP, rs11500237 located 93 kb upstream of KCNA4. Rs11500237 was nearly genome-wide significant (P = 2.99 × 10−7) after meta-analysis with the replication sample.
Fig. 4
Fig. 4. Association of stimulant dependence with SNPs located in the GNAO1 region in the African American discovery sample.
SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes African reference panel with the top-ranked SNP, rs116441240. Rs116441240 was nearly genome-wide significant (P = 1.09 × 10−7) after meta-analysis with the replication sample.
Fig. 5
Fig. 5. Association of stimulant dependence with SNPs located in the CPVL region in the combined African American and European ancestry discovery sample.
SNPs are color-coded according to the correlation coefficient (r2) in the 1000 Genomes combined European and African reference panels with the top-ranked SNP, rs116441240. Rs116441240 was nearly genome-wide significant (P = 3.05 × 10−7) after meta-analysis with the replication sample.
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