Genome-Wide Association Study of Opioid Cessation

Jiayi W Cox, Richard M Sherva, Kathryn L Lunetta, Emma C Johnson, Nicholas G Martin, Louisa Degenhardt, Arpana Agrawal, Elliot C Nelson, Henry R Kranzler, Joel Gelernter, Lindsay A Farrer, Jiayi W Cox, Richard M Sherva, Kathryn L Lunetta, Emma C Johnson, Nicholas G Martin, Louisa Degenhardt, Arpana Agrawal, Elliot C Nelson, Henry R Kranzler, Joel Gelernter, Lindsay A Farrer

Abstract

The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in PTPRD (pAA + EA = 2.24 × 10-6), rs36098404 in MYOM2 (pEA = 2.24 × 10-6), and rs592026 in SNAP25-AS1 (pEA = 6.53 × 10-6). Significant pathways identified in persons of European ancestry (EA) are related to vitamin D metabolism (p = 3.79 × 10-2) and fibroblast growth factor (FGF) signaling (p = 2.39 × 10-2). UK Biobank traits including smoking and drinking cessation and chronic back pain were significantly associated with opioid cessation using GWAS-derived polygenic risk scores. These results provide evidence for genetic influences on opioid cessation, suggest genetic overlap with other relevant traits, and may indicate potential novel therapeutic targets for OUD.

Keywords: genome-wide association study; opioid cessation; opioid use disorder; polygenic risk score; shared genetic risk.

Conflict of interest statement

H.R.K. is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported for the last three years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. Drs. Kranzler and Gelernter are named as inventors on PCT patent application #15/878,640 entitled: "Genotype-guided dosing of opioid agonists," filed January 24, 2018. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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