Genetic Contributions to Alcohol Use Disorder Treatment Outcomes: A Genome-wide Pharmacogenomics Study

Abstract

Naltrexone can aid in reducing alcohol consumption, while acamprosate supports abstinence; however not all patients with alcohol use disorder (AUD) benefit from these treatments. Here we present the first genome-wide association study of AUD treatment outcomes based on data from the COMBINE and PREDICT studies of acamprosate and naltrexone, and the Mayo Clinic CITA study of acamprosate. Primary analyses focused on treatment outcomes regardless of pharmacological intervention and were followed by drug-stratified analyses to identify treatment-specific pharmacogenomic predictors of acamprosate and naltrexone response. Treatment outcomes were defined as: (1) time until relapse to any drinking (TR) and (2) time until relapse to heavy drinking (THR; ≥5 drinks for men, ≥4 drinks for women in a day), during the first three months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies (N=1090 European ancestry participants). SNPs in the BRE gene were associated with THR (min p=1.6E-08) in the entire sample, while two intergenic SNPs were associated with medication-specific outcomes (naltrexone THR: rs12749274, p=3.9E-08; acamprosate TR: rs77583603, p=3.1E-09). The top association signals for TR (p=7.7E-08) and second strongest signal in the THR (p=6.1E-08) analysis of the naltrexone-treated subset map to PTPRD, a gene previously implicated in addiction phenotypes in human and animal studies. Leave-one-out polygenic score (PGS) analyses showed significant associations with TR (p=3.7E-04) and THR (p=2.6E-04). This study provides the first evidence of a polygenic effect on AUD treatment response, and identifies genetic variants associated with potentially medication-specific effects on AUD treatment response.

A randomized, double‐blind, placebo‐controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder

“…Despite evidence that statistical power is enhanced in the study of treatment‐relevant variants relative to disease‐related ones (Maranville & Cox 2016), it may be unduly optimistic to expect that a single or even a handful of genetic variants could moderate treatment response, particularly for a pharmacodynamic effect. An alternative approach, such as the use of polygenic risk scores derived from genome‐wide analyses of the response to the pharmacological treatment of AUD (Biernacka et al, 2021), is a promising alternative approach to advancing the precision medicine treatment of the disorder.…”

Post‐treatment effects of topiramate on alcohol‐related outcomes: A combined analysis of two placebo‐controlled trials

“…Specifically, determined, 17 it is a complex trait influenced by multiple genetic variants of small effect. 18,19 Thus, it is unlikely that a single, non-coding SNP could serve clinically as a moderator of treatment response among individuals with AUD. The findings reported here, together with negative findings on the moderating effect of naltrexone treatment by a polymorphism in the mu-opioid receptor gene, 20 suggest that the use of candidate SNPs is not clinically useful in predicting the response to AUD pharmacotherapy.…”

“…The findings reported here, together with negative findings on the moderating effect of naltrexone treatment by a polymorphism in the mu‐opioid receptor gene, 20 suggest that the use of candidate SNPs is not clinically useful in predicting the response to AUD pharmacotherapy. Thus, it appears that efforts to identify pharmacogenetic moderators for AUD should focus on genome‐wide analyses, 19 from which polygenic risk measures can be derived, as these could prove to be clinically useful in selecting medications to treat AUD.…”

“…Although treatment response is partially genetically determined, 17 it is a complex trait influenced by multiple genetic variants of small effect 18,19 . Thus, it is unlikely that a single, non‐coding SNP could serve clinically as a moderator of treatment response among individuals with AUD.…”

Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study

“…The Mayo Clinic Center for the Individualized Treatment of Alcoholism Study previously recruited 442 participants with AUD (ClinicalTrials.gov Identifier: NCT00662571) (Biernacka et al, 2021;Karpyak et al, 2014Karpyak et al, , 2019. All participants in the study initially received acamprosate (one 333-mg tablet three times a day) to determine tolerance to acamprosate treatment.…”