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 3 months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies (N = 1083 European ancestry participants). Single nucleotide polymorphisms (SNPs) in the BRE gene were associated with THR (min p = 1.6E−8) in the entire sample, while two intergenic SNPs were associated with medication-specific outcomes (naltrexone THR: rs12749274, p = 3.9E−8; acamprosate TR: rs77583603, p = 3.1E−9). The top association signal for TR (p = 7.7E−8) and second strongest signal in the THR (p = 6.1E−8) analysis of naltrexone-treated patients maps to PTPRD, a gene previously implicated in addiction phenotypes in human and animal studies. Leave-one-out polygenic risk score analyses showed significant associations with TR (p = 3.7E−4) and THR (p = 2.6E−4). 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.

Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism

“…This research strategy has been used repeatedly to generate and test genomic and pharmacogenomic hypotheses and has proven to be a powerful research tool for identifying novel biology [ 9 , [24] , [25] , [26] ]. Specifically, we previously recruited 442 subjects with AUD for an acamprosate clinical trial ( Table 1 ) [ 27 ]. Alcohol consumption was measured by self-report using Timeline Followback (TLFB).…”

“…The genomic dataset was derived from the Mayo Clinic Center for the Individualized Treatment of Alcoholism Study, as described previously [ 8 ]. Genome-wide associations between genetic variants and plasma FGF21 levels were examined using linear regression, adjusted for sex, age, and study site.…”

“…The Mayo Clinic Center for the Individualized Treatment of Alcoholism recruited 442 AUD subjects with clinical data, and DNA samples were obtained prior to treatment [ 8 ]. We designed the present study to apply our established pharmaco-omics-informed genomics research strategy to identify genetic variants that might contribute to the concentrations of plasma FGF21 and its functional role in AUD.…”

Plasma TNFSF10 levels associated with acamprosate treatment response in patients with alcohol use disorder

“…We previously conducted an acamprosate clinical trial to identify potential biomarkers associated with acamprosate treatment response using metabolomics and genomics ( Hinton et al, 2017 ; Ho et al, 2020 ; Biernacka et al, 2021 ). Those AUD patients were treated with acamprosate for 3 months in community-based treatment programs ( Karpyak et al, 2014 ; Karpyak et al, 2019 ).…”

“…Those AUD patients were treated with acamprosate for 3 months in community-based treatment programs ( Karpyak et al, 2014 ; Karpyak et al, 2019 ). The primary outcome was abstinence, but we also collected comprehensive clinical information for this study cohort before and after 3 months of acamprosate treatment ( Karpyak et al, 2019 ; Biernacka et al, 2021 ). Our previous study suggested that genetic variants in the TSPAN5 gene were associated with acamprosate treatment response ( Ho et al, 2020 ).…”