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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.

SUBMITTER: Biernacka JM

PROVIDER: S-EPMC8505452 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study.

Biernacka Joanna M JM Coombes Brandon J BJ Batzler Anthony A Ho Ada Man-Choi AM Geske Jennifer R JR Frank Josef J Hodgkinson Colin C Skime Michelle M Colby Colin C Zillich Lea L Pozsonyiova Sofia S Ho Ming-Fen MF Kiefer Falk F Rietschel Marcella M Weinshilboum Richard R O'Malley Stephanie S SS Mann Karl K Anton Ray R Goldman David D Karpyak Victor M VM

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20210723 12

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 b ...[more]

PMID: 34302059

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Project description:We tested whether aspects of the childhood/adolescent home environment mediate genetic risk for alcohol problems within families across generations. Parental relationship discord and parental divorce were the focal environments examined. The sample included participants of European ancestry (N = 4806, 51% female) and African ancestry (N = 1960, 52% female) from the high-risk Collaborative Study on the Genetics of Alcoholism. Alcohol outcomes in the child generation included lifetime criterion counts for DSM-5 Alcohol Use Disorder (AUD), lifetime maximum drinks in 24 h, age at initiation of regular drinking, and age at first alcohol intoxication. Predictors in the parent generation included relationship discord, divorce, alcohol measures parallel to those in the child generation, and polygenic scores for alcohol problems. Parental polygenic scores were partitioned into alleles that were transmitted and non-transmitted to the child. The results from structural equation models were consistent with genetic nurture effects in European ancestry families. Exposure to parental relationship discord and parental divorce mediated, in part, the transmission of genetic risk for alcohol problems from parents to children to predict earlier ages regular drinking (βindirect = -0.018 [-0.026, -0.011]) and intoxication (βindirect = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (βindirect = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (βindirect = 0.011 [0.006, 0.016]). In contrast, there was no evidence that parental alleles had indirect effects on offspring alcohol outcomes via parental relationship discord or divorce in the smaller number of families of African ancestry. In conclusion, parents transmit genetic risk for alcohol problems to their children not only directly, but also indirectly via genetically influenced aspects of the home environment. Further investigation of genetic nurture in non-European samples is needed.

Project description:ImportanceAlcohol genome-wide association studies (GWASs) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc).ObjectivesTo identify genetic loci associated with MaxAlc and to elucidate the genetic architecture across alcohol traits.Design, setting, and participantsThis MaxAlc genetic association study was performed among Million Veteran Program participants enrolled from January 10, 2011, to September 30, 2020. Ancestry-specific GWASs were conducted in participants with European (n = 218 623) and African (n = 29 132) ancestry, then meta-analyzed (N = 247 755). Linkage-disequilibrium score regression was used to estimate single nucleotide variant (SNV)-heritability and genetic correlations (rg) with other alcohol and psychiatric traits. Genomic structural equation modeling (gSEM) was used to evaluate genetic associations between MaxAlc and other alcohol traits. Mendelian randomization was used to examine potential causal relationships between MaxAlc and liver enzyme levels. MTAG (multitrait analysis of GWAS) was used to analyze MaxAlc and problematic alcohol use (PAU) jointly.ExposuresGenetic associations.Main outcomes and measuresMaxAlc was defined from the following survey item: "in a typical month, what is/was the largest number of drinks of alcohol you may have had in one day?" with ordinal responses from 0 to 15 or more drinks.ResultsGWASs were conducted on sample sizes of as many as 247 455 US veterans. Participants were 92.68% male and had mean (SD) age of 65.92 (11.70) years. The MaxAlc GWAS resulted in 15 genome-wide significant loci. Top associations in European-ancestry and African-ancestry participants were with known functional variants in the ADH1B gene, namely rs1229984 (P = 3.12 × 10-101) and rs2066702 (P = 6.30 × 10-17), respectively. Novel associations were also found. SNV-heritability was 6.65% (SE, 0.41) in European-ancestry participants and 3.42% (SE, 1.46) in African-ancestry participants. MaxAlc was positively correlated with PAU (rg = 0.79; P = 3.95 × 10-149) and AUD (rg = 0.76; P = 1.26 × 10-127) and had negative rg with the UK Biobank "alcohol usually taken with meals" (rg = -0.53; P = 1.40 × 10-50). For psychiatric traits, MaxAlc had the strongest genetic correlation with suicide attempt (rg = 0.40; P = 3.02 × 10-21). gSEM supported a 2-factor model with MaxAlc loading on a factor with PAU and AUD and other alcohol consumption measures loading on a separate factor. Mendelian randomization supported an association between MaxAlc and the liver enzyme gamma-glutamyltransferase (β = 0.012; P = 2.66 × 10-10). MaxAlc MTAG resulted in 31 genome-wide significant loci.Conclusions and relevanceThe findings suggest that MaxAlc closely aligns genetically with PAU traits. This study improves understanding of the mechanisms associated with normative alcohol consumption vs problematic habitual use and AUD as well as how MaxAlc relates to psychiatric and medical conditions genetically and biologically.

Dataset Information

Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study.

Publications

Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study.

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