Pharmacogenomics of Treatment Outcomes in Alcohol Use Disorders

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Abstract Large meta-analyses indicate that acamprosate and naltrexone improve alcohol use disorder (AUD) treatment outcomes. However, these medications are only effective in a subset of individuals with AUDs, prompting the need for reliable predictors of treatment outcomes that can be used to personalize treatment selection optimizing clinical benefits. It is widely known that genetic variation contributes to inter-individual differences in drug response, and it is expected that genomic factors can aid in prediction of clinical response to treatment of alcohol dependence. Prior candidate gene studies have identified several genetic variations associated with differential outcomes following treatment of alcohol dependence. However, no genome- wide pharmacogenomic studies of acamprosate or naltrexone treatment response have been published. We propose to perform a comprehensive set of genome-wide association studies using samples from three of the largest studies of acamprosate and naltrexone completed to date (COMBINE, PREDICT and CITA), to identify genetic markers associated with AUD treatment outcomes. Data from patients treated with acamprosate, naltrexone, or placebo will be used to identify predictors of drinking outcomes regardless of pharmacological intervention, while stratified analyses and gene-drug interaction analyses will be used to identify treatment- specific (i.e. pharmacogenomic) predictors of acamprosate and naltrexone treatment outcomes. Pathway-based gene set analyses will complement genome-wide association analyses of single nucleotide polymorphisms, as a powerful approach to aggregate modest genetic association signals to identify biological pathways involved in treatment outcomes and drug-specific response. The comprehensive genome-wide search for genetic markers associated with response to acamprosate and naltrexone may not only provide essential information for advancement of precision medicine for AUDs, but may also advance knowledge about the mechanism of action of these medications enabling further drug discovery. Being the first study of its kind, this exploratory/developmental R21 grant will also provide critical information for designing future studies aimed at developing genomic predictors of AUD treatment response.