title: Which alcohol use disorder criteria contribute to the association of ADH1B with alcohol dependence?
abstract: Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM-IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding.
authors.affiliation: Center for Studies of Addiction, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Hart
authors.affiliation: Center for Studies of Addiction, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Lynch
authors.affiliation: Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Genetics & Genomics, Biostatistics, and Epidemiology, Schools of Medicine and Public Health, Boston University, Boston, MA, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Farrer
authors.affiliation: Departments of Psychiatry, Division of Human Genetics, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT, USA.|VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Center for Studies of Addiction, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|VISN4 MIRECC, Philadelphia VAMC, Philadelphia, PA, USA.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics / Q000706:statistics & numerical data; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D019973:Alcohol-Related Disorders / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics; D004327:Drinking Behavior; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
chemical_list: C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase
keywords: Alcohol dehydrogenase 1B; DSM; tolerance
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