Which alcohol use disorder criteria contribute to the association ofADH1Bwith 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.

Genome‐wide association studies of alcohol dependence, DSM‐IV criterion count and individual criteria

“…Although GWS was only noted in the trans-ancestral (EA + AA) analysis, as shown in Table S7, rs1229984 was associated with the AD criterion count and criteria indexing physiological dependence and Desire to cut drinking at GWS levels, and with other AD criteria at nominal levels of significance. Similar to another study, 16 we found that while rs1229984 was associated with each individual criterion (EA all P < 3.61E−04; EA + AA all P < 4.54E 6 However, for DSM-IV AD criterion count, rs1229984 was GWS in both the EA and EA + AA analyses.…”

“…9 Genomic data also support this variability with Palmer et al reporting a SNP-based heritability ranging from 13% (Time spent drinking) to 34% (Tolerance). 16 Another strategy to improve the ability to detect variants contributing to DSM-IV AD is to consider the severity of the AD. In addition, in one study, the observed associations with ADH1B loci were also differentially attributable to Tolerance, Withdrawal, Drinking more than intended, and Time spent drinking, relative to other criteria.…”

“…In addition, in one study, the observed associations with ADH1B loci were also differentially attributable to Tolerance, Withdrawal, Drinking more than intended, and Time spent drinking, relative to other criteria. 16 Another strategy to improve the ability to detect variants contributing to DSM-IV AD is to consider the severity of the AD. One approach is to analyze a quantitative variable representing the total number of criteria that a person endorses.…”

Addiction Biomarkers: Dimensional Approaches to Understanding Addiction

“…Notwithstanding, the present-day diagnostic framework for mental disorders might, without drastic revision, be improved with the aid of such measures. For addictive disorders, the story is much the same and, for example, ADH1B genotypes (alcohol), while associated with DSM criteria, are not integrated within this framework [11]. Furthermore, downregulation of striatal dopamine D2 receptor protein expression, observable by raclopride PET [12] and disturbances of the stress axis [13,14], have long been recognized to occur among patients who are addicts, but have not been incorporated into clinical practice, or used in clinical research in any systematic way.…”

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

“…We chose these variants on the basis of numerous GWAS (Gelernter et al, 2014;Xu et al, 2015) and candidate-locus studies (Sherva et al, 2010;Hart et al, 2015;Jensen et al, 2015), and a recent meta-analysis of genetic studies of nicotine and alcohol traits (Buhler et al, 2015) and GWAS performed previously in different population groups (David et al, 2012;Gelernter et al, 2014).…”