Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study

Abstract

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. While a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic Whites, Hispanic/Latinos, East Asians, and African Americans. We examined two statistically independent phenotypes reflecting subjects’ alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status), and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously-reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (OR=0.40, p=2.28×10−72) in East Asians, and also an effect on drinks/week (beta=−0.17, p=5.42×10−4) in the same group. We also observed a genome-wide significant association in non-Hispanic Whites between the previously-reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, p=2.47×10−20 for drinker status and beta=−0.19, p=1.91×10−35 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, p=4.35×10−7 and beta=−0.21, p=2.58×10−6, respectively). While prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=−0.04, p=3.41×10−10 for drinks/week and OR=0.96, p=4.08×10−5 for drinker status), and rs4665985 (beta = 0.04, p=2.26×10−8 for drinks/week and OR=1.04, p=5.00×10−4 for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1, and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

Genome-wide association study meta-analysis of the Alcohol Use Disorder Identification Test (AUDIT) in two population-based cohorts (N=141,932)

“…In addition, two other regions in 4q23 were associated with AUDIT total score in the meta-analysis: one of the index SNPs was located in the ADH1C gene; however, conditional analysis of this region in UKB alone suggests that these multiple hits may in fact be tagging the rs1229984 signal. This region has been previously associated with alcohol consumption, AUD, and AUDIT scores (6,7,9,10) We also replicated the association between KLB ( Supplementary Table 12), on chromosome 4q14, and alcohol consumption (9,11,12); the index SNP rs11940694, which is located in the intron of KLB, was associated with AUDIT total score in the present study. Clump based pruning identified rs11940694 and rs4975012 as independent hits in the KLB region.…”

“…Variants in this region were associated with AUDIT total score, AUDIT-C and AUDIT-P, demonstrating that alcohol metabolism is a risk factor for both alcohol consumption and problematic use. The second strongest signal, also associated with the three AUDIT phenotypes, is located in KLB, confirming the robust association of this gene with both alcohol consumption (9,11,12) in humans, and in mice (12). However, the biology of this locus could be more complex than previously described.…”

“…( Supplementary Table 13). AUDIT total score was also associated with SNPs that localized to GCKR on chromosome 2p23.3, which has been previously associated with alcohol consumption (9,11). Five SNPs comprised the credible set at the GCKR locus, which also spans the SNX17 gene, including the missense variant (rs1260326) in GCKR that was identified as the index SNP.…”

“…This approach has allowed for the relatively rapid collection of much larger sample sizes (e.g. >100,000s individuals) and has identified numerous loci associated with both pharmacokinetic and pharmacodynamic factors that influence alcohol consumption, including ADH1B/ADH1C/ADH5 (9)(10)(11), KLB (encoding β -klotho) (9,11,12) and GCKR, encoding the glucokinase regulatory protein (9,11). However, the genetic overlap between alcohol consumption (units per week) and DSM-IV diagnosed alcohol dependence is moderate (r g = 0.38) (13), reinforcing the notion that alcohol consumption cannot be used as a surrogate for alcohol dependence or AUD.…”

Genome-wide association study of alcohol consumption in Russian population

“…A meta-analysis included >105,000 individuals of European ancestry revealed that rs11940694 in KLB gene is associated with alcohol intake [12] . Genetic factors of AC vary by race and ethnicity [13] ; thereby GWAS in different population are needed to reveal the genetic pattern of AC.…”