Genomewide Association Study for Maximum Number of Alcoholic Drinks in European Americans and African Americans

Abstract

Background We conducted a genome-wide association study (GWAS) for maximum number of alcoholic drinks consumed in a 24-hour period (“MaxDrinks”), in two independent samples comprised of over 9,500 subjects, following up on our GWAS for alcohol dependence (AD) in European Americans (EAs) and African Americans (AAs). Methods The samples included our GWAS samples (Yale-UPenn) recruited for studies of the genetics of drug or alcohol dependence, and a public available sample: the Study of Addiction: Genetics and Environment (SAGE). Genome-wide association analysis was performed for ∼890,000 single nucleotide polymorphisms (SNPs) using linear association random effects models. European Americans and African Americans were separately analyzed. Results The results confirmed significant associations of the well-known functional loci at ADH1B with MaxDrinks in EAs (rs1229984 Arg48His p= 5.96 x10-15) and AAs (rs2066207 Arg370Cys, p=2.50 x 10-10). The region of significant association on chromosome 4 was extended to LOC100507053 in AAs but not EAs. We also identified potentially novel significant common SNPs for MaxDrinks in EAs in the Yale-UPenn sample: rs1799876 at SERPINC1 on chromosome 1 (4.00 x 10-8) and rs2309169 close to ANKRD36 on chromosome 2 (p=5.58 x 10-9). After adjusting for the peak SNP rs1229984 on ADH1B, rs1799876 was nearly significant (p= 1.99 x 10-7) and rs2309169 remained highly significant (2.12 x 10-9). Conclusions The results provide further support that ADH1B modulates alcohol consumption. Future replications of potential novel loci are warranted. This is the largest MaxDrinks GWAS to date, the first in AAs.

Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424)

“…The GWAS for AUDIT-C (Figure 1a, Table 1 and Supplementary Tables 1 and 2) identified 13 independent loci in EAs, 2 in AAs, 1 in LAs (Hispanic and Latino Americans) and 1 in EAAs (East Asian Americans) (Supplementary Figures 4 and 5). Meta-analysis across the 5 populations (see Methods) also yielded 13 independent loci, 5 of which were previously associated with a self-reported measure of alcohol consumption: GCKR 21 , KLB 20,21 , ADH1B 18,21 , ADH1C 21 , and SLC39A8 8 . The 8 novel trans-population signals for AUDIT-C included VRK2 (Vaccinia related kinase 2), DCLK2 (Doublecortin like kinase 2), ISL1 (ISL LIM Homeobox 1), FTO (Alpha-Ketoglutarate Dependent Dioxygenase), IGF2BP1 (Insulin like growth factor 2 MRNA binding protein 1), PPR1R3B (Protein phosphatase 1 regulatory subunit 3B), BRAP (BRCA1 associated protein), BAHCC1 (BAH domain and coiled-coil containing 1), and RBX1 (Ring-box 1).…”

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

“…The best replicated loci for drinking behaviors map to genes encoding alcohol-metabolizing enzymes. Minor alleles at ADH1B (ie, rs1229984 and rs2066702) are associated with lower levels of drinking (Xu et al, 2015). Consistent with the genetic associations, these variants increase the alcohol oxidization rate, raising acetaldehyde levels and its related aversive symptoms, including facial flushing, nausea, headache, and tachycardia (Edenberg, 2007).…”

“…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).…”

Emerging roles for ncRNAs in alcohol use disorders

“…For example, variants located within an alcohol dehydrogenase (ADH) cluster included a large antisense-overlapping lncRNA, LOC100507053 (Xu et al, 2015), covering multiple loci for ADH genes that form a risk-genomic region for alcohol dependence identified by GWAS and candidate gene studies (Gelernter et al, 2009; Li, Zhao, & Gelernter, 2011; Xu et al, 2015). This class of antisense-overlapping lncRNAs frequently uses diverse transcriptional and post-transcriptional regulatory mechanisms to fulfill a wide variety of biological roles (Sartor et al, 2012; St Laurent, Wahlestedt, & Kapranov, 2015), and thus may significantly regulate cellular responses to alcohol.…”