Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder

Abstract

ImportanceAlcohol genome-wide association studies (GWASs) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc).ObjectivesTo identify genetic loci associated with MaxAlc and to elucidate the genetic architecture across alcohol traits.Design, Setting, and ParticipantsThis MaxAlc genetic association study was performed among Million Veteran Program participants enrolled from January 10, 2011, to September 30, 2020. Ancestry-specific GWASs were conducted in participants with European (n = 218 623) and African (n = 29 132) ancestry, then meta-analyzed (N = 247 755). Linkage-disequilibrium score regression was used to estimate single nucleotide variant (SNV)–heritability and genetic correlations (rg) with other alcohol and psychiatric traits. Genomic structural equation modeling (gSEM) was used to evaluate genetic associations between MaxAlc and other alcohol traits. Mendelian randomization was used to examine potential causal relationships between MaxAlc and liver enzyme levels. MTAG (multitrait analysis of GWAS) was used to analyze MaxAlc and problematic alcohol use (PAU) jointly.ExposuresGenetic associations.Main Outcomes and MeasuresMaxAlc was defined from the following survey item: “in a typical month, what is/was the largest number of drinks of alcohol you may have had in one day?” with ordinal responses from 0 to 15 or more drinks.ResultsGWASs were conducted on sample sizes of as many as 247 455 US veterans. Participants were 92.68% male and had mean (SD) age of 65.92 (11.70) years. The MaxAlc GWAS resulted in 15 genome-wide significant loci. Top associations in European-ancestry and African-ancestry participants were with known functional variants in the ADH1B gene, namely rs1229984 (P = 3.12 × 10−101) and rs2066702 (P = 6.30 × 10−17), respectively. Novel associations were also found. SNV-heritability was 6.65% (SE, 0.41) in European-ancestry participants and 3.42% (SE, 1.46) in African-ancestry participants. MaxAlc was positively correlated with PAU (rg = 0.79; P = 3.95 × 10−149) and AUD (rg = 0.76; P = 1.26 × 10−127) and had negative rg with the UK Biobank “alcohol usually taken with meals” (rg = −0.53; P = 1.40 × 10−50). For psychiatric traits, MaxAlc had the strongest genetic correlation with suicide attempt (rg = 0.40; P = 3.02 × 10−21). gSEM supported a 2-factor model with MaxAlc loading on a factor with PAU and AUD and other alcohol consumption measures loading on a separate factor. Mendelian randomization supported an association between MaxAlc and the liver enzyme gamma-glutamyltransferase (β = 0.012; P = 2.66 × 10−10). MaxAlc MTAG resulted in 31 genome-wide significant loci.Conclusions and RelevanceThe findings suggest that MaxAlc closely aligns genetically with PAU traits. This study improves understanding of the mechanisms associated with normative alcohol consumption vs problematic habitual use and AUD as well as how MaxAlc relates to psychiatric and medical conditions genetically and biologically.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals

“…We confirmed significant positive genetic correlations ( r g ) in EUR between PAU and substance use and psychiatric traits 6 (Supplementary Table 15). AD 5 showed the highest correlation with PAU ( r g =0.85, SE=0.07, p =4.49×10 −34 ), followed by maximum habitual alcohol intake 9 ( r g =0.79, SE=0.03, p =1.24×10 −191 ), opioid use disorder 41 ( r g =0.78, SE=0.04, p =1.20×10 −111 ), drinks per week 11 ( r g =0.76, SE=0.02, p <1×10 −200 ), smoking trajectory 42 ( r g =0.63, SE=0.02, p =2.47×10 −176 ), and cannabis use disorder 14 ( r g =0.61, SE=0.04, p =4.85×10 −63 ). We next tested r g between AUD and 13 published traits with large GWAS in AFR (Figure 3, Supplementary Table 16).…”

“…As in EUR, the traits with the strongest correlations were substance use traits. Maximum habitual alcohol intake 9 ( r g =0.67, SE=0.15, p =8.13×10 −6 ) showed the highest correlation with AUD, followed by opioid use disorder 41 ( r g =0.62, SE=0.10, p =6.70×10 −10 ), and smoking trajectory 42 ( r g =0.57, SE=0.08, p =3.64×10 −4 ). Major depressive disorder 43 and smoking initiation 11 showed nominally significant ( p <0.05) positive correlation with AUD and type 2 diabetes 44 showed a nominally significant negative correlation.…”

“…We confirmed significant positive genetic correlations (rg) in EUR between PAU and substance use and psychiatric traits 6 (Supplementary Table 15). AD 5 showed the highest correlation with PAU (rg=0.85, SE=0.07, p=4.49×10 -34 ), followed by maximum habitual alcohol intake 9 ). We next tested rg between AUD and 13 published traits with large GWAS in AFR (Figure 3, Supplementary Table 16).…”

“…Alcohol use disorder (AUD) is a chronic relapsing disease associated with a host of adverse medical, psychiatric, and social consequences 1 . Given observed heritability (h 2 ~50% 2 ), there has been substantial progress made in genome-wide association studies (GWAS) of AUD and problematic drinking [3][4][5][6][7][8][9] , and also for measures of alcohol consumption 10,11 . A prior GWAS of problematic alcohol use (PAU, a phenotype based on a meta-analysis of highly genetically correlated (genetic correlations >0.7) AUD 7 , alcohol dependence [AD] 5 , and AUDIT-P [Alcohol Use Disorders Identification Test-Problem score, a measure of problematic drinking] 4,12 , N=435,563) identified 29 independent risk variants, predominantly in European (EUR) ancestry subjects 6 .…”

The Promise of an Evolutionary Perspective of Alcohol Consumption

“… 51 These data provide persuasive evidence that Homo sapiens underwent recent selection with respect to alcohol consumption, at least in Southeast Asia, although alternative selective scenarios that predate the invention of fermentation—such as toxins produced by fungi found on moldy rice or infectious disease—have been suggested. 52 Other studies, 53 - 55 including a recent well-powered GWA study of alcohol-use traits, 56 indicate that ADH1B underwent a similar selection process in Africa. A distinct ADH1B gain-of-function Arg369Cys variant, rs2066702, found in African-American and some Native American populations was found to correlate with lower incidence of alcoholism, lower maximal habitual alcohol intake, and less problematic alcohol use.…”