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

paper Cited Public

Authors: Jorgenson, E; Thai, K K; Hoffmann, T J; Sakoda, L C; Kvale, M N; Banda, Y; Schaefer, C; Risch, N; Mertens, J; Weisner, C; Choquet, H
Year: 2017
Journal: Molecular psychiatry
PMID: 28485404
DOI: 10.1038/mp.2017.101
PMCID: PMC5568932

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although 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 (odd ratio (OR)=0.40, P=2.28 × 10) in East Asians, and also an effect on drinks/week (beta=-0.17, P=5.42 × 10) 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 for drinker status and beta=-0.19, P=1.91 × 10 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10 and beta=-0.21, P=2.58 × 10, respectively). Although 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 for drinks/week and OR=0.96, P=4.08 × 10 for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10 for drinks/week and OR=1.04, P=5 × 10 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.

#	Section	Preview
0	INTRODUCTION	Alcohol consumption is a common, complex trait, and heavy alcohol use increases the risk of alcohol…
1	INTRODUCTION	Alcohol drinking behavior can be measured in a number of ways, including cross-sectional measures of…
2	INTRODUCTION	explain a small proportion of the genetic contribution to variation in alcohol use reported in twin…
3	INTRODUCTION	To address this gap, we conducted a GWAS of alcohol consumption in the large and ethnically diverse…
4	MATERIALS AND METHODS — Study Population	We analyzed participants from the Genetic Epidemiology Research in Adult Health and Aging (GERA)…
5	MATERIALS AND METHODS — Phenotype Definitions	Two statistically independent alcohol consumption phenotypes were examined: any intake…
6	MATERIALS AND METHODS — Genotyping and Quality Control Procedures	DNA samples were extracted from Oragene kits (DNA Genotek Inc., Ottawa, ON, Canada) at KPNC and…
7	MATERIALS AND METHODS — Imputation	Imputation was also conducted on an array-wise basis and has been described elsewhere.35 Following…
8	MATERIALS AND METHODS — Single Nucleotide Polymorphisms (SNPs) Selection for Extending Prior GWAS Findings	SNPs previously reported to be associated at the genome-wide level of significance (p<5×10−8)…
9	MATERIALS AND METHODS — Statistical Analysis — GWAS Analyses and Covariate Adjusment	GWA analyses were conducted using PLINK44 v1.07 (http://pngu.mgh.harvard.edu/purcell/plink/) and R45…
10	MATERIALS AND METHODS — Statistical Analysis — GWAS Analyses and Covariate Adjusment	as a covariate, and those analyses without lean body mass produced relatively similar results…
11	MATERIALS AND METHODS — Statistical Analysis — Trans-Ethnic Meta-Analysis	For the combined meta-analysis of the two alcohol consumption phenotypes across the 4 race/ethnicity…
12	MATERIALS AND METHODS — Statistical Analysis — Association Analysis of Previously Reported SNPs	To determine whether the 12 SNPs previously-reported as genome-wide significant in GWAS for alcohol…
13	MATERIALS AND METHODS — Statistical Analysis — Conditional Analysis	To assess whether the GCKR, and KLB SNPs recently reported by Schumann et al.,29 contribute to…
14	RESULTS — Study Population	In this study, the proportion of subjects that report consuming alcohol (drinkers) was greatest for…
15	RESULTS — Top GWAS Findings	We first conducted a GWAS analysis of the two alcohol consumption phenotypes, stratified by…
16	RESULTS — Top GWAS Findings	second strongest association was detected in non-Hispanic white subjects for the well-known…
17	RESULTS — Top GWAS Findings	non-stratified East Asian sample. However, for the quantitative trait drinks/week, we found a…
18	RESULTS — Trans-Ethnic Meta-Analysis	We then conducted a combined meta-analysis across the 4 race/ethnicity groups (non-Hispanic Whites,…
19	RESULTS — Extending Findings from Prior GWAS	Finally, we investigated a total of 12 SNPs (6 SNPs for European ancestry subjects, 4 SNPs for East…

Name	Type
1000 Genomes Project	cohort
12 SNPs local	variant
acetaldehyde	drug
acetaldehyde accumulation local	phenotype
ADH1B	gene
ADH1B rs2066702 local	variant
Affymetrix Axiom arrays local	drug
African American	cohort
African ancestry population local	cohort
African ancestry subjects local	cohort
alcohol	phenotype
alcohol consumption-related traits local	phenotype
Alcohol consumption-related traits local	phenotype
alcohol dependence	phenotype
alcohol drinker status local	phenotype
alcohol-related phenotypes	phenotype
Alcohol Use	phenotype
Alcohol Use Disorder	phenotype
alcohol use disorders	phenotype
ALDH2	gene
ancestry principal components (PCs) local	drug
any intake local	phenotype
any intake (drinker/non-drinker status) local	phenotype
Ashkenazi ancestry local	phenotype
Asian	cohort
Asian ancestry populations local	cohort
AUTS2	gene
blood alcohol concentration	phenotype
Body size local	phenotype
C12orf51	gene
cancer	phenotype
cardiovascular disease	phenotype
CCDC63	gene
common variants (MAF ≥ 1%) local	variant
DDC	gene
DDC rs11575537 local	variant
Drinker/non-drinker status local	phenotype
drinkers	phenotype
drinker status local	phenotype
Drinker status local	phenotype
drinks per week	phenotype
East Asian	cohort
East Asian ancestry subjects local	cohort
ethanol consumption	phenotype
European ancestry	cohort
European-ancestry population local	cohort
European population	cohort
GCKR	gene
Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort local	cohort
genome-wide association studies	cohort
GERA	cohort
heavy drinking	phenotype
Hispanic	phenotype
Hispanic/Latinos local	cohort
Impute2	drug
Infectious disease	phenotype
Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) local	cohort
Klb	gene
KPNC local	cohort
KPNC health plan local	cohort
Large and ethnically diverse populations local	cohort
lean body mass	phenotype
liver disease	phenotype
LOC100507053	gene
maxdrinks	phenotype
Maximum drinks in 24-hour period local	phenotype
men	cohort
missense variant in ADH1B local	variant
missense variant in ALDH2 local	variant
Motor vehicle accidents	phenotype
MYL2	gene
nausea	phenotype
neuropsychiatric disorders	phenotype
non-Hispanic whites	cohort
non-Hispanic white sample local	cohort
OAS3	gene
Oragene kits local	drug
other race/ethnicity groups local	cohort
Quantity of alcoholic drinks consumed per week local	phenotype
Race/Ethnicity groups local	cohort
rare functional variants local	variant
Regular quantity at the time of heaviest drinking local	phenotype
regular quantity of alcoholic drinks consumed per week local	phenotype
Research Program on Genes, Environment, and Health (RPGEH) local	cohort
rs11128951 local	variant
rs11940694	variant
rs1229984	variant
rs1799876	variant
rs200475889	variant
rs2066702	variant
rs2309169	variant
rs28864441	variant
rs4665985 local	variant
rs671	variant
rs6943555	variant
rs7686419 local	variant
rs780094 local	variant
Schumann et al. study local	cohort
SERPINC1	gene
SGOL1	gene
Shape-IT local	drug
tolerance	phenotype
trans-ethnic meta-analysis local	cohort
trauma	phenotype
Twin cohort	cohort
women	cohort

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Predicting risk for Alcohol Use Disorder using longitudinal data with multimodal biomarkers and family history: a machine learning study.	Kinreich S et al.	—	2021	→
Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis.	Wang Q et al.	—	2021	→
Secondary Analysis of a Randomized Clinical Trial of Naltrexone Among Women Living With HIV: Correlations Between Reductions in Self-Reported Alcohol Use and Changes in Phosphatidylethanol.	Richards VL et al.	—	2021	→
Sociodemographic and clinical factors associated with transdermal alcohol concentration from the SCRAM biosensor among persons living with and without HIV.	Richards VL et al.	—	2021	→
The Aldehyde Dehydrogenase ALDH2*2 Allele, Associated with Alcohol Drinking Behavior, Dates Back to Prehistoric Times.	Lin CL et al.	—	2021	→
Using Mendelian randomization analysis to better understand the relationship between mental health and substance use: a systematic review.	Treur JL et al.	—	2021	→
Whole Genome Interpretation for a Family of Five.	Corpas M et al.	—	2021	→
A Complex Systems Model of Breast Cancer Etiology: The Paradigm II Conceptual Model.	Hiatt RA et al.	—	2020	→
ADH1B∗2 Is Associated With Reduced Severity of Nonalcoholic Fatty Liver Disease in Adults, Independent of Alcohol Consumption.	Vilar-Gomez E et al.	—	2020	→
A Genome-Wide Association Study Identifies the Association between the 12q24 Locus and Black Tea Consumption in Japanese Populations.	Furukawa K et al.	—	2020	→
Alcohol consumption and its associated factors among pregnant women in Sub-Saharan Africa: a systematic review and meta-analysis' as given in the submission system.	Addila AE et al.	—	2020	→
Comprehensive genomic analysis of dietary habits in UK Biobank identifies hundreds of genetic associations.	Cole JB et al.	—	2020	→
Flying Together: <i>Drosophila</i> as a Tool to Understand the Genetics of Human Alcoholism.	Lathen DR et al.	—	2020	→
Functional validity, role, and implications of heavy alcohol consumption genetic loci.	Thompson A et al.	—	2020	→
Genetics of Obesity in East Asians.	Sun C et al.	—	2020	→
GWAS of 165,084 Japanese individuals identified nine loci associated with dietary habits.	Matoba N et al.	—	2020	→
Potential influence of socioeconomic status on genetic correlations between alcohol consumption measures and mental health.	Marees AT et al.	—	2020	→
Role of aldehyde dehydrogenases, alcohol dehydrogenase 1B genotype, alcohol consumption, and their combination in breast cancer in East-Asian women.	Park B et al.	—	2020	→
Translational Molecular Approaches in Substance Abuse Research.	Fulton SL et al.	—	2020	→
A genome-wide association study of bitter and sweet beverage consumption.	Zhong VW et al.	—	2019	→
Alcohol use disorders.	Carvalho AF et al.	—	2019	→
ALDH2 and Cardiovascular Disease.	Chen CH et al.	—	2019	→
Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.	Liu M et al.	—	2019	→
Beyond genome-wide significance: integrative approaches to the interpretation and extension of GWAS findings for alcohol use disorder.	Salvatore JE et al.	—	2019	→
Convergent Evidence From Humans and Drosophila melanogaster Implicates the Transcription Factor MEF2B/Mef2 in Alcohol Sensitivity.	Schmitt RE et al.	—	2019	→
Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use.	Brazel DM et al.	—	2019	→
Genetic determinants of beverage consumption: Implications for nutrition and health.	Cornelis MC	—	2019	→
Genetic evidence for assortative mating on alcohol consumption in the UK Biobank.	Howe LJ et al.	—	2019	→
Genetic loci for alcohol-related life events and substance-induced affective symptoms: indexing the "dark side" of addiction.	Peng Q et al.	—	2019	→
Genetics of alcohol use disorder: a review.	Deak JD et al.	—	2019	→
Genome-Wide Association Study Meta-Analysis of the Alcohol Use Disorders Identification Test (AUDIT) in Two Population-Based Cohorts.	Sanchez-Roige S et al.	—	2019	→
Genome-wide association study of alcohol dependence in male Han Chinese and cross-ethnic polygenic risk score comparison.	Sun Y et al.	—	2019	→
Genome-wide association study of alcohol use disorder identification test (AUDIT) scores in 20 328 research participants of European ancestry.	Sanchez-Roige S et al.	—	2019	→
Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.	Gelernter J et al.	—	2019	→
GWAS and network analysis of co-occurring nicotine and alcohol dependence identifies significantly associated alleles and network.	Xiang B et al.	—	2019	→
GWAS of habitual coffee consumption reveals a sex difference in the genetic effect of the 12q24 locus in the Japanese population.	Jia H et al.	—	2019	→
Multivariate Analyses Reveal Biological Components Related to Neuronal Signaling and Immunity Mediating Electroencephalograms Abnormalities in Alcohol-Dependent Individuals from the Collaborative Study on the Genetics of Alcoholism Cohort.	Meda SA et al.	—	2019	→
New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders.	Evangelou E et al.	—	2019	→
The Genetic Relationship Between Alcohol Consumption and Aspects of Problem Drinking in an Ascertained Sample.	Johnson EC et al.	—	2019	→
Alcohol consumption and risk of gastric cardia adenocarcinoma and gastric noncardia adenocarcinoma: A 16-year prospective analysis from the NIH-AARP diet and health cohort.	Wang S et al.	—	2018	→
Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review.	Edenberg HJ et al.	—	2018	→
Association between ALDH2 and ADH1B polymorphisms, alcohol drinking and gastric cancer: a replication and mediation analysis.	Ishioka K et al.	—	2018	→
A Whole Methylome Study of Ethanol Exposure in Brain and Blood: An Exploration of the Utility of Peripheral Blood as Proxy Tissue for Brain in Alcohol Methylation Studies.	Clark SL et al.	—	2018	→
Electronic health records: the next wave of complex disease genetics.	Wolford BN et al.	—	2018	→
GABA<sub>A</sub> receptor polymorphisms in alcohol use disorder in the GWAS era.	Koulentaki M et al.	—	2018	→
Genomewide Association Study of Alcohol Dependence and Related Traits in a Thai Population.	Gelernter J et al.	—	2018	→
Human Genetics of Addiction: New Insights and Future Directions.	Hancock DB et al.	—	2018	→
Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.	Edwards AC et al.	—	2018	→
Polygenic risk for alcohol consumption and its association with alcohol-related phenotypes: Do stress and life satisfaction moderate these relationships?	Mies GW et al.	—	2018	→
Recent Selection on a Class I ADH Locus Distinguishes Southwest Asian Populations Including Ashkenazi Jews.	Gu S et al.	—	2018	→
Genome-wide association study of Alcohol Use Disorder Identification Test (AUDIT) scores in 20,328 research participants of European ancestry	Sanchez-Roige S et al.	—	2017	—
Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis.	Larsson SC et al.	—	2017	→