A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals

Abstract

Background: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

Methods: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses.

Findings: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort.

Interpretation: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine.

Funding: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Keywords: ADH1B; ADH1C; Alcohol; Metabolising enzyme genes; PheWAS; rs1229984.

Fig. 1

Overview of the study. Four variants (rs1229984-T, rs2066702-A, rs698-T, rs671-A) were selected based on a systematic literature review of genes (ADH1B, ADH1C, ALDH2) implicated in alcohol use disorder and other alcohol-related traits. rs671-A could not be tested due to extremely low allele frequency in the populations studied. We tested the association of the three remaining SNPs and 1109 traits available in 23andMe via a phenome-wide association study (PheWAS). We included traits with >1000 responses per cohort (EUR N = 1012–2,619,939; LA N = 1006–446,646; AA N = 1000–146,776). To assess evidence of a causal effect of more alcohol consumption by ethanol metabolising enzyme SNPs and PheWAS significant traits, a two-sample MR analysis and a one-sample replication Mendelian randomisation (MR) analysis were conducted. SNP effects associated with AUDIT Consumption and number of drinks consumed over the past 2 weeks were treated as exposures for the two- and one-sample MR analyses respectively. ∗In order to have a minimum of three SNPs for MR analyses, an additional ADH1B SNP (rs3114045) was added to replace replaced rs2066702, as this SNP was not available in the AUDIT Consumption GWAS.

Fig. 2

FDR (5%)-significant PheWAS associations between rs1229984-T and a selection of traits from multiple categories in the European (EUR), Latin American (LA), and African American (AA) cohorts. The full list of FDR-significant associations is shown in Supplementary Tables S11–S13.

Fig. 3

a) Integrated bar chart featuring significant traits identified in both the PheWAS and MR analyses, grouped by categories. Each bar represents the number of outcomes for each category. The percentage represents the proportion of significant outcomes from the total possible number of outcomes within that specific category. b) Integrated network analysis of PheWAS and MR results in the European cohort. Each node in the network denotes one of the 233 PheWAS or 35 MR significant traits (annotated), with colour indicating the category of the association, the width of the line denoting the magnitude (beta) of the effect size, and the size of the shape reflecting the association strength (log10 p values).