Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations

Henry R Kranzler,William C Becker,Scott M Damrauer ,Amy C Justice,Daniel J Rader,Renato Polimanti,Rachel Vickers‐Smith ,Janet P Tate,Derek Klarin,Philip S Tsao,John D Overton ,Aris Baras,Hang Zhou,Rachel L Kember,Hongyu Zhao,Ke Xu,John Concato,Zhongshan Cheng,Jeffrey G Reid ,Joel Gelernter

doi:10.1038/s41467-019-09480-8

Abstract

Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits’ PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

Highlights

139 million disability-adjusted life years, and 5.1% of the burden of disease and injury were attributable to alcohol consumption, with the magnitude of harm determined by the volume of alcohol consumed and the drinking pattern[1]
Using Functional Mapping and Annotation (FUMA)[26] software to investigate the pathway or biological process enrichment with summary statistics as input and false discovery rate (FDR) correction for multiple testing, we find multiple reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are significantly enriched for AUDIT-C (Supplementary Data 11, Supplementary Fig. 15) and alcohol use disorder (AUD) (Supplementary Data 12, Supplementary Fig. 16) in each population
We report here a genomewide association studies (GWASs) of two alcohol-related traits in a sample of 274,424 Million Veteran Program (MVP) participants from five population groups—EA, AA, Latino American (LA), East Asian American (EAA), and South Asian American (SAA)—using two electronic health record (EHR)-derived phenotypes: age-adjusted AUDIT-C score and AUD diagnostic codes

Summary

Introduction

139 million disability-adjusted life years, and 5.1% of the burden of disease and injury were attributable to alcohol consumption, with the magnitude of harm determined by the volume of alcohol consumed and the drinking pattern[1]. A GWAS of AUD that included AUDIT-C as a covariate identified five GWS loci in EAs and one in AAs (Supplementary Data 8).

Results

Conclusion