Multi-ancestry Whole-exome Sequencing Study of Alcohol Use Disorder in Two Cohorts

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. There has been substantial progress in identifying genetic variants underlying AUD. However, there are few whole-exome sequencing (WES) studies of AUD. We analyzed WES of 4,530 samples from the Yale-Penn cohort and 469,835 samples from the UK Biobank (UKB). After quality control, 1,420 AUD cases and 619 controls of European ancestry (EUR) and 1,142 cases and 608 controls of African ancestry (AFR) from Yale-Penn were retained for subsequent analyses. WES data from 415,617 EUR samples (12,861 cases), 6,142 AFR samples (130 cases) and 4,607 South Asian (SAS) samples (130 cases) from UKB were also analyzed. Single-variant association analysis identified the well-known functional variant rs1229984 in ADH1B ( P =4.88×10 ^-31 ) and several other common variants in ADH1C . Gene-based tests identified ADH1B ( P =1.00×10 ^-31 ), ADH1C ( P =5.23×10 ^-7 ), CNST ( P =1.19×10 ^-6 ), and IFIT5 (3.74×10 ^-6 ). This study extends our understanding of the genetic basis of AUD.