Investigating the contribution of coding variants in alcohol use disorder using whole-exome sequencing across ancestries.

Abstract

Background: 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, whole-exome sequencing (WES) studies of AUD are hampered by the lack of available samples.

Methods: We analyzed WES data of 4,530 samples from the Yale-Penn cohort and 469,835 samples from the UK Biobank (UKB), which represents an unprecedented resource for exploring the contribution of coding variants in AUD. After quality controls, 2,039 European-ancestry (EUR: 1,420 cases) and 1,750 African-ancestry samples (AFR: 1,142 cases) from Yale-Penn, and 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 included in the analyses.

Results: We confirmed the well-known functional variant rs1229984 in ADH1B (P=4.88×10^-31) and several other variants in ADH1C. Gene-based collapsing tests considering the high allelic heterogeneity revealed the previously unreported genes, CNST (P=1.19×10^-6) attributable to rare variants with allele frequency < 0.001, and IFIT5 (P=3.74×10^-6) driven by the burden of both common and rare loss-of-function and missense variants.

Conclusions: This study extends our understanding of the genetic architecture of AUD, by providing insights into the contribution of rare coding variants, separately and convergently with common variants in AUD.