Investigating the Contribution of Coding Variants in Alcohol Use Disorder Using Whole-Exome Sequencing Across...

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. There has been substantial progress in identifying genetic variants that underlie AUD. However, whole-exome sequencing studies of AUD have been hampered by the lack of available samples.

We analyzed whole-exome sequencing data of 4530 samples from the Yale-Penn cohort and 469,835 samples from the UK Biobank, which represent an unprecedented resource for exploring the contribution of coding variants in AUD. After quality control, 1750 African-ancestry (1142 cases) and 2039 European-ancestry (1420 cases) samples from the Yale-Penn and 6142 African-ancestry (130 cases), 415,617 European-ancestry (12,861‬ cases), and 4607 South Asian (130 cases) samples from the UK Biobank cohorts were included in the analyses.

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 that considered 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.

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.