Abstract
BACKGROUND: 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.
METHODS: 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.
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 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.
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.