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

IF 9.6 1区医学 Q1 NEUROSCIENCES

Biological Psychiatry Pub Date : 2025-01-30 DOI:10.1016/j.biopsych.2025.01.020

Lu Wang, Henry R Kranzler, Joel Gelernter, Hang Zhou

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引用次数: 0

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.

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来源期刊

Biological Psychiatry 医学-精神病学

CiteScore

18.80

自引率

2.80%

发文量

1398

审稿时长

33 days

期刊介绍： Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.