| Title: | Investigating the Contribution of Coding Variants in Alcohol Use Disorder Using Whole-Exome Sequencing Across Ancestries |
| Journal: | Biological Psychiatry |
| Published: | 30 Jan 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39892688/ |
| DOI: | https://doi.org/10.1016/j.biopsych.2025.01.020 |
Publication 14470
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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.</p>
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.</p>
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.</p>
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.</p>
15 Keywords
- Adult
- Alcohol Dehydrogenase
- Alcoholism
- Asian People
- Black People
- Cohort Studies
- Exome Sequencing
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- United Kingdom
- White People
4 Authors
- Lu Wang
- Henry R Kranzler
- Joel Gelernter
- Hang Zhou
1 Application
| Application ID | Title |
|---|---|
| 41910 | Genetics of complex diseases, comorbidities, and other traits in multi-ethnic samples |
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