Multi-ancestry Whole-exome Sequencing Study of Alcohol Use Disorder in Two Cohorts

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

doi:10.1101/2024.04.05.24305412

Cited by 2 publications

References 59 publications

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Whole-exome sequencing study of opioid dependence offers novel insights into the contributions of exome variants

Wang,

Nuñez,

Kranzler

et al. 2024

Preprint

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Opioid dependence (OD) is epidemic in the United States and it is associated with a variety of adverse health effects. Its estimated heritability is ~50%, and recent genome-wide association studies have identified more than a dozen common risk variants. However, there are no published studies of rare OD risk variants. In this study, we analyzed whole-exome sequencing data from the Yale-Penn cohort, comprising 2,100 participants of European ancestry (EUR; 1,321 OD cases) and 1,790 of African ancestry (AFR; 864 cases). A novel low-frequency variant (rs746301110) in the RUVBL2 gene was identified in EUR (p=6.59*10-10). Suggestive associations (p<1*10-5) were observed in TMCO3 in EUR, in NEIL2 and CFAP44 in AFR, and in FAM210B in the cross-ancestry meta-analysis. Gene-based collapsing tests identified SLC22A10, TMCO3, FAM90A1, DHX58, CHRND, GLDN, PLAT, H1-4, COL3A1, GPHB5 and QPCTL as top genes (p<1*10-4) with most associations attributable to rare variants and driven by the burden of predicted loss-of-function and missense variants. This study begins to fill the gap in our understanding of the genetic architecture of OD, providing insights into the contribution of rare coding variants and potential targets for future functional studies and drug development.

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Whole-exome sequencing study of opioid dependence offers novel insights into the contributions of exome variants

Wang,

Nuñez,

Kranzler

et al. 2024

Preprint

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Human genetics and epigenetics of alcohol use disorder

Zhou,

Gelernter

2024

Journal of Clinical Investigation

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Alcohol use disorder (AUD) is a prominent contributor to global morbidity and mortality. Its complex etiology involves genetics, epigenetics, and environmental factors. We review progress in understanding the genetics and epigenetics of AUD, summarizing the key findings. Advancements in technology over the decades have elevated research from early candidate gene studies to present-day genome-wide scans, unveiling numerous genetic and epigenetic risk factors for AUD. The latest GWAS on more than one million participants identified more than 100 genetic variants, and the largest epigenome-wide association studies (EWAS) in blood and brain samples have revealed tissue-specific epigenetic changes. Downstream analyses revealed enriched pathways, genetic correlations with other traits, transcriptome-wide association in brain tissues, and drug-gene interactions for AUD. We also discuss limitations and future directions, including increasing the power of GWAS and EWAS studies as well as expanding the diversity of populations included in these analyses. Larger samples, novel technologies, and analytic approaches are essential; these include whole-genome sequencing, multiomics, single-cell sequencing, spatial transcriptomics, deep-learning prediction of variant function, and integrated methods for disease risk prediction.

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Multi-ancestry Whole-exome Sequencing Study of Alcohol Use Disorder in Two Cohorts

Cited by 2 publications

References 59 publications

Whole-exome sequencing study of opioid dependence offers novel insights into the contributions of exome variants

Whole-exome sequencing study of opioid dependence offers novel insights into the contributions of exome variants

Human genetics and epigenetics of alcohol use disorder

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