Case-only exome variation analysis of severe alcohol dependence using a multivariate hierarchical gene clustering approach.

Autor: Gentry AE; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America., Alexander JC; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America., Ahangari M; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Integrative Life Sciences Ph.D. Program, Virginia Commonwealth University, Richmond, Virginia, United States of America., Peterson RE; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Psychiatry and Behavioral Sciences, Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, New York, United States of America.; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America., Miles MF; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America., Bettinger JC; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America., Davies AG; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America., Groteweil M; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America., Bacanu SA; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America.; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America., Kendler KS; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America.; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America., Riley BP; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America.; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America., Webb BT; VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.; GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, North Caroline, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Apr 25; Vol. 18 (4), pp. e0283985. Date of Electronic Publication: 2023 Apr 25 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0283985
Abstrakt: Background: Variation in genes involved in ethanol metabolism has been shown to influence risk for alcohol dependence (AD) including protective loss of function alleles in ethanol metabolizing genes. We therefore hypothesized that people with severe AD would exhibit different patterns of rare functional variation in genes with strong prior evidence for influencing ethanol metabolism and response when compared to genes not meeting these criteria.
Objective: Leverage a novel case only design and Whole Exome Sequencing (WES) of severe AD cases from the island of Ireland to quantify differences in functional variation between genes associated with ethanol metabolism and/or response and their matched control genes.
Methods: First, three sets of ethanol related genes were identified including those a) involved in alcohol metabolism in humans b) showing altered expression in mouse brain after alcohol exposure, and altering ethanol behavioral responses in invertebrate models. These genes of interest (GOI) sets were matched to control gene sets using multivariate hierarchical clustering of gene-level summary features from gnomAD. Using WES data from 190 individuals with severe AD, GOI were compared to matched control genes using logistic regression to detect aggregate differences in abundance of loss of function, missense, and synonymous variants, respectively.
Results: Three non-independent sets of 10, 117, and 359 genes were queried against control gene sets of 139, 1522, and 3360 matched genes, respectively. Significant differences were not detected in the number of functional variants in the primary set of ethanol-metabolizing genes. In both the mouse expression and invertebrate sets, we observed an increased number of synonymous variants in GOI over matched control genes. Post-hoc simulations showed the estimated effects sizes observed are unlikely to be under-estimated.
Conclusion: The proposed method demonstrates a computationally viable and statistically appropriate approach for genetic analysis of case-only data for hypothesized gene sets supported by empirical evidence.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Gentry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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