Year: 2022
Type: article
Study design: Observational Study
Abstract: ABSTRACT Genome-wide association studies (GWAS) in admixed populations such as African American (AA) have limited sample sizes, resulting poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within boundaries of these genes, we proposed a novel gene-based PRS method (PRS gene ) by using variants located in these shared disease-causing genes. Using AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and EA GWAS of problematic alcohol use as the discovery datasets, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRS gene calculated using these variants were significantly associated with AUD in three AA cohorts (P-values: 7.61E-05-6.27E-03; Betas: 0.15-0.21) and outperformed PRS calculated using all variants (P-values: 7.28E-03-0.16; Betas: 0.06-0.18). PRS gene was also associated with AUD in an EA cohort (P-value=0.02, Beta=0.11). In AA, individuals in the highest PRS gene decile had an Odds Ratio of 1.76 (95% CI: 1.32-2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving synaptic system, which are known to be AUD-related. Additionally, 26 genes were targets of drugs to treat AUD or other diseases, but may be repurposed to treat AUD. Our study demonstrated that our gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into identification of AUD genes.
Source: Translational Psychiatry
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,590
Funders: U.S. Department of Health and Human Services, Eli Lilly and Company, Oracle, Children's Hospital of Philadelphia, University of Pennsylvania, Indiana Clinical and Translational Sciences Institute, Lilly Endowment, State University of New York, Washington University in St. Louis, University of Connecticut, Virginia Commonwealth University, National Institutes of Health, SUNY Downstate Medical Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, National Institute on Drug Abuse, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1083756078, G1187501382, G1309605592, G15963542, G1644766664, G1679780777, G1937324514, G2988863959, G3452148273, G3754633476, G3958151055, EXTRAMURAL RESEARCH FACILITIES IMPROVEMENT, G4954646042, G5184311545, COLLABORATIVE STUDIES ON THE GENETICS OF ALCOHOLISM, G6060684585, G6223059496, DELINEATING THE ROLE OF GENETIC INFLUENCES ON CANNABIS INVOLVEMENT, G6875631655, G7047943440, G724942601, G747985126, 7/7 Psychiatric Genomics Consortium: Advancing Discovery and Impact, G8085881000, G8300140112, G9000025954, G9000044128, G9000066888, G9000167144, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
OpenAlex ID: W4283820899