Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans.
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Author
Lai, DongbingSchwantes-An, Tae-Hwi
Abreu, Marco
Chan, Grace
Hesselbrock, Victor
Kamarajan, Chella
Liu, Yunlong
Meyers, Jacquelyn L
Nurnberger, John I
Plawecki, Martin H
Wetherill, Leah
Schuckit, Marc
Zhang, Pengyue
Edenberg, Howard J
Porjesz, Bernice
Agrawal, Arpana
Foroud, Tatiana
Journal title
Translational psychiatryDate Published
2022-07-05Publication Volume
12Publication Issue
1Publication Begin page
266
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Show full item recordAbstract
Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in 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 the boundaries of these genes, we proposed a novel gene-based PRS framework (PRS) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRS calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E-05 to 6.27E-03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E-03 to 0.16; Betas ranged from 0.06 to 0.18). PRS were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRS 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 the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.Citation
Lai D, Schwantes-An TH, Abreu M, Chan G, Hesselbrock V, Kamarajan C, Liu Y, Meyers JL, Nurnberger JI Jr, Plawecki MH, Wetherill L, Schuckit M, Zhang P, Edenberg HJ, Porjesz B, Agrawal A, Foroud T. Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans. Transl Psychiatry. 2022 Jul 5;12(1):266. doi: 10.1038/s41398-022-02029-2. PMID: 35790736; PMCID: PMC9256707.DOI
10.1038/s41398-022-02029-2ae974a485f413a2113503eed53cd6c53
10.1038/s41398-022-02029-2
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- Creative Commons
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