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Diversity is key for cross-ancestry transferability of glaucoma genetic risk scores in Hispanic Veterans in the Million Veteran Program.

Waksmunski AR, Kinzy TG, Cruz LA, Nealon CL, Halladay CW, Anthony SA, Greenberg PB, Sullivan JM, Wu WC, Iyengar SK, Crawford DC, Peachey NS, Cooke Bailey JN. Diversity is key for cross-ancestry transferability of glaucoma genetic risk scores in Hispanic Veterans in the Million Veteran Program. Pacific Symposium On Biocomputing. Pacific Symposium On Biocomputing. 2023 Jan 1; 28:413-424.

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A major goal of precision medicine is to stratify patients based on their genetic risk for a disease to inform future screening and intervention strategies. For conditions like primary open-angle glaucoma (POAG), the genetic risk architecture is complicated with multiple variants contributing small effects on risk. Following the tepid success of genome-wide association studies for high-effect disease risk variant discovery, genetic risk scores (GRS), which collate effects from multiple genetic variants into a single measure, have shown promise for disease risk stratification. We assessed the application of GRS for POAG risk stratification in Hispanic-descent (HIS) and European-descent (EUR) Veterans in the Million Veteran Program. Unweighted and cross-ancestry meta-weighted GRS were calculated based on 127 genomic variants identified in the most recent report of cross-ancestry POAG meta-analyses. We found that both GRS types were associated with POAG case-control status and performed similarly in HIS and EUR Veterans. This trend was also seen in our subset analysis of HIS Veterans with less than 50% EUR global genetic ancestry. Our findings highlight the importance of evaluating GRS based on known POAG risk variants in different ancestry groups and emphasize the need for more multi-ancestry POAG genetic studies.

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