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The impact of ancestry on performance of type 1 diabetes genetic risk scores: high discrimination performance is maintained in African ancestry populations, but population specific thresholds may improve risk prediction

Article scientifique 2025 Anglais

Résumé

OBJECTIVE: Genetic risk scores (GRSs) for type 1 diabetes (T1D) may assist T1D classification and prediction but are often developed from European populations. To improve health outcomes, it is important to understand the performance and utility of GRSs in diverse ancestry populations. RESEARCH DESIGN AND METHODS: We assessed performance of three previously published T1D GRSs in differentiating people with and without Type 1 diabetes in African (with/without T1D=194/235), European (n=1109/125), and Hispanic (266/170) ancestry populations in the USA, and from Cameroon and Uganda (n=144/5001). The assessed GRSs were developed from European ancestry populations (GRS1, GRS2) and from an African ancestry population (AAGRS). RESULTS: The discriminative power, as measured by the area under the receiver operating characteristic curve (AUC), for GRS2 and AAGRS were equivalent on the African ancestry populations, and both outperformed the GRS1: the AUCs produced by the GRS2, AAGRS and GRS1 on Uganda/Cameroon data were 0.882 (0.845-0.914), 0.874 (0.838-0.907) and 0.816 (0.772-0.857) respectively. GRS2 outperformed the AAGRS and GRS1 on Hispanic and European populations. The GRS2 distributions varied by population, with lower average scores for African populations. If the same GRS2 risk thresholds of 11.5 were set for European and African populations, the sensitivities were 0.91 and 0.53, respectively. CONCLUSIONS: The GRS2 produced similar or improved discriminative power across the populations but the AAGRS matched performance on African ancestry participants with fewer single nucleotide polymorphisms. Varying GRS2 risk thresholds may be required for different populations due to the divergent distributions.

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Squires, S., Katte, J., Dabelea, D., Pihoker, C., Divers, J., Sobngwi, E., Nyirenda, M., Kreienkamp, R., Liese, A., SHAH, A., Dolan, L., Reynolds, K., REDONDO, M., Hagopian, W., Fatumo, S., Dehayem, M., Hattersley, A., Weedon, M., Jones, A., Oram, R. (2025). The impact of ancestry on performance of type 1 diabetes genetic risk scores: high discrimination performance is maintained in African ancestry populations, but population specific thresholds may improve risk prediction. https://doi.org/10.1101/2025.07.17.25330632

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Auteur(s)

Steven Squires Jean-Claude Katte Dana Dabelea Catherine Pihoker Jasmin Divers Eugène Sobngwi Moffat Nyirenda Raymond J. Kreienkamp Angela D. Liese AMY SANGHAVI SHAH Lawrence M. Dolan Kristi Reynolds MARIA JOSE REDONDO William Hagopian Segun Fatumo Mesmin Dehayem Andrew T. Hattersley Michael N. Weedon Angus G. Jones Richard A. Oram

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