Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity
Smith, K.; Deutsch, A.; McGrail, C.; Kim, H.; Hsu, S.; Mandla, R.; Schroeder, P. H.; Westerman, K. E.; Szczerbinski, L.; Majarian, T. D.; Kaur, V.; Williamson, A.; Claussnitzer, M.; Florez, J. C.; Manning, A. K.; Mercader, J. M.; Gaulton, K. J.; Udler, M. S.
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We identified genetic subtypes of type 2 diabetes (T2D) by analyzing genetic data from diverse groups, including non-European populations. We implemented soft clustering with 650 T2D-associated genetic variants, capturing known and novel T2D subtypes with distinct cardiometabolic trait associations. The twelve genetic clusters were distinctively enriched for single-cell regulatory regions. Polygenic scores derived from the clusters differed in distribution between ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a BMI of 30 kg/m2 in the European subpopulation and 24.2 (22.9- 25.5) kg/m2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg/m2 in the East Asian group, explaining about 75% of the difference in BMI thresholds. Thus, these multi-ancestry T2D genetic subtypes encompass a broader range of biological mechanisms and help explain ancestry-associated differences in T2D risk profiles.
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