Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity

• Published in: Research square
• Main Authors: Smith, Kirk, Deutsch, Aaron J, McGrail, Carolyn, Kim, Hyunkyung, Hsu, Sarah, Mandla, Ravi, Schroeder, Philip H, Westerman, Kenneth E, Szczerbinski, Lukasz, Majarian, Timothy D, Kaur, Varinderpal, Williamson, Alice, Claussnitzer, Melina, Florez, Jose C, Manning, Alisa K, Mercader, Josep M, Gaulton, Kyle J, Udler, Miriam S
• Format: Journal Article
• Language: English
• Published: United States 09.10.2023

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/m in the European subpopulation and 24.2 (22.9-25.5) kg/m 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/m 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.