Multi-ancestry polygenic mechanisms of type 2 diabetes.
Nature medicine 2024
Smith K, Deutsch AJ, McGrail C, Kim H, Hsu S, Huerta-Chagoya A, Mandla R, Schroeder PH, Westerman KE, Szczerbinski L, Majarian TD, Kaur V, Williamson A, Zaitlen N, Claussnitzer M, Florez JC, Manning AK, Mercader JM, Gaulton KJ, Udler MS
DOI : 10.1038/s41591-024-02865-3
PubMed ID : 38443691
PMCID :
URL : https://www.nature.com/articles/s41591-024-02865-3
Abstract
Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel T2D clusters with distinct cardiometabolic trait associations across two independent biobanks representing diverse genetic ancestral populations (African, n = 21,906; Admixed American, n = 14,410; East Asian, n =2,422; European, n = 90,093; and South Asian, n = 1,262). The 12 genetic clusters were enriched for specific single-cell regulatory regions. Several of the polygenic scores derived from the clusters differed in distribution among ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a body mass index (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. Thus, these multi-ancestry T2D genetic clusters encompass a broader range of biological mechanisms and provide preliminary insights to explain ancestry-associated differences in T2D risk profiles.