Multiancestry Genetic Clustering of Type 2 Diabetes Loci Highlights the Contribution of Non-European Variants to Disease Heterogeneity

To identify potential subtypes of type 2 diabetes (T2D) anchored in genetics but informed by physiology, we previously used a soft clustering method to cluster T2D single nucleotide variants (SNVs) by their associated metabolic traits. The resulting European-based clusters represent likely disease mechanistic pathways. However, ancestry-specific SNVs, phenotype characteristics and prevalence rates suggest that a portion of the T2D’s heterogeneity is population-based, requiring expansion of this work to non-European populations. We created a semi-automated Bayesian non-negative matrix factorization (bNMF) pipeline to generate new ancestry-specific clusters in European (EUR, 390 SNVs), East Asian (EAS, 326 SNVs) and African (AFR, 172 SNVs), as well as trans-ancestry (TA, 498 SNVs), using up to 89 T2D-related traits. We validated the clusters by replicating their trait associations in the Mass General Brigham Biobank cohort (MGBB, N=62,252). The new ancestry-specific and TA clusters captured previously identified clusters, as well as novel clusters related to possible mechanisms of insulin resistance. In the 11 TA clusters, 127/498 SNVs were from non-EUR T2D studies, with 87 SNVs not represented in the EUR clusters. In the non-European subset of MGBB (N=8,990), 8 of 10 TA cluster pPS were more strongly associated with T2D compared to the corresponding EUR cluster pPS. We assessed in MGBB whether the proportion of cumulative genetic risk attributed to each cluster differed between sub populations. A significantly higher proportion was attributed to the Lipodystrophy cluster in EAS, to the Obesity cluster in EUR, and to the Liver/Lipid cluster in AFR (all t-test P<10-15). By expanding our previous clusters to include non-European SNVs, we were able to identify new genetic clusters and improve the predictive ability of cluster pPS. Our results suggest that polygenic processes contribute in different proportions across populations. Disclosure K.Smith: None. A.Manning: None. J.M.Mercader: None. M.Udler: None. H.Kim: None. K.E.Westerman: None. S.Hsu: None. R.Mandla: None. P.H.Schroeder: None. T.Majarian: Employee; Vertex Pharmaceuticals Incorporated. V.Kaur: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R03DK131249)