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

Kirk Smith; Aaron J Deutsch; Carolyn McGrail; Hyunkyung Kim; Sarah Hsu; Ravi Mandla; Philip H Schroeder; Kenneth E Westerman; Lukasz Szczerbinski; Timothy D Majarian; Varinderpal Kaur; Alice Williamson; Melina Claussnitzer; Jose C Florez; Alisa K Manning; Josep M Mercader; Kyle J Gaulton; Miriam S Udler

doi:10.1101/2023.09.28.23296294

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

medRxiv [Preprint]. 2023 Sep 29:2023.09.28.23296294. doi: 10.1101/2023.09.28.23296294.

Authors

Kirk Smith^{1

2

3}, Aaron J Deutsch^{1

2

3

4}, Carolyn McGrail⁵, Hyunkyung Kim^{1

2

3

6

7}, Sarah Hsu^{3

8}, Ravi Mandla^{1

2

3}, Philip H Schroeder^{1

2

3}, Kenneth E Westerman^{3

4

8}, Lukasz Szczerbinski^{1

2

3

9

10}, Timothy D Majarian^{3

8}, Varinderpal Kaur^{1

2

3}, Alice Williamson^{11

12}, Melina Claussnitzer^{3

13

4

1}, Jose C Florez^{1

2

3

4}, Alisa K Manning^{3

4

8}, Josep M Mercader^{3

2

1

4}, Kyle J Gaulton⁵, Miriam S Udler^{1

2

3

4}

Affiliations

¹ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁵ Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
⁶ Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
⁷ Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.
¹⁰ Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland.
¹¹ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
¹² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
¹³ The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Abstract

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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