Multi-ancestry polygenic mechanisms of type 2 diabetes

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

doi:10.1038/s41591-024-02865-3

Multi-ancestry polygenic mechanisms of type 2 diabetes

Nat Med. 2024 Apr;30(4):1065-1074. doi: 10.1038/s41591-024-02865-3. Epub 2024 Mar 5.

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}, Alicia Huerta-Chagoya^{1

2

3}, 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

11}, Varinderpal Kaur^{1

2

3}, Alice Williamson^{12

13}, Noah Zaitlen^{14

15

16}, Melina Claussnitzer^{1

2

3

4

17}, Jose C Florez^{1

2

3

4}, Alisa K Manning^{3

4

8}, Josep M Mercader^{1

2

3

4}, Kyle J Gaulton¹⁸, Miriam S Udler^{19

20

21

22}

Affiliations

¹ Diabetes Unit, Endocrine Division, Department of Medicine, 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 Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, 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 Vertex Pharmaceuticals, Boston, MA, USA.
¹² Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
¹³ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
¹⁴ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁵ Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁶ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁷ Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁸ Department of Pediatrics, University of California, San Diego, San Diego, CA, USA.
¹⁹ Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
²⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
²¹ Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
²² Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

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^-² in the European subpopulation and 24.2 (22.9-25.5) kg m^-² 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^-² 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.

MeSH terms

Diabetes Mellitus, Type 2* / genetics
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study
Humans
Multifactorial Inheritance / genetics
Phenotype
Risk Factors

Abstract

MeSH terms

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