A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies

Shylaja Srinivasan¹, Peitao Wu², Josep M Mercader^{3

4

5}, Miriam S Udler^{3

4

5}, Bianca C Porneala⁶, Traci M Bartz^{7

8}, James S Floyd^{8

9

10}, Colleen Sitlani^{8

9}, Xiquing Guo¹¹, Jeffrey Haessler¹², Charles Kooperberg¹², Jun Liu^{13

14}, Shahzad Ahmad¹³, Cornelia van Duijn^{13

14}, Ching-Ti Liu⁴, Mark O Goodarzi¹⁵, Jose C Florez^{3

4

5}, James B Meigs^{3

4

6}, Jerome I Rotter¹¹, Stephen S Rich¹⁶, Josée Dupuis², Aaron Leong^{3

5

6}

Affiliations

¹ Division of Pediatric Endocrinology, University of California at San Francisco, San Francisco, CA 94158, USA.
² Department of Biostatistics, Boston University School of Public Health, Boston, MA 02215, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁴ Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard & Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁵ Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
⁸ Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98195, USA.
⁹ Department of Medicine, University of Washington, Seattle, WA 98195, USA.
¹⁰ Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
¹¹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
¹² Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
¹³ Department of Epidemiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands.
¹⁴ Nuffield Department of Population Health, University of Oxford, Oxford OX1 2JD, UK.
¹⁵ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁶ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903, USA.

PMID: 37841955
PMCID: PMC10576255
DOI: 10.1210/jendso/bvad123

A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies

Shylaja Srinivasan et al. J Endocr Soc. 2023.

. 2023 Oct 5;7(11):bvad123.

doi: 10.1210/jendso/bvad123. eCollection 2023 Oct 9.

Authors

Affiliations

¹ Division of Pediatric Endocrinology, University of California at San Francisco, San Francisco, CA 94158, USA.
² Department of Biostatistics, Boston University School of Public Health, Boston, MA 02215, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁴ Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard & Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁵ Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
⁸ Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98195, USA.
⁹ Department of Medicine, University of Washington, Seattle, WA 98195, USA.
¹⁰ Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
¹¹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
¹² Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
¹³ Department of Epidemiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands.
¹⁴ Nuffield Department of Population Health, University of Oxford, Oxford OX1 2JD, UK.
¹⁵ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁶ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903, USA.

PMID: 37841955
PMCID: PMC10576255
DOI: 10.1210/jendso/bvad123

Abstract

Context: Both type 1 diabetes (T1D) and type 2 diabetes (T2D) have significant genetic contributions to risk and understanding their overlap can offer clinical insight.

Objective: We examined whether a T1D polygenic score (PS) was associated with a diagnosis of T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

Methods: We constructed a T1D PS using 79 known single nucleotide polymorphisms associated with T1D risk. We analyzed 13 792 T2D cases and 14 169 controls from CHARGE cohorts to determine the association between the T1D PS and T2D prevalence. We validated findings in an independent sample of 2256 T2D cases and 27 052 controls from the Mass General Brigham Biobank (MGB Biobank). As secondary analyses in 5228 T2D cases from CHARGE, we used multivariable regression models to assess the association of the T1D PS with clinical outcomes associated with T1D.

Results: The T1D PS was not associated with T2D both in CHARGE (P = .15) and in the MGB Biobank (P = .87). The partitioned human leukocyte antigens only PS was associated with T2D in CHARGE (OR 1.02 per 1 SD increase in PS, 95% CI 1.01-1.03, P = .006) but not in the MGB Biobank. The T1D PS was weakly associated with insulin use (OR 1.007, 95% CI 1.001-1.012, P = .03) in CHARGE T2D cases but not with other outcomes.

Conclusion: In large biobank samples, a common variant PS for T1D was not consistently associated with prevalent T2D. However, possible heterogeneity in T2D cannot be ruled out and future studies are needed do subphenotyping.

Keywords: genetics; polygenic score; type 1 diabetes; type 2 diabetes.

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Figures

**Figure 1.**
Forest plot showing association of the T1D PS with T2D in the individual cohorts and in the meta-analyses. Garnet, HIPFX, LLS, MOPMAP, WHIMS, and ONCOCHIP are Women's Health Initiative (WHI) substudies; MESA, Multi-Ethnic Study of Atherosclerosis; FHS, Framingham Heart Study; CHS, Cardiovascular Health Study; PartnerBB, Mass General Brigham Biobank.

See this image and copyright information in PMC

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A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies

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A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies

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