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Genetics of diabetes mellitus and diabetes complications

Nature Reviews Nephrology volume 16, pages 377–390 (2020)Cite this article

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Abstract

Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.

Key points

  • A moderate genetic component and significant genetic overlap exists for diabetes and microvascular and macrovascular diabetes complications.

  • Large biobanks and aggregation of diabetes cohorts have more than doubled the number of genetic associations with diabetes and diabetes complications discovered in genome-wide association studies.

  • Sequencing studies remain limited by sample size, although work in type 2 diabetes mellitus highlights their use in gene variant characterization.

  • Future genetic discovery of diabetes and its complications will rely on large sample sizes, interrogation of sequencing datasets, diverse populations and improved phenotyping and sub-phenotyping.

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Fig. 1: Phenotypic complexity of diabetic kidney disease.
Fig. 2: Manhattan plot of data from the GWAS on DKD from the DNCRI, which included >19,000 patients.
Fig. 3: A missense coding SNP, rs55703767, in COL4A3 is associated with DKD.

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Acknowledgements

J.B.C. is supported by an American Diabetes Postdoctoral Fellowship (1-19-PDF-028). J.C.F. is supported by NIDDK K24 DK110550 and R01 DK105154.

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Authors and Affiliations

  1. Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Joanne B. Cole & Jose C. Florez

  2. Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Joanne B. Cole & Jose C. Florez

  3. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA

    Joanne B. Cole

  4. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Jose C. Florez

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J.B.C. researched data for the article, made a substantial contribution to discussion of the content and wrote and reviewed/edited the manuscript before submission. J.C.F. reviewed/edited the manuscript before submission.

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J.C.F. has received consulting honoraria from Janssen Pharmaceuticals and Goldfinch Bio, and a speaker honorarium from Novo Nordisk. J.B.C. declares no competing interests.

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Cole, J.B., Florez, J.C. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 16, 377–390 (2020). https://doi.org/10.1038/s41581-020-0278-5

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