Genetics of diabetes and diabetes complications

By J. Cole, J. Florez. Nature Reviews Nephrology, 2020

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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. This Review describes advances in genomic analysis that have enabled novel genetic discoveries, more than doubled the number of genetic loci associated with type 2 diabetes mellitus and uncovered several novel candidate genes for diabetes complications. 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.

Subfields: Endocrinology, Diabetes and Metabolism, Genetics, Surgery

View Paper: https://www.semanticscholar.org/paper/221471e97de6a60314769a822265a2c6ff9bb7c3

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