Genetics of Type 2 Diabetes: Implications from Large-Scale Studies

Abstract

Purpose of review: Type 2 diabetes (T2D) is a multifactorial, heritable syndrome characterized by dysregulated glucose homeostasis that results from impaired insulin secretion and insulin resistance. Genetic association studies have successfully identified hundreds of T2D risk loci implicating many genes in disease pathogenesis. In this review, we provide an overview of the recent T2D genetic studies from the past 3 years with particular focus on the effects of sample size and ancestral diversity on genetic discovery as well as discuss recent work on the use and limitations of genetic risk scores (GRS) for T2D risk prediction.

Recent findings: Recent large-scale, multi-ancestry genetic studies of T2D have identified over 500 novel risk loci. The genetic variants (i.e., single nucleotide polymorphisms (SNPs)) marking these novel loci in general have smaller effect sizes than previously discovered loci. Inclusion of samples from diverse ancestral backgrounds shows a few ancestry specific loci marked by common variants, but overall, the majority of loci discovered are common across ancestries. Inclusion of common variant GRS, even with hundreds of loci, does not substantially increase T2D risk prediction over standard clinical risk factors such as age and family history. Common variant association studies of T2D have now identified over 700 T2D risk loci, half of which have been discovered in the past 3 years. These recent studies demonstrate that inclusion of ancestrally diverse samples can enhance locus discovery and improve accuracy of GRS for T2D risk prediction. GRS based on common variants, however, only minimally enhances risk prediction over standard clinical risk factors.

Keywords: GWAS; Genetic risk score; Human genetics; Multi-ancestry; Polygenic risk score; Type 2 diabetes.

Fig. 1

Genetic risk scores for T2D do not substantially enhance risk prediction over traditional clinical risk factors. Displayed are the outcomes from independent, large-scale studies which have constructed genetic risk scores (GRS) for T2D [, , –, –37]. Studies are shown along the x-axis, ordered by the number of variants used to construct the genetic risk scores (top panel). (bottom panel) The accuracy of the GRS alone and the GRS with clinical T2D risk factors to predict T2D from each study, quantified by the area under the receiver operating characteristic curve (AUC). The dashed red line and shaded red box represent the current predictive power and 95% confidence interval respectively of T2D clinical risk factors (age, sex, parental T2D, BMI, systolic blood pressure, fasting glucose, HDL cholesterol, and triglycerides) to predict T2D [36]