ESPE Yearbook of Paediatric Endocrinology

In Brief The authors report a genome-wide association study (GWAS) on Type 2 diabetes (T2D), including data from 2 535 601 individuals (39.7% non-European ancestry), including 428 452 with T2D. They identify 1,289 independent GWAS signals (at P < 5×10⁻⁸), of which 145 loci are novel. These genetic signals cluster into 8 groups, with differing cardiometabolic trait associations and differing cell-specific profiles of gene activation (open chromatin), including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells.

This paper reports the largest (GWAS) study to date of the common genetic determinants of T2D, generated through a new international collaboration with a nearly 3-fold larger sample size than previously. They combine the findings with single-cell data derived from disease-relevant tissues. Five genetic clusters were similar to previous reports: 1) beta-cell dysfunction positively or 2) negatively related with proinsulin, and also insulin resistance via 3) obesity, 4) lipodystrophy, or 5) liver and lipid metabolism. Three new clusters associated with cardiometabolic profiles of 1) metabolic syndrome, 2) body fat and 3) residual glycaemic effects.

GWAS for several traits have now reached the milestone of finding ~1000 independent common genetic signals. A major aspect of such studies is their power to separate different biological processes that contribute to the disease in question. This also informs us that different individuals may have developed the same disease but through differing predominant patho-aetiologies, e.g. beta cell dysfunction, general obesity, fat distribution, or other pathways to insulin resistance. It supports the prospect of precision medicine – that the optimal treatments and preventive strategies might be tailored to each individual.

The differing genetic clusters also showed differing strengths of association with other complex metabolic diseases. Gestational diabetes was more strongly related to beta cell dysfunction and lipodystrophy, whereas polycystic ovary syndrome was related more to obesity-related insulin resistance. Another recent genetics study portrayed youth-onset T2D also as a heterogeneous disease, but with a greater burden of rare mutations, and hence appears to be on a spectrum between monogenic diabetes and adult-onset T2D (1).

Reference: 1. Kwak SH, et al. Genetic architecture and biology of youth-onset type 2 diabetes. Nature Metabolism volume 6, pages226–237 (2024)