Genetic Loci and Physiologic Pathways Involved in Gestational Diabetes Implicated Through Clustering

Hundreds of common genetic variants acting through distinguishable physiologic pathways influence the risk of type 2 diabetes (T2D). It is unknown to what extent the physiology underlying gestational diabetes (GDM) is distinct from that underlying T2D. In this study of over 5,000 pregnant women from three cohorts, we aimed to identify physiologically related groups of maternal variants associated with GDM using two complementary approaches based on Bayesian non-negative matrix factorization (bNMF) clustering. First, we tested five bNMF clusters of maternal T2D-associated variants grouped based on physiology outside of pregnancy for association with GDM. We found that cluster polygenic scores representing genetic determinants of reduced beta-cell function and abnormal hepatic lipid metabolism were associated with GDM; these clusters were not associated with infant birthweight. Second, we derived bNMF clusters of maternal variants based on pregnancy physiology and tested these clusters for association with GDM. We identified a cluster which was strongly associated with GDM and also associated with higher infant birthweight. The effect size for this cluster’s association with GDM appeared greater than that for T2D. Our findings imply that the genetic and physiologic pathways that lead to GDM differ, at least in part, from those that lead to T2D.