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

Abstract

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 mellitus (GDM) is distinct from that underlying T2D. In this study of >5,000 pregnant women from three cohorts, we aimed to identify physiologically related groups of maternal variants associated with GDM using two complementary approaches that were based on Bayesian nonnegative matrix factorization (bNMF) clustering. First, we tested five bNMF clusters of maternal T2D-associated variants grouped on the basis of physiology outside of pregnancy for association with GDM. We found that cluster polygenic scores representing genetic determinants of reduced β-cell function and abnormal hepatic lipid metabolism were associated with GDM; these clusters were not associated with infant birth weight. Second, we derived bNMF clusters of maternal variants on the basis of pregnancy physiology and tested these clusters for association with GDM. We identified a cluster that was strongly associated with GDM as well as associated with higher infant birth weight. 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.

Altered Lipid Metabolism in Obese Women With Gestational Diabetes and Associations With Offspring Adiposity

“…Lipid physiology in pregnancy is complex, as both fetus and placenta play an active role, with enhanced de novo lipogenesis occurring in early pregnancy ( 31-33 ).While de novo lipogenesis is generally considered to be a response to excess dietary carbohydrate ( 34 ), the propensity to increased de novo lipogenesis activity observed in obese pregnant women may have had a causal role in the development of their obesity and hence GDM. Genetic studies of GDM risk have consistently identified associations with genes related to pancreatic beta cell function and insulin synthesis ( 35 ), but a recent report identified a liver lipid-related gene cluster related to GDM ( 36 ).…”

Axon Guidance Molecules in the Islets of Langerhans

“…Transcriptomic analyses reveal that ROBO1 and ROBO2 genes are differentially expressed in islets from T2D patients ( 46 – 48 ). Using cluster polygenic scores, ROBO2 was also shown to be associated with human gestational diabetes ( 52 ).…”

Genetics and Epigenetics: Implications for the Life Course of Gestational Diabetes

“…This approach has been applied recently to GDM in a study that included more than 5000 women in a multi-ancestry cohort [ 76 ]. Initial studies examined the association of the five T2DM clusters with GDM.…”

“…The liver-lipid cluster was associated with GDM in the full multi-ancestry cohort, while the other three clusters were not associated with GDM. In a second approach, a subset of the cohort was used to derive five pregnancy-related clusters that were characterized by different glycemic traits and genetic variants [ 76 ]. One cluster that was characterized by postload glucose levels, lower disposition index, and higher adiposity measures was associated with GDM.…”