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

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posted on 2020-10-13, 15:20 authored by Ada AdminAda Admin, Camille E. Powe, Miriam S. Udler, Sarah Hsu, Catherine Allard, Alan Kuang, Alisa K. Manning, Patrice Perron, Luigi Bouchard, William L. Lowe Jr, Denise Scholtens, Jose C. Florez, Marie-France Hivert
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.


CEP is supported by NIH K23DK113218 and the Robert Wood Johnson Foundation’s Harold Amos Medical Faculty Development Program. MSU is supported by NIH K23DK114551. LB is a senior research scholar from the Fond de la recherche du Québec en santé (FRQS). MFH and Gen3G are supported by American Diabetes Association’s Pathways Award #1-15-ACE-26. HAPO was supported by grants from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-34242 and HD-34243), National Human Genome Research Institute (HG-004415), and NIDDK (R01DK097534). MGH2 is supported by the Massachusetts General Hospital Physician Scientist Development Award (to CEP).


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