Background: We previously described physiology-informed genetically-anchored type 2 diabetes (T2D) clusters based on associations between glycemic traits and T2D-associated variants discovered in prior GWAS. Cluster polygenic scores (PSs) delineate T2D subtypes with distinct features (e.g., reduced beta-cell function, obesity, lipodystrophy-like). These PSs have not been tested for association with gestational diabetes (GDM).

Methods: We tested for associations between PSs (beta-cell, proinsulin, lipodystrophy, obesity, liver/lipid) and traits at 24-30 weeks gestation in the Gen3G cohort (N=582, 97% white non-Hispanic) with linear regression (β=change per 1 SD increase in PS). In 3 cohorts [Gen3G, HAPO (N=1369, 100% white non-Hispanic) MGH2(N=621, 62% white non-Hispanic)], we tested for associations between PSs and GDM using logistic regression and conducted fixed effects meta-analyses.

Results: The beta-cell PS was associated with higher 1-hr OGTT glucose (β=4.5 mg/dl, P<0.001) and lower insulin secretory response (β=-45.7 Stumvoll 1st phase index, P=0.02). The obesity PS was associated with higher BMI (β=0.5 kg/m2, P=0.03) and HbA1c (β=0.03%, P=0.02). The lipodystrophy PS was associated with higher 1-hr OGTT glucose (β=2.6 mg/dl, P=0.03), higher fasting triglycerides (TGs) (β=6 mg/dl, P=0.01), and lower insulin sensitivity (β=-0.6 Matsuda index, P=0.005). The liver/lipid PS was associated with lower fasting TGs (β=-11 mg/dl, P<0.001). In 3-cohort meta-analyses (297 cases), only the beta-cell PS was associated with GDM (OR 1.19, P=0.009). There was heterogeneity across cohorts for the liver/lipid PS-GDM association. No PS was associated with birth weight. Adjustment for maternal age and genetic principal components did not alter results.

Conclusion: Clusters of T2D-associated genetic variants derived based on physiology outside of pregnancy are associated with expected traits in pregnancy. A cluster representing reduced beta-cell function is associated with GDM.


C.E. Powe: None. M. Udler: None. S. Hsu: None. A. Kuang: None. C. Allard: None. A. Manning: None. L. Bouchard: None. P. Perron: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. W. Lowe: None. D. Scholtens: None. M. Hivert: None.


American Diabetes Association (1-15-ACE-26 to M-F.H.); National Institutes of Health (K23DK113218); Robert Wood Johnson Foundation; Harold Amos Medical Faculty Development Award (72456)

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