A Polygenic Risk Score Associated with Gestational Diabetes Mellitus in an American Indian Population

Introduction: Gestational diabetes mellitus (GDM) is a state of hyperglycemia during pregnancy, increasing the risk of birth complications, and subsequent type 2 diabetes mellitus in the mother and offspring. Risk factors such as diet, obesity, and family history have demonstrated strong association with GDM, but no clear pathophysiology has been ascertained. Methods: Analysis was conducted on 38 women with and 296 without GDM, within a case/control study of pre-eclampsia. The genetic variants examined were selected from among a published polygenic risk score of 10 variants (PRS-10).1 Genetic models were evaluated for each variant by multivariate logistic regression methods adjusted for age, body mass index, nulliparity and pre-eclampsia. A risk score comprised of the total risk alleles among the 7 variants (PRS-7) was evaluated. Results: Multivariate logistic regression showed significant, independent, positive associations between body-mass index (BMI), age, the posited PRS-7 (OR 1.87, 95% CI 1.43-2.45, p=5.3x10-6) and GDM. In univariate analysis, rs1421085 was associated with GDM (OR 0.50, 95% CI 0.26-0.95, p=0.034), but not after adjustment for covariates and paradoxically not for the expected risk allele. None of the other 6 variants showed individual association with GDM. An independent association of PRS-7, rs1421085 and established risk factors (age and BMI) with GDM is demonstrated. The previously published meta-analysis of PRS-10 showed a degree of heterogeneity (pQ=0.03) among the 3 cohorts analyzed, suggesting that variant effects may differ according to genetic background. Conclusion: We replicate and further refine results of a previously published polygenic risk score for GDM in an ethically unrelated population.