Genetic variants of gestational diabetes mellitus: a study of 112 SNPs among 8722 women in two independent populations

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy complication which has substantial short- and long-term adverse health implications for women and their children. However, large-scale studies on genetic risk loci for GDM remain sparse. METHODS: We conducted a case-control study among 2,636 GDM cases and 6,086 non GDM controls from the Nurses’ Health Study II (NHSII) and the Danish National Birth Cohort (DNBC). One hundred and twelve susceptibility genetic variants confirmed by genome-wide association studies for type 2 diabetes (T2D) were selected and measured. A weighted genetic risk score (GRS) was created based on variants that were significantly associated with risk of GDM after correcting for false discovery rate (FDR). RESULTS: For the first time, we identified eight variants associated with GDM, namely rs7957197 (HNF1A), rs10814916 (GLIS3), rs3802177 (SLC30A8), rs9379084 (RREB1), rs34872471 (TCF7L2), rs7903146 (TCF7L2), rs11787792 (GPSM1), and rs7041847 (GLIS3). Additionally, we confirmed three variants, rs10830963 (MTNR1B), rs1387153 (MTNR1B), and rs4506565 (TCF7L2), that were previously significantly associated with GDM risk. Furthermore, compared to participants in the first (lowest) quartile of weighted GRS based on these 11 SNPs, the odds ratios of GDM were 1.07 (95% CI: 0.93, 1.22), 1.23 (95% CI 1.07, 1.41), and 1.53 (95% CI 1.34, 1.74) in the second, third, and fourth (highest) quartile, respectively. The significant positive associations between the weighted GRS and risk of GDM persisted across most of the strata of major risk factors for GDM including family history of type 2 diabetes, smoking status, body mass index, and age. CONCLUSION: In this large-scale case-control study with women from two independent populations, eight novel GDM SNPs were identified, which offers potential to improve our understanding on GDM etiology, particularly biological mechanisms related to beta cell function.