Predicting future risk of type 1 and type 2 diabetes after gestational diabetes mellitus using polygenic scores: a cohort study

AIMS/HYPOTHESIS: Women with previous gestational diabetes mellitus (GDM) have an increased risk of developing both type 1 and type 2 diabetes. However, predicting the risk on a personal level is challenging. Polygenic scores (PGSs), which capture an individual's genetic susceptibility to disease, may improve risk prediction. We aimed to examine the utility of PGSs for type 1 diabetes (T1D-PGS) and type 2 diabetes (T2D-PGS) to predict overt diabetes in women with previous GDM, with a median follow-up time of 30 years after index pregnancy. METHODS: We conducted an observational study including 370 women diagnosed with GDM between 1978 and 1996. Development of type 1 and type 2 diabetes was identified using national registry data comprising ICD-10 diagnosis codes on diabetes until 2019, combined with a glucose tolerance test performed in 2000-2002. The predictive ability of T1D-PGS and T2D-PGS and clinical risk factors during index pregnancy for type 1 and type 2 diabetes, including maternal age at delivery, pre-pregnancy BMI, fasting plasma glucose, insulin treatment and family history of diabetes, was evaluated using receiver operating characteristic area under the curve (AUC). RESULTS: During a median follow-up of 30 years, 200 (54.1%) women were diagnosed with diabetes: 30 (8.1%) with type 1 diabetes, 157 (42.4%) with type 2 diabetes and 13 (3.5%) carried monogenic diabetes variants. The mean T1D-PGS was higher in women with type 1 diabetes compared with those without (13.6 vs 11.5, p<0.001), while the T2D-PGS was similar between women with and without type 2 diabetes (52.9 vs 52.8, p=0.16). The T1D-PGS and clinical risk factors during pregnancy were discriminative of type 1 diabetes with AUCs of 0.788 and 0.839, respectively, while a combined model yielded an AUC of 0.887. The T2D-PGS and clinical risk factors during pregnancy yielded AUCs of 0.539 and 0.745, respectively. The combined model had an AUC of 0.752. CONCLUSIONS/INTERPRETATION: In women with previous GDM, the T1D-PGS showed good predictive ability for the development of type 1 diabetes, especially when combined with clinical risk factors during pregnancy, and may have potential to guide targeted follow-up and early treatment interventions. The T2D-PGS showed no predictive ability for type 2 diabetes.