Genome-Wide Polygenic Risk Scores and Prediction of Gestational Diabetes in South Asian Women

ABSTRACT Gestational diabetes Mellitus (GDM) affects 1 in 7 births and is associated with numerous adverse health outcomes for both mother and child. GDM is suspected to share a large common genetic background with type 2 diabetes (T2D). The first aim of this study, was to characterize different GDM polygenic risk scores (PRSs) using data from the South Asian Birth Cohort (START). The second aim of this study was to estimate the heritability of GDM. PRSs were derived for 832 South Asian women from START using the pruning and thresholding (P+T), LDpred, and GraBLD methods. Weights were derived from multi-ethnic (Mahajan et al ., 2014) and white Caucasian (Scott et al ., 2017) studies of the DIAGRAM consortium. Association with GDM was tested using logistic regression. Heritability of GDM was estimated using the GRMEL approach. Results were replicated in samples from the UK Biobank (UKB) study. The top P+T, LDpred and GraBLD PRSs were all based on Mahajan et al . The best PRS was highly associated with GDM in START (AUC=0.62, OR=1.60 [95% CI=1.44–1.69]), and in South Asian (AUC=0.65) and white British (AUC=0.58) women from UKB. Heritability of GDM approximated 0.55±0.83 in START and 0.18±0.22 in white British women from UKB. Our results highlight the importance of combining genome-wide genotypes and summary statistics from large multi-ethnic studies to optimize PRSs in South Asians.