Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects

Abstract Gestational diabetes mellitus (GDM) affects ∼14% of pregnancies and is linked to adverse pregnancy outcomes and increased maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium conducted trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identified 37 GDM-associated loci (19 novel) and five novel loci for glycemic traits, all operating through the maternal genome. Most GDM loci overlapped with T2DM and non-pregnant glycemic traits, with limited evidence for pregnancy-specific effects. MTNR1B showed pregnancy-enhanced effects on 2-hour glucose, potentially mediated by interaction with GPR61 , a novel GDM locus, suggesting a gestation-specific melatonin-glucose signalling axis. We also observed ancestry-specific effects at the fasting glucose locus ABCB11 , with opposite directions in European and East Asian populations. Our findings provide new insights into the genetic architecture of GDM and highlight the need for larger, ancestrally diverse studies.