Oral Presentation GENEMAPPERS 2024

Multi-ancestral, trans-generational genome-wide association meta-analysis of gestational diabetes mellitus and glycaemic traits during pregnancy (#24)

Caroline Brito Nunes 1 , Gunn-Helen Moen 1 2 3 4 5 6 , on behalf of the GENetics of Diabetes In Pregnancy (GenDiP) Consortium 7
  1. The University of Queensland Institute for Molecular Bioscience, St Lucia, Queensland, Australia
  2. Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
  3. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
  4. K. G Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology,, Trondheim, Norway
  5. Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
  6. Frazer Institute, The University of Queensland, Brisbane, Australia
  7. -

During pregnancy, natural fluctuations in maternal glucose metabolism are essential to meet maternal and fetal energy demands. For some, this metabolic change can lead to the development of gestational diabetes mellitus (GDM), a condition characterized by glucose intolerance and hyperglycaemia, and diagnosed in approximately 14.0% of pregnancies globally. Elevated glucose or a GDM diagnosis has been shown to increase the risk of birth complications. Additionally, up to 50% of mothers who have had GDM develop type 2 diabetes (T2D) 5-10 years after pregnancy, suggesting a shared aetiology between these two conditions. To improve our understanding of both fetal and maternal genetic variants associated with GDM and maternal glycaemic traits during pregnancy, the GenDiP Consortium has performed the world’s largest multi-ancestral GWAS meta-analysis of these traits. We investigated maternal i) GDM diagnoses (maternal analyses including 38,241 cases and 775,169 controls; fetal analyses containing 3,039 cases 89,763 controls), ii) Fasting glucose (N maternal=55,371; N fetal=15,855), iii) 1-hour glucose post-oral glucose tolerance test (OGTT) (N maternal=38,439; N fetal=9,365), iv) 2-hour glucose post-OGTT (N maternal=46,401; N fetal=15,046) and v) HbA1c (N maternal=9,724; N fetal=7,035). Using new statistical methods, we were able to i) identify 38 new genetic loci associated with GDM and/or glycaemic traits during pregnancy and replicate previously reported associations ii) elucidate the degree to which GDM and T2D represent distinct conditions, iii) partition maternal and offspring genetic contributions to GDM and maternal glycaemic traits, and iv) unveil distinct genetic determinants of maternal fasting and post-OGTT glycaemic values, with variants in genes such as MTNR1B, HKDC1, CDKAL1 exhibiting distinct associations across different time points. In conclusion, our study provides novel insights into the genetic architecture of GDM and maternal glycaemic traits during pregnancy, offering a deeper understanding of their aetiology and potential targets for intervention.