Genome-wide association and Mendelian randomisation analysis among 30,699 Chinese pregnant women identifies novel genetic and molecular risk factors for gestational diabetes and glycaemic traits

Abstract Aims/hypothesis Gestational diabetes mellitus (GDM) is the most common disorder in pregnancy; however, its underlying causes remain obscure. This study aimed to investigate the genetic and molecular risk factors contributing to GDM and glycaemic traits. Methods We collected non-invasive prenatal test (NIPT) sequencing data along with four glycaemic and 55 biochemical measurements from 30,699 pregnant women during a 2 year period at Shenzhen Baoan Women’s and Children’s Hospital in China. Genome-wide association studies (GWAS) were conducted between genotypes derived from NIPTs and GDM diagnosis, baseline glycaemic levels and glycaemic levels after glucose challenges. In total, 3317 women were diagnosed with GDM, while 19,565 served as control participants. The results were replicated using two independent cohorts. Additionally, we performed one-sample Mendelian randomisation to explore potential causal associations between the 55 biochemical measurements and risk of GDM and glycaemic levels. Results We identified four genetic loci significantly associated with GDM susceptibility. Among these, MTNR1B exhibited the highest significance (rs10830963-G, OR [95% CI] 1.57 [1.45, 1.70], p =4.42×10 -29 ), although its effect on type 2 diabetes was modest. Furthermore, we found 31 genetic loci, including 14 novel loci, that were significantly associated with the four glycaemic traits. The replication rates of these associations with GDM, fasting plasma glucose levels and 0 h, 1 h and 2h OGTT glucose levels were four out of four, six out of nine, 10 out of 11 five out of seven and four out of four, respectively. Mendelian randomisation analysis suggested that a genetically regulated higher lymphocytes percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with elevated glucose levels and an increased risk of GDM. Conclusions/interpretation Our findings provide new insights into the genetic basis of GDM and glycaemic traits during pregnancy in an East Asian population and highlight the potential role of inflammatory pathways in the aetiology of GDM and variations in glycaemic levels. Data availability Full summary statistics of GDM, FPG, OGTT0H, OGTT1H and OGTT2H will be made available in the GVM database and the GWAS Catalog upon publication. Research in context What is already known about this subject? Previous genome-wide association studies on gestational diabetes mellitus (GDM) and glycaemic levels in Asian populations have been limited to sample sizes of a few thousand participants. There is a lack of research investigating the potential causal relationships between various pregnancy indicators and GDM as well as glycaemic levels. What is the key question? What are the genetic and molecular factors that contribute to GDM and glycaemic levels in an under-represented population of Chinese pregnant women in East Asia? What are the new findings? Four genetic loci were significantly associated with GDM risk, with MTNR1B being the most prominent. A total of 31 genetic loci, including 14 novel loci, were significantly associated with four commonly measured glycaemic traits. A genetically higher lymphocyte percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with increased glucose levels and an elevated risk of GDM. How might this impact on clinical practice in the foreseeable future? Individuals with GDM risk variants could receive special attention during early pregnancy to mitigate the risk of adverse pregnancy outcomes associated with GDM and higher glycaemic levels. Clinical trials may be warranted to examine the potential of interventions such as nutrition therapy or medication for modulating inflammatory responses and reducing GDM incidence.