Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy.

Can we identify genetic variants associated with ectopic pregnancy by undertaking the first genome-wide association study (GWAS) leveraging two large-scale biobank initiatives? We identified two novel genome-wide significant associations with ectopic pregnancy, highlighting MUC1 (mucin 1) as the most plausible affected gene. Ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Despite being a common early pregnancy complication, the genetic predisposition to this condition remains understudied and no large scale genetic studies have been performed so far. A GWAS meta-analysis including 7070 women with ectopic pregnancy and 248 810 controls from Estonian Biobank and the FinnGen study. We identified ectopic pregnancy cases from national registers by ICD (International Classification of Disease) codes (ICD-10 O00), and all remaining women were considered controls. We carried out standard GWAS meta-analysis and additionally annotated GWAS signals, analysed co-localization with quantitative trait loci, estimated genetic correlations and identified associated phenotypes to characterize the genetic signals, as well as to analyse the genetic and phenotypic relationships with the condition. We identified two genome-wide significant loci on chromosomes 1 (rs4971091, P = 5.32×10-9) and 10 (rs11598956, P = 2.41×10-8) potentially associated with ectopic pregnancy. Follow-up analyses propose MUC1, which codes for an epithelial glycoprotein with an important role in barrier function, as the most likely candidate gene for the association on chromosome 1. We also characterize the phenotypic and genetic correlations with other phenotypes, identifying a genetic correlation with smoking and diseases of the (genito)urinary and gastrointestinal system, and phenotypic correlations with various reproductive health diagnoses, reflecting the previously known epidemiological associations. The GWAS meta-analysis summary statistics are available from the GWAS Catalogue (GCST90272883). The main limitation is that the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes. Additionally, further larger meta-analysis or independent studies are needed to validate these findings. This study encourages the use of large-scale genetic datasets to unravel genetic factors linked to ectopic pregnancy, which is difficult to study in experimental settings. Increased sample size might bring additional genetic factors associating with ectopic pregnancy and inform its heritability. Altogether, our results provide more insight into the biology of ectopic pregnancy and, accordingly, the biological processes governing embryo implantation. N.P.G. was supported by MATER Marie Sklodowska-Curie which received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 813707. This study was funded by European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Computations were performed in the High-Performance Computing Center of University of Tartu. The authors declare no competing interests.

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© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.