{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:41:57Z","timestamp":1790858517705,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MATER Marie Sklodowska-Curie"},{"name":"European Union\u2019s Horizon 2020","award":["813707"],"award-info":[{"award-number":["813707"]}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["2014-2020.4.01.15-0012"],"award-info":[{"award-number":["2014-2020.4.01.15-0012"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>Can we identify genetic variants associated with ectopic pregnancy by undertaking the first genome-wide association study (GWAS) leveraging two large-scale biobank initiatives?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>We identified two novel genome-wide significant associations with ectopic pregnancy, highlighting MUC1 (mucin 1) as the most plausible affected gene.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>A GWAS meta-analysis including 7070 women with ectopic pregnancy and 248\u200a810 controls from Estonian Biobank and the FinnGen study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>We identified two genome-wide significant loci on chromosomes 1 (rs4971091, P\u2009=\u20095.32\u00d710\u22129) and 10 (rs11598956, P\u2009=\u20092.41\u00d710\u22128) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LARGE SCALE DATA<\/jats:title>\n                    <jats:p>The GWAS meta-analysis summary statistics are available from the GWAS Catalogue (GCST90272883).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>N.P.G. was supported by MATER Marie Sklodowska-Curie which received funding from the European Union\u2019s 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humrep\/dead217","type":"journal-article","created":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T18:04:03Z","timestamp":1697047443000},"page":"2516-2525","source":"Crossref","is-referenced-by-count":9,"title":["Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy"],"prefix":"10.1093","volume":"38","author":[{"given":"Nat\u00e0lia","family":"Pujol Gualdo","sequence":"first","affiliation":[{"name":"Estonian Genome Centre, Institute of Genomics, University of Tartu , Tartu, Estonia"},{"name":"Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, University of Oulu , Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Estonian Biobank Research Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reedik","family":"M\u00e4gi","sequence":"additional","affiliation":[{"name":"Estonian Genome Centre, Institute of Genomics, University of Tartu , Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1501-9030","authenticated-orcid":false,"given":"Triin","family":"Laisk","sequence":"additional","affiliation":[{"name":"Estonian Genome Centre, Institute of Genomics, University of Tartu , Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,24]]},"reference":[{"key":"2023120405584716800_dead217-B1","doi-asserted-by":"crossref","first-page":"2582","DOI":"10.1093\/humrep\/dep233","article-title":"The expression of MUC1 in human fallopian tube during the menstrual cycle and in ectopic pregnancy","volume":"24","author":"Al-Azemi","year":"2009","journal-title":"Hum Reprod"},{"key":"2023120405584716800_dead217-B2","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1038\/s41467-021-21512-w","article-title":"Control of oviductal fluid flow by the G-protein coupled receptor Adgrd1 is essential for murine embryo transit","volume":"12","author":"Bianchi","year":"2021","journal-title":"Nat Commun"},{"key":"2023120405584716800_dead217-B3","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1080\/01443610802058742","article-title":"Ectopic pregnancy in primary ciliary dyskinesia","volume":"28","author":"Blyth","year":"2008","journal-title":"J Obstet Gynaecol"},{"key":"2023120405584716800_dead217-B4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/aje\/kwf190","article-title":"Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control, population-based study in France","volume":"157","author":"Bouyer","year":"2003","journal-title":"Am J Epidemiol"},{"key":"2023120405584716800_dead217-B5","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1101\/gr.137323.112","article-title":"Annotation of functional variation in personal genomes using RegulomeDB","volume":"22","author":"Boyle","year":"2012","journal-title":"Genome Res"},{"key":"2023120405584716800_dead217-B6","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1086\/521987","article-title":"Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering","volume":"81","author":"Browning","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2023120405584716800_dead217-B7","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"key":"2023120405584716800_dead217-B8","doi-asserted-by":"crossref","first-page":"e1004219","DOI":"10.1371\/journal.pcbi.1004219","article-title":"MAGMA: generalized gene-set analysis of GWAS data. 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