MR-PheWAS for the causal effects of serum magnesium on multiple disease outcomes in Caucasian descent

Li, Longman; Yang, Wenjun; Huang, Lulu; Feng, Xiuming; Cheng, Hong; Ge, Xiaoting; Zan, Gaohui; Tan, Yanli; Xiao, Lili; Liu, Chaoqun; Chen, Xing; Mo, Zengnan; Yang, Xiaobo

doi:10.1016/j.isci.2021.103191

Cited by 4 publications

(2 citation statements)

References 62 publications

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“…Altered barrier function of MUC1 in the Fallopian tubes is also a plausible explanation for its association with ectopic pregnancy. In line with this, rs4072037 has been associated with pregnancy loss and ectopic pregnancy also in the UK Biobank 39 . However, due to the age structure of the UK Biobank, the results should be interpreted with caution since many of the actual cases are mislabelled as controls, resulting in extremely low prevalence of pregnancy phenotypes in this biobank cohort.…”

Section: Discussionsupporting

confidence: 68%

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

Pujol-Gualdo

Mägi

Laisk

2022

Preprint

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Ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. To better understand the genetic risk factors underlying this pregnancy complication, we conduct a GWAS meta-analysis and identify two genome-wide significant loci on chromosomes 1 (rs4971091, p=5.32x10-9) and 10 (rs11598956, p=2.41x10-8). Follow-up analyses propose MUC1, an epithelial glycoprotein with an important role in barrier function, as the most likely candidate for the association on chromosome 1. We also characterise 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.

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Section: Discussionsupporting

confidence: 68%

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

Pujol-Gualdo

Mägi

Laisk

2022

Preprint

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show abstract

“…Altered barrier function of MUC1 in the Fallopian tubes is also a plausible explanation for its association with ectopic pregnancy. In line with this, rs4072037 has been associated with pregnancy loss and ectopic pregnancy also in the UK Biobank ( Li et al , 2021 ). However, due to the age structure of the UK Biobank, the results should be interpreted with caution since many of the actual cases are mislabelled as controls, resulting in extremely low prevalence of pregnancy phenotypes in this biobank cohort.…”

Section: Discussionmentioning

confidence: 58%

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

Pujol Gualdo,

Mägi,

Laisk

2023

Human Reproduction

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STUDY QUESTION Can we identify genetic variants associated with ectopic pregnancy by undertaking the first genome-wide association study (GWAS) leveraging two large-scale biobank initiatives? SUMMARY ANSWER We identified two novel genome-wide significant associations with ectopic pregnancy, highlighting MUC1 (mucin 1) as the most plausible affected gene. WHAT IS KNOWN ALREADY 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. STUDY DESIGN, SIZE, DURATION A GWAS meta-analysis including 7070 women with ectopic pregnancy and 248 810 controls from Estonian Biobank and the FinnGen study. PARTICIPANTS/MATERIALS, SETTING, METHODS 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. MAIN RESULTS AND THE ROLE OF CHANCE 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. LARGE SCALE DATA The GWAS meta-analysis summary statistics are available from the GWAS Catalogue (GCST90272883). LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE 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. STUDY FUNDING/COMPETING INTEREST(S) 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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Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study

et al. 2022

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MR-PheWAS for the causal effects of serum magnesium on multiple disease outcomes in Caucasian descent

Cited by 4 publications

References 62 publications

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

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

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

Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study

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