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Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality

Abstract

Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (PFsig-permuted = 9.99 × 10−4). Linkage disequilibrium score regression (LDSC) analysis estimated a positive and highly significant genetic correlation between the two traits (rG = 0.27, P = 8.85 × 10−27). A meta-analysis of endometriosis and depression GWAS (sample size = 709,111), identified 20 independent genome-wide significant loci (P < 5 × 10−8), of which eight are novel. Mendelian randomization analysis (MR) suggests a causal effect of depression on endometriosis. Combining gene-based association results across endometriosis and depression GWAS, we identified 22 genes with a genome-wide significant Fisher’s combined P value (FCPgene < 2.75 × 10−6). Genes with a nominal gene-based association (Pgene < 0.05) were significantly enriched across endometriosis and depression (Pbinomial-test = 2.90 × 10−4). Also, genes overlapping the two traits at Pgene < 0.1 (Pbinomial-test = 1.31 × 10−5) were significantly enriched for the biological pathways ‘cell–cell adhesion’, ‘inositol phosphate metabolism’, ‘Hippo-Merlin signaling dysregulation’ and ‘gastric mucosa abnormality’. These results reveal a shared genetic etiology for endometriosis and depression. Indeed, additional analyses found evidence of a causal association between each of endometriosis and depression and at least one abnormal condition of gastric mucosa. Our study confirms the comorbidity of endometriosis and depression, implicates links with gastric mucosa abnormalities in their causal pathways and reveals potential therapeutic targets for further investigation.

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Acknowledgments

We acknowledge all the study participants in the 11 individual endometriosis studies that provided an opportunity for the current study. We also thank many hospital directors and staff, gynaecologists, general practitioners, and pathology services in Australia who helped with confirmation of diagnoses. We would like to thank the research participants and employees of 23andMe for making this work possible. We thank the subjects of the Icelandic deCODE study for their participation. We thank the research staff and clinicians for providing diagnostic confirmation for the OX data set. We would like to express our gratitude to the staff and members of the Biobank Japan and Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences for their outstanding assistance. A full list of the investigators who contributed to the generation of these data is available from http://www.wtccc.org.uk. We gratefully appreciate the PGC for providing access to their depression and MDD GWAS summary data. Also, we acknowledge the generosity of UKB and other relevant bodies (QSKIN study, and GWAS Atlas) for providing open access to their GWAS summary data. Last but not least, we appreciate members of the Statistical and Genomic Epidemiology Laboratory (SGEL) at the Queensland University of Technology, Brisbane (Dale, Divya, Anita, Emmanuel, Ammarah, Sana, Linduni, Hamzeh, and, Rafiqul), for their support and encouragement towards the successful completion of this work.

Members of Consortia

International Endogene Consortium

Yadav Sapkota2, Kosuke Yoshihara5, Mette Nyegaard6,7 Valgerdur Steinthorsdottir10, Andrew P. Morris11,12, Amelie Fassbender13,14, Nilufer Rahmioglu12, Immaculata De Vivo15,16, Julie E. Buring15,17, Futao Zhang8, Todd L. Edwards18, Sarah Jones19, Dorien13,14, Danie¨lle Peterse13,14, Kathryn M. Rexrode15,17, Paul M. Ridker15,17, Andrew J. Schork20,21, Stuart MacGregor22, Nicholas G. Martin22, Christian M. Becker23, Sosuke Adachi5, Takayuki Enomoto5, Atsushi Takahashi24, Yoichiro Kamatani24, Koichi Matsuda25, Michiaki Kubo24, Gudmar Thorleifsson10, Reynir T. Geirsson26,27, Unnur Thorsteinsdottir10,27, Leanne M. Wallace 22,8, Jian Yang8, Digna R. Velez Edwards28, Siew-Kee Low24, Krina T. Zondervan 12,23, Stacey A. Missmer15,16, Thomas D’Hooghe 13,14,29, Kari Stefansson10,27, Joyce Y. Tung3, Grant W. Montgomery8, Daniel I. Chasman9, and Dale R. Nyholt1.

The 23andMe Research Team

Michelle Agee3, Babak Alipanahi3, Adam Auton3, Robert K. Bell3, Katarzyna Bryc3, Sarah L. Elson3, Pierre Fontanillas3, Nicholas A. Furlotte3, Karen E. Huber3, Aaron Kleinman3, Nadia K. Litterman3, Matthew H. McIntyre3, Joanna L. Mountain3, Elizabeth S. Noblin3, Carrie A.M. Northover3, Steven J. Pitts3, J. Fah Sathirapongsasuti3, Olga V. Sazonova3, Janie F. Shelton3, Suyash Shringarpure3, Chao Tian3, Vladimir Vacic3 & Catherine H. Wilson3.

Affliations

1School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. 2Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA. 323andMe, Inc., 899 W. Evelyn Avenue, Mountain View, California 94041, USA. 4School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom. 5Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 950–2181, Japan. 6Department of Biomedicine—Human Genetics, Aarhus University, DK-8000 Aarhus, Denmark. 7iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark. 8Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. 9Divisions of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 10deCODE Genetics/Amgen, 101 Reykjavik, Iceland. 11Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK. 12Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.13KULeuven, Department of Development and Regeneration, Organ systems, 3000 Leuven, Belgium. 14Department of Obstetrics and Gynaecology, Leuven University Fertility Centre, University Hospital Leuven, 3000 Leuven, Belgium. 15Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA. 16Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. 17Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA. 18Institute of Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA. 19Vanderbilt Genetics Institute, Division of Epidemiology, Institute of Medicine and Public Health, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA. 20Cognitive Science Department, University of California, San Diego, La Jolla, California 92093, USA. 21Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark. 22Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. 23Endometriosis CaRe Centre, Nuffield Dept of Obstetrics & Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. 24Center for Integrative Medical Sciences, RIKEN, Yokohama 230–0045, Japan. 25Institute of Medical Sciences, The University of Tokyo, Tokyo 108–8639, Japan. 26Department of Obstetrics and Gynecology, Landspitali University Hospital, 101 Reykjavik, Iceland. 27Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. 28Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute of Medicine and Public Health, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA. 29Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany.

Funding

EOA was supported by the Queensland University of Technology Postgraduate Research Awards (QUTPRA). The QIMR study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241,944, 339,462, 389,927, 389,875, 389,891, 389,892, 389,938, 443,036, 442,915, 442,981, 496,610, 496,739, 552,485, 552,498, 1,026,033 and 1,050,208), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne) and donations from N. Hawkins and S. Hawkins. Analyses of the QIMRHCS and OX GWAS were supported by the Wellcome Trust (WT084766/Z/08/Z) and makes use of WTCCC2 control data generated by the Wellcome Trust Case–Control Consortium (awards 076113 and 085475). The iPSYCH study was funded by The Lundbeck Foundation, Denmark (R102-A9118, R155-2014-1724), and the research has been conducted using the Danish National Biobank resource supported by the Novo Nordisk Foundation. The Japanese GWA study was funded by the BioBank Japan project, which is supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government.

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Correspondence to Emmanuel O. Adewuyi or Dale R. Nyholt.

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All researchers had full independence from the funders. The authors report no biomedical financial interests or potential conflicts of interest.

Ethical approval

This study has been included in the ‘genetic analysis and comorbid PSYCHIATRIC disorders using twin families’ (P5890) project in the ‘genetic epidemiology portfolio’. The Human Research Ethics Committee had earlier granted ethical approval for the project and approval for the addition of the present study was granted on the 3rd of November 2017.

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Availability of data and material (data transparency)

The present study was based on a secondary analysis of GWAS data and all data generated during the study are included in this published article [and its supplementary files]. The GWAS data analyzed for depression and MDD are available and accessible online by contacting the PGC. The GWAS data for GERD and gastritis/duodenitis are freely accessible using the links provided within the articles. The endometriosis GWAS data were sourced from the International Endogen Consortium (IEC); for access to these, contact the consortium directly.

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International Endogene Consortium, 23andMe Research Team Collaborators members are listed in the Acknowledgement section.

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Adewuyi, E.O., Mehta, D., Sapkota, Y. et al. Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality. Hum Genet 140, 529–552 (2021). https://doi.org/10.1007/s00439-020-02223-6

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