Meta-Analysis

. 2023 Mar;55(3):423-436.

doi: 10.1038/s41588-023-01323-z. Epub 2023 Mar 13.

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Nilufer Rahmioglu^{1

2}, Sally Mortlock³, Marzieh Ghiasi⁴, Peter L Møller⁵, Lilja Stefansdottir⁶, Geneviève Galarneau⁷, Constance Turman⁸, Rebecca Danning⁹, Matthew H Law^{10

11}, Yadav Sapkota¹², Paraskevi Christofidou¹³, Sini Skarp¹⁴, Ayush Giri¹⁵, Karina Banasik¹⁶, Michal Krassowski^{17

18}, Maarja Lepamets¹⁹, Błażej Marciniak²⁰, Margit Nõukas¹⁹, Danielle Perro¹⁸, Eeva Sliz^{21

22}, Marta Sobalska-Kwapis²⁰, Gudmar Thorleifsson⁶, Nura F Topbas-Selcuki¹⁸, Allison Vitonis^{23

24}, David Westergaard¹⁶, Ragnheidur Arnadottir²⁵, Kristoffer S Burgdorf²⁶, Archie Campbell²⁷, Cecilia S K Cheuk^{17

18}, Caterina Clementi⁷, James Cook²⁸, Immaculata De Vivo⁸, Amy DiVasta^{23

29}, O Dorien^{30

31}, Jacqueline F Donoghue³², Todd Edwards¹⁵, Pierre Fontanillas³³, Jenny N Fung³, Reynir T Geirsson²⁵, Jane E Girling^{32

34}, Paivi Harkki³⁵, Holly R Harris³⁶, Martin Healey³², Oskari Heikinheimo³⁵, Sarah Holdsworth-Carson³², Isabel C Hostettler^{37

38

39}, Henry Houlden³⁸, Sahar Houshdaran⁴⁰, Juan C Irwin⁴⁰, Marjo-Riitta Jarvelin^{12

21

41

42}, Yoichiro Kamatani⁴³, Stephen H Kennedy¹⁸, Ewa Kepka²⁰, Johannes Kettunen^{21

22

44}, Michiaki Kubo⁴³, Bartosz Kulig⁴⁵, Venla Kurra^{46

47}, Hannele Laivuori^{46

47

48

49}, Marc R Laufer^{23

29

50

51}, Cecilia M Lindgren^{17

18

52}, Stuart MacGregor^{10

53}, Massimo Mangino^{13

54}, Nicholas G Martin⁵⁵, Charoula Matalliotaki⁵⁶, Michail Matalliotakis⁵⁶, Alison D Murray⁵⁷, Anne Ndungu^{17

18}, Camran Nezhat⁵⁸, Catherine M Olsen⁵⁹, Jessica Opoku-Anane⁴⁰, Sandosh Padmanabhan⁶⁰, Manish Paranjpe⁶¹, Maire Peters^{62

63}, Grzegorz Polak⁶⁴, David J Porteous²⁷, Joseph Rabban⁶⁵, Kathyrn M Rexrode^{66

67}, Hanna Romanowicz⁶⁸, Merli Saare^{62

63}, Liisu Saavalainen³⁵, Andrew J Schork^{69

70

71}, Sushmita Sen⁴⁰, Amy L Shafrir^{23

29}, Anna Siewierska-Górska²¹, Marcin Słomka²¹, Blair H Smith⁷², Beata Smolarz⁶⁸, Tomasz Szaflik⁴⁵, Krzysztof Szyłło⁴⁵, Atsushi Takahashi^{43

73}, Kathryn L Terry^{8

23

24}, Carla Tomassetti^{30

31}, Susan A Treloar⁵⁵, Arne Vanhie^{30

31}, Katy Vincent¹⁸, Kim C Vo⁴⁰, David J Werring³⁷, Eleftheria Zeggini^{74

75

76}, Maria I Zervou⁷⁷; DBDS Genomic Consortium; FinnGen Study; FinnGen Endometriosis Taskforce; Celmatix Research Team; 23andMe Research Team; Sosuke Adachi⁷⁸, Julie E Buring^{9

67}, Paul M Ridker^{9

67}, Thomas D'Hooghe^{31

79

80}, George N Goulielmos⁷⁷, Dharani K Hapangama⁸¹, Caroline Hayward⁸², Andrew W Horne⁸³, Siew-Kee Low⁸⁴, Hannu Martikainen^{85

86

87}, Daniel I Chasman^{9

67}, Peter A W Rogers³², Philippa T Saunders⁸⁸, Marina Sirota^{61

89}, Tim Spector¹³, Dominik Strapagiel²⁰, Joyce Y Tung³³, David C Whiteman⁵⁹, Linda C Giudice⁴⁰, Digna R Velez-Edwards¹⁵, Outi Uimari^{85

86

87}, Peter Kraft^{8

90}, Andres Salumets^{19

62

63

91}, Dale R Nyholt^{55

92}, Reedik Mägi¹⁹, Kari Stefansson^{6

93}, Christian M Becker¹⁸, Piraye Yurttas-Beim⁷, Valgerdur Steinthorsdottir⁶, Mette Nyegaard^{5

94}, Stacey A Missmer^{8

23

29

95}, Grant W Montgomery³, Andrew P Morris⁹⁶, Krina T Zondervan^{97

98}

Collaborators, Affiliations

Collaborators

Kari Stefansson, Mette Nyegaard, Paivi Harkki, Oskari Heikinheimo, Johannes Kettunen, Venla Kurra, Hannele Laivuori, Outi Uimari, Geneviève Galarneau, Caterina Clementi, Piraye Yurttas-Beim, Pierre Fontanillas, Joyce Y Tung

Affiliations

¹ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. nilufer.rahmioglu@well.ox.ac.uk.
² Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, UK. nilufer.rahmioglu@well.ox.ac.uk.
³ The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
⁴ Department of Epidemiology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
⁵ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁶ deCODE genetics/Amgen, Reykjavik, Iceland.
⁷ Celmatix Inc., New York, NY, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹¹ School of Biomedical Sciences, Faculty of Health, and Institute of health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
¹² Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹³ Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, Kings College London, London, UK.
¹⁴ Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁵ Department of Obstetrics and Gynecology, Institute of Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁷ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹⁸ Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, UK.
¹⁹ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
²⁰ Biobank Lab, Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland.
²¹ Computational Medicine and Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
²² Biocenter Oulu, University of Oulu, Oulu, Finland.
²³ Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA, USA.
²⁴ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁵ Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland.
²⁶ Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.
²⁷ Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
²⁸ Department of Biostatistics, University of Liverpool, Liverpool, UK.
²⁹ Division of Adolescent and Young Adult Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Department of Obstetrics and Gynaecology, Leuven University Fertility Centre, University Hospital Leuven, Leuven, Belgium.
³¹ KULeuven (University of Leuven), Department of Development and Regeneration, Organ systems, Leuven, Belgium.
³² University of Melbourne Department of Obstetrics and Gynaecology, Royal Women's Hospital, Melbourne, Victoria, Australia.
³³ 23andMe, Inc., Sunnyvale, CA, USA.
³⁴ Department of Anatomy, School of Biomedical Sciences, University of Otago, Otago, New Zealand.
³⁵ Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³⁶ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³⁷ Stroke Research Centre, University College London, Institute of Neurology, London, UK.
³⁸ Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London, UK.
³⁹ Department of Neurosurgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
⁴⁰ Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
⁴¹ Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland.
⁴² Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.
⁴³ Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
⁴⁴ Institute for Health and Welfare, Helsinki, Finland.
⁴⁵ Department of Operative Gynecology and Oncological Gynecology, Polish Mother's Memorial Hospital-Research Institute, Łódź, Poland.
⁴⁶ Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland.
⁴⁷ Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland.
⁴⁸ Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁴⁹ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
⁵⁰ Division of Gynecology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁵¹ Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵² Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
⁵³ Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
⁵⁴ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
⁵⁵ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁶ Third Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁵⁷ The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK.
⁵⁸ Center For Special Minimally Invasive and Robotic Surgery, Camran Nezhat Institute, Palo Alto, CA, USA.
⁵⁹ Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁶⁰ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁶¹ Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA.
⁶² Institute of Clinical Medicine, Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia.
⁶³ Competence Centre on Health Technologies, Tartu, Estonia.
⁶⁴ 1st Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland.
⁶⁵ Department of Pathology, University of California, San Francisco, CA, USA.
⁶⁶ Division of Women's Health, Brigham and Women's Hospital, Boston, MA, USA.
⁶⁷ Harvard Medical School, Boston, MA, USA.
⁶⁸ Laboratory of Cancer Genetics, Department of Clinical Pathomorphology, Polish Mother's Memorial Hospital-Research Institute, Łódź, Poland.
⁶⁹ Institute of Biological Psychiatry, Mental Health Center, Sct. Hans, Mental Health Services, Copenhagen, Denmark.
⁷⁰ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
⁷¹ Neurogenomics Division, The Translational Genomics Research Institute (TGEN), Phoenix, AZ, USA.
⁷² Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁷³ Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁷⁴ Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁵ Wellcome Sanger Institute, Hinxton, UK.
⁷⁶ TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
⁷⁷ Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece.
⁷⁸ Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
⁷⁹ Global Medical Affairs Fertility, Research and Development, Merck, Germany.
⁸⁰ Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
⁸¹ Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
⁸² MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁸³ MRC Centre for Reproductive Health, University of Edinburgh Institute for Regeneration and Repair, Edinburgh, UK.
⁸⁴ Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁸⁵ Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.
⁸⁶ Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland.
⁸⁷ Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
⁸⁸ Centre for Inflammation Research, University of Edinburgh, Institute for Regeneration and Repair, Edinburgh, UK.
⁸⁹ Department of Pediatrics, University of California, San Francisco, CA, USA.
⁹⁰ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹¹ Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁹² School of Biomedical Sciences, Faculty of Health, and Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, Queensland, Australia.
⁹³ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁹⁴ Department of Health, Science and Technology, Aalborg University, Aalborg, Denmark.
⁹⁵ Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
⁹⁶ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
⁹⁷ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. krina.zondervan@wrh.ox.ac.uk.
⁹⁸ Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, UK. krina.zondervan@wrh.ox.ac.uk.

PMID: 36914876
PMCID: PMC10042257
DOI: 10.1038/s41588-023-01323-z

Meta-Analysis

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Nilufer Rahmioglu et al. Nat Genet. 2023 Mar.

. 2023 Mar;55(3):423-436.

doi: 10.1038/s41588-023-01323-z. Epub 2023 Mar 13.

Authors

Collaborators

Kari Stefansson, Mette Nyegaard, Paivi Harkki, Oskari Heikinheimo, Johannes Kettunen, Venla Kurra, Hannele Laivuori, Outi Uimari, Geneviève Galarneau, Caterina Clementi, Piraye Yurttas-Beim, Pierre Fontanillas, Joyce Y Tung

Affiliations

¹ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. nilufer.rahmioglu@well.ox.ac.uk.
² Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, UK. nilufer.rahmioglu@well.ox.ac.uk.
³ The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
⁴ Department of Epidemiology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
⁵ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁶ deCODE genetics/Amgen, Reykjavik, Iceland.
⁷ Celmatix Inc., New York, NY, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹¹ School of Biomedical Sciences, Faculty of Health, and Institute of health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
¹² Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹³ Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, Kings College London, London, UK.
¹⁴ Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁵ Department of Obstetrics and Gynecology, Institute of Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁷ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹⁸ Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, UK.
¹⁹ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
²⁰ Biobank Lab, Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland.
²¹ Computational Medicine and Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
²² Biocenter Oulu, University of Oulu, Oulu, Finland.
²³ Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA, USA.
²⁴ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁵ Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland.
²⁶ Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.
²⁷ Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
²⁸ Department of Biostatistics, University of Liverpool, Liverpool, UK.
²⁹ Division of Adolescent and Young Adult Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Department of Obstetrics and Gynaecology, Leuven University Fertility Centre, University Hospital Leuven, Leuven, Belgium.
³¹ KULeuven (University of Leuven), Department of Development and Regeneration, Organ systems, Leuven, Belgium.
³² University of Melbourne Department of Obstetrics and Gynaecology, Royal Women's Hospital, Melbourne, Victoria, Australia.
³³ 23andMe, Inc., Sunnyvale, CA, USA.
³⁴ Department of Anatomy, School of Biomedical Sciences, University of Otago, Otago, New Zealand.
³⁵ Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³⁶ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³⁷ Stroke Research Centre, University College London, Institute of Neurology, London, UK.
³⁸ Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London, UK.
³⁹ Department of Neurosurgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
⁴⁰ Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
⁴¹ Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland.
⁴² Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.
⁴³ Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
⁴⁴ Institute for Health and Welfare, Helsinki, Finland.
⁴⁵ Department of Operative Gynecology and Oncological Gynecology, Polish Mother's Memorial Hospital-Research Institute, Łódź, Poland.
⁴⁶ Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland.
⁴⁷ Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland.
⁴⁸ Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁴⁹ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
⁵⁰ Division of Gynecology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁵¹ Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵² Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
⁵³ Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
⁵⁴ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
⁵⁵ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁶ Third Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁵⁷ The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK.
⁵⁸ Center For Special Minimally Invasive and Robotic Surgery, Camran Nezhat Institute, Palo Alto, CA, USA.
⁵⁹ Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁶⁰ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁶¹ Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA.
⁶² Institute of Clinical Medicine, Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia.
⁶³ Competence Centre on Health Technologies, Tartu, Estonia.
⁶⁴ 1st Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland.
⁶⁵ Department of Pathology, University of California, San Francisco, CA, USA.
⁶⁶ Division of Women's Health, Brigham and Women's Hospital, Boston, MA, USA.
⁶⁷ Harvard Medical School, Boston, MA, USA.
⁶⁸ Laboratory of Cancer Genetics, Department of Clinical Pathomorphology, Polish Mother's Memorial Hospital-Research Institute, Łódź, Poland.
⁶⁹ Institute of Biological Psychiatry, Mental Health Center, Sct. Hans, Mental Health Services, Copenhagen, Denmark.
⁷⁰ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
⁷¹ Neurogenomics Division, The Translational Genomics Research Institute (TGEN), Phoenix, AZ, USA.
⁷² Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁷³ Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁷⁴ Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁵ Wellcome Sanger Institute, Hinxton, UK.
⁷⁶ TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
⁷⁷ Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece.
⁷⁸ Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
⁷⁹ Global Medical Affairs Fertility, Research and Development, Merck, Germany.
⁸⁰ Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
⁸¹ Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
⁸² MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁸³ MRC Centre for Reproductive Health, University of Edinburgh Institute for Regeneration and Repair, Edinburgh, UK.
⁸⁴ Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁸⁵ Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.
⁸⁶ Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland.
⁸⁷ Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
⁸⁸ Centre for Inflammation Research, University of Edinburgh, Institute for Regeneration and Repair, Edinburgh, UK.
⁸⁹ Department of Pediatrics, University of California, San Francisco, CA, USA.
⁹⁰ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹¹ Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁹² School of Biomedical Sciences, Faculty of Health, and Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, Queensland, Australia.
⁹³ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁹⁴ Department of Health, Science and Technology, Aalborg University, Aalborg, Denmark.
⁹⁵ Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
⁹⁶ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
⁹⁷ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. krina.zondervan@wrh.ox.ac.uk.
⁹⁸ Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, UK. krina.zondervan@wrh.ox.ac.uk.

PMID: 36914876
PMCID: PMC10042257
DOI: 10.1038/s41588-023-01323-z

Abstract

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

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Conflict of interest statement

Competing Interests

L.S., G.T., K.S. and V.S. are employees of deCODE Genetics/Amgen. G.G., C.C. and P.Y.B. are employees of Celmatix Inc., and hold stock or stock options in Celmatix Inc. P.F. and J.Y.T. are employees of 23andMe Inc. O.H. serves occasionally on advisory boards for Bayer AG, Gedeon Richter, HRA Pharma, and Vifor Pharma, and has lectured at educational events for Bayer AG, Gedeon Richter, and Sandoz AG. C.M.L. receives grant support from Bayer AG, Novo Nordisk and her husband works for Vertex. J.R. spouse receives salary and stock options from Merck & Co. K.V. receives research funding from Bayer Healthcare and Honorarium for Consultancy and Lectures from Bayer Healthcare, Grunenthal GmBH, AbbVie and Eli Lilly. T.D. is employee of Merck Healthcare KGaA, Darmstadt, Germany. T. S. is the co-founder and shareholder of Zoe Global Ltd. P.A.W.R. is an advisory board member for Bayer AG. O.U. lectured at educational events for Exeltis and Merck. K.L.T. report an endometriosis grant from Aspira which is not relevant to the submitted work. K.T.Z. and C.M.B. reported grants from Bayer AG, AbbVie Inc, Volition Rx, MDNA Life Sciences, Roche Diagnostics Inc. outside the submitted work. The remaining authors declare no competing interests.

Figures

**Extended Data Figure 1.. Q-Q plots for genome-wide association results.**
Q-Q plot for genome-wide association results for a. overall endometriosis, b. rASRM stage I/II endometriosis, c. rASRM stage III/IV endometriosis, d. endometriosis-associated infertility, e. only studies with >300 cases.

**Extended Data Figure 2.. Manhattan plots for genome-wide association results.**
Manhattan plot for genome-wide association results for a. overall endometriosis, b. rASRM stage I/II endometriosis, c. rASRM stage III/IV endometriosis, d. endometriosis associated infertility. The GWAS meta-analysis results are shown on the y-axis as −log10(P-value) and on the x-axis is the chromosomal location. The red vertical line illustrates the genome-wide significance (p<5×10⁻⁸) and the blue vertical line shows the nominal genome-wide results (p<1×10⁻⁵).

**Extended Data Figure 3.. Comparison of mixed female and male controls GWAS meta-analysis vs. female only controls GWAS meta-analysis results.**
Results from meta-analysis contrasting GWAS studies with mixed female and male controls (N cases=5,222, N controls=44,176) vs. GWAS studies with only female controls (N cases=44,176, N controls=657,747). Significant heterogeneity: p-value<1.19×10–3 (0.05/42). The error bars represent standard error estimates for the beta co-efficient estimates. * SNPs with nominal heterogeneity p-values: rs1430787, p=0.03, rs1451383, p=0.01.

**Extended Data Figure 4.. Tissue-specific gene enrichment results.**
Tissue-specific gene enrichment using RNA-Seq data across 35 human tissues from the Human Protein Atlas (a and b) and 29 human tissues from GTEx (c and d). The x-axis shows each of the tissues, and the y-axis represents the tissue-specific gene enrichment −Log10(P−Value) (left) and the fold-change values of the tissue-specific gene enrichment (right).

**Extended Data Figure 5.. SKAP1/17q21.32 locus.**
a. Illustration of the regional association plot for the SKAP1/17q21.32 locus including the 99% credible sets. eSMR endometrium SNP: SMR SNP identified as causal for endometriosis utilizing the eQTL data from endometrium; The shaded region in the credible sets panel is further annotated in panel c. b. SMR significant endometrial eQTL for HOXB9 (SMR p-value=2×10⁻⁶). The lower and upper bounds of the boxes represent the first and third quantiles, the whiskers extend 1.5 times the interquartile range from the bounds of the box and the line represents the median. c. position of the SMR-significant eQTL in the SKAP1/17q21.32 locus along with HOXB9 promoter-associated chromatin loops with anchor points containing the lead SNP and the SMR SNP. The SMR-significant SNP associated with expression of HOXB9 in endometrium (eQTL) and endometriosis is shown in black and the associated HOXB9¬ target is shown in red. Valid promoter-associated chromatin loops were generated from H3K27Ac HiChIP libraries from a normal immortalized endometrial cell line (E6E7hTERT) and three endometrial cancer cell lines (ARK1, Ishikawa and JHUEM-14).

**Extended Data Figure 6.. sICAM-1 level results.**
Box plots of log scale sICAM-1 levels in a. overall endometriosis cases (N=136) vs. controls (N=54), b. rASRM stage I/II cases (N=85) vs. controls and rASRM stage III/IV (N=51) vs. controls. Reported p-values are from the adjusted logistic regression model (see Supplementary Information: Methods) (Supplementary Table 19). The lower and upper bounds of the boxes represent the first and third quantiles, the whiskers extend 1.5 times the interquartile range from the bounds of the box and the line represents the median.

**Extended Data Figure 7.. Single cell expression profiles.**
Single cell expression profiles for 18/23 genes regulated by endometriosis risk variants in GTEx Multi-Gene Single Cell Viewer (5 were not included in the database). This is an aster plot where the fraction of cells in which a gene is detected is shown. The cells are categorised by cell-type.

**Extended Data Figure 8.. Correlation of 42 GWAS loci between endometriosis surgical sub-types and adenomyosis.**
Correlation between the effect sizes of 42 endometriosis-associated GWAS loci contrasting endometriosis surgical sub-types and adenomyosis: a. Adenomyosis vs. rASRM stage I/II, b. Adenomyosis vs. rASRM stage III/IV, c. Adenomyosis vs. endometrioma, d. Adenomyosis vs. deep lesions, e. Adenomyosis vs. superficial lesions. Minor allele frequency for each of the 42 variants is given by shade of grey: Lighter shade of grey designates a smaller MAF, darker shade of grey a larger MAF. Nominal associations (p<0.05) are annotated with locus name and larger circles. The solid black line represents the linear regression line and the dotted black line is the x=y with a slope of 1 for reference of change in ORs. Test statistics including p-values for all the associations are provided in Supplementary Table 21.

**Extended Data Figure 9.. Genetic correlation results between only surgically or medically confirmed endometriosis and 32 traits/conditions.**
Genetic correlation between only surgically or medically confirmed endometriosis (N=8,390 cases) and 32 immune/inflammatory, pain, reproductive, and metabolic traits/conditions using LD score regression analysis (LDSC). Heritability of each trait is noted in parenthesis on the x-axis. The significance threshold is adjusted for multiple testing using Bonferroni correction. Significant (p<1.56×10⁻³) correlations are denoted with a red star (*), nominal correlation (p<0.05) with a green star (*). Bars present the genetic correlation (rg) for each trait in relation to endometriosis and the error bars are standard errors. The exact p-values are provided in Supplementary Table 25.

**Extended Data Figure 10.. Genetic correlation results between endometriosis and 19 brain imaging traits in UKBB.**
Genetic correlation between 19 brain imaging traits in UKBB and a. endometriosis (N=58,961) and b. surgically or medically confirmed endometriosis (N=8,390 cases) using LD score regression analysis (LDSC). A total of 6 functional MRI measures (netmat_ICA_09Aug2017_001–006), structural MRI measures including 11 freesurfer derived variables (aseg_lh_volume_Left-Thalamus-Proper, aseg_lh_volume_Left-Hippocampus, aseg_lh_ volume_Left-Amygdala, aseg_lh_volume_Right-Thalamus-Proper, aseg_lh_volume_Right-Hippocampus, aseg_lh_volume_Right-Amygdala, aseg_lh_volume_CC_Posterior, aseg_lh_volume_CC_Mid_Posterior, aseg_lh_volume_CC_Central, aseg_lh_volume_CC_Mid_Anterior, aseg_lh_volume_CC_Anterior) and 2 FAST calculations for insula region (IDP_T1_FAST_ROIs_L_insular_cortex, IDP_T1_FAST_ROIs_R_insular_cortex) were analysed. Heritability of each trait is noted in parenthesis on the x-axis. Nominal correlations are denoted with a green star (*). Bars present the genetic correlation (rg) for each trait in relation to endometriosis and the error bars are standard errors. The exact p-values are provided in Supplementary Table 27 and 28.

**Fig. 1.. Circular Manhattan plots for genome-wide association analysis for overall endometriosis, rASRM stage III/IV disease, rASRM stage I/II disease and infertility.**
Circular Manhattan plots for genome-wide association analysis for overall endometriosis (blue), revised American Society of Reproductive Medicine (rASRM) stage III/IV disease (green), rASRM stage I/II disease (orange), and endometriosis associated infertility (yellow). Genome-wide significant signals are marked in red and their chromosomal location is denoted with dotted grey lines. The 6 loci with significantly larger effect sizes in rASRM stage III/IV vs. rASRM stage I/II analysis are annotated in green.

Fig. 2.. *GDAP1*/8q21.11 regional association results and summary data-based mendelian randomisation (SMR) evidence based on expression (eQTL) and methylation (mQTL) quantitative trait loci data in blood.
a) Illustration of the regional association plot for the *GDAP1*/8q21.11 locus. eSMR blood single nucleotide polymorphism (SNP): SMR SNP identified as causal for endometriosis utilizing the eQTL data from blood tissue. mSMR blood SNP: SMR SNP identified as causal for endometriosis utilizing the mQTL data from blood tissue. b) SMR significant blood based eQTL for *GDAP1* and mQTL of probe cg23779890 located in *GDAP1* gene are shown. c) The genic content and locations for the region are illustrated.

**Fig. 3.. *SRP14-AS1*/15q15.1 regional association results and SMR evidence based on eQTL and mQTL data in endometrium and blood.**
a) Illustration of the regional association plot for the *SRP14-AS1*/15q15.1 locus. eSMR endometrium SNP: SMR SNP identified as causal for endometriosis utilizing the eQTL data from endometrium; mSMR blood SNP: SMR SNP identified as causal for endometriosis utilising the mQTL data from blood tissue. eSMR blood SNP: SMR SNP identified as causal for endometriosis utilizing the eQTL data from blood tissue. SMR SNPs not passing the HEIDI-heterogeneity test are annotated in black. b) SMR significant eQTLs and mQTLs in the *SRP14-AS1*/15q15.1 locus along with *SRP14* promoter associated chromatin loops with anchor points containing the lead SNP and the SMR SNPs. SMR significant SNPs associated with expression of *SRP14* in endometrium and blood (eQTL), methylation at cg27155939 in blood (mQTL), and endometriosis are shown in black and the associated *SRP14*/CpG target is shown in red. Valid promoter associated chromatin loops were generated from H3K27Ac HiChIP libraries from a normal immortalized endometrial cell line (E6E7hTERT) and three endometrial cancer cell lines (ARK1, Ishikawa and JHUEM-14).

**Fig. 4.. *SYNE1*/6q25.1 regional association results with 5 distinct signals and SMR evidence based eQTL and mQTL data in endometrium and blood.**
Illustration of the regional association plot for the *SYNE1*/6q25.1 locus that includes 5 distinct signals from approximate conditional analysis. On the plot are also the SMR significant eQTL and mQTLs from endometrium and blood tissue along with promoter associated chromatin loops with anchor points containing the lead SNP and the SMR SNPs. Multiple distinct signals significantly associated with endometriosis were identified in this region and r² values displayed are relative to the closest lead SNP. eSMR endometrium SNP: SMR SNP identified as causal for endometriosis utilizing the eQTL data from endometrium; mSMR endometrium SNP: SMR SNP identified as causal for endometriosis utilizing the mQTL data from endometrium; mSMR blood SNP: SMR SNP identified as causal for endometriosis utilising the mQTL data from blood tissue. eSMR blood SNP: SMR SNP identified as causal for endometriosis utilizing the eQTL data from blood tissue. SMR SNPs not passing the HEIDI-heterogeneity test are annotated in black. SMR significant SNPs associated with expression of *ESR1* in blood (eQTL), methylation at cg24075332 (mQTL1), cg14416726 (mQTL2), cg18745416 (mQTL3) and cg01066157 (mQTL4) in blood, and endometriosis are shown in black and the associated *ESR1*/CpG targets are shown in red. Ovarian enhancers were available from the Roadmap Epigenomics Project. Valid promoter associated chromatin loops were generated from H3K27Ac HiChIP libraries from a normal immortalized endometrial cell line (E6E7hTERT) and three endometrial cancer cell lines (ARK1, Ishikawa and JHUEM-14).

**Fig. 5.. Correlation of the effect sizes of lead SNPs between rASRM disease stage and surgical subtypes and extended of pelvic pain.**
Correlation between the effect sizes of 42 endometriosis associated lead SNPs comparing rASRM stage III/IV disease vs. surgical subtypes (endometrioma; deep lesions; superficial lesions; panels a-c) and rASRM stage I/II, rASRM stage III/IV, deep lesions vs. risk of reporting more than 2 types of pelvic pain (panels d-f). Loci nominally associated (p<0.05) with individual sub-phenotypes are annotated with locus name and larger circles. Circle size represent significance level of correlation: Larger circles have smaller p-values and smaller circles have larger p-values. Solid black line represents the linear regression line, dotted black line is the x=y reference slope, dotted grey lines x=1 and y=1 are reference to odds ratio (OR). The grey error band represents 95% confidence interval. Test statistics including p-values for all the associations are provided in Supplementary Table 21.

**Fig. 6.. Genetic correlation between endometriosis and 32 immune/inflammatory, pain, reproductive, and metabolic traits/conditions.**
Genetic correlation between endometriosis and 32 immune/inflammatory, pain, reproductive, and metabolic traits/conditions using linkage disequilibrium score regression analysis (LDSC). Heritability of each trait is noted in parenthesis on the x-axis. The significance threshold is adjusted for multiple testing using Bonferroni correction. Significant (p<1.56×10⁻³) correlations are denoted with a red asterisk (*). Bars present the genetic correlation (rg) for each trait in relation to endometriosis and the error bars are standard errors. The exact p-values are provided in Supplementary Table 24.

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References

1. Zondervan KT, Becker CM & Missmer SA Endometriosis. N Engl J Med 382, 1244–1256 (2020). - PubMed
1. Nnoaham KE et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 96, 366–373 e8 (2011). - PMC - PubMed
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The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

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The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

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