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.
| Original language | English |
|---|---|
| Pages (from-to) | 423-436 |
| Number of pages | 14 |
| Journal | Nature Genetics |
| Volume | 55 |
| Issue number | 3 |
| Early online date | 13 Mar 2023 |
| DOIs | |
| Publication status | Published - 13 Mar 2023 |
Bibliographical note
Funding Information:Further information on research design is available in the linked to this article. This research was funded in part by The Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission.
We thank all the study participants in the individual studies. We also thank many hospital directors and staff, gynecologists, general practitioners and pathology services who provided assistance with confirmation of diagnoses. We would like to thank the research participants and employees of 23andMe for making this work possible. We thank the women of the Icelandic deCODE study for their participation. 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. We thank all the UK Biobank participants. Part of this research has been conducted using the UK Biobank Resource under application 9637. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFH samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award ‘STratifying Resilience and Depression Longitudinally’ (STRADL) reference 104036/Z/14/Z). The QIMR study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (GNT241944, GNT339462, GNT389927, GNT389875, GNT389891, GNT389892, GNT389938, GNT443036, GNT442915, GNT442981, GNT496610, GNT496739, GNT552485, GNT552498, GNT1026033, GNT1050208 and GNT1147846), 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 made use of WTCCC2 control data generated by the Wellcome Trust Case-Control Consortium (awards 076113 and 085475). The ENDOX gene expression analyses were funded by the Medical Research Council UK (MR/K011480/1). We thank the participants of the Women’s Health Study: From Adolescence to Adulthood (A2A) for their valuable contributions and all staff of the Boston Center for Endometriosis. Financial support for the establishment of and data collection within the A2A cohort was provided by the J. Willard and Alice S. Marriott Foundation. A.L.S., K.L.T. and S.A.M. were supported by NICHD R01 HD094842 and NICHD R21 HD096358 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. We would like to thank the participants and staff of the Nurses’ Health Study (NHS) and Nurses’ Health Study 2 (NHS2) cohorts for their contributions. NHS/NHS2 are supported by grants UM1 CA186107 and UM1 CA176726 from the National Institutes of Health. C.T., P.K. and S.A.M. were supported by NICHD R01 HD096033. S.A.M. and K.T.Z. gratefully acknowledge funding provided by the Nezhat Family Foundation on behalf of Worldwide EndoMarch to their research programs. N.R. was supported by a grant from Wellbeing of Women UK (RG2031) and the EU Horizon 2020-funded project FEMaLe (ID 101017562). G.W.M. was supported by NHMRC Fellowships (GNT0613667, GNT1078399 and GNT1177194). D.R.N. was supported by NHMRC Fellowship (GNT0613674) and ARC Future Fellowship (FT0991022). S. Mortlock was supported by the Australian Government Medical Research Future Fund Research Grant (MRF1199785) and S. MacGregor by Australian National Health and Medical Research Council Fellowship. A.P.M. was supported in part by Versus Arthritis (grant 21754). The Melbourne study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (GNT1026033, GNT1046880, GNT1049472, GNT1105321 and GNT1147846). R.M. and M.L. were supported by Estonian Research Council grant PRG1911, M.S. and M.P. by Estonian Research Council grant PRG1076 and A.S. by Estonian Research Council grant PRG1076, Horizon 2020 innovation (ERIN; EU952516) of the European Commission and Enter-prise Estonia (EU48695), MSCA-RISE-2020 project TRENDO (101008193). B.M., M.S.K., E.K., M.S., A.S.G. and D.S. were supported by Polish POIG grant 01.01.02-10-005/08 TESTOPLEK from the European Regional Development Fund. B.N. and D.W. were supported by NNF14CC0001, NNF17OC0027594 and NNF18SA0034956. J.F.D., J.E.G., M.H., S.H.C. and P.A.W.R. were supported by NHMRC GNT1105321. S.H., J.C.I., S.S., M.P., K.C.V., M.S. and L.C.G. were supported by NIH NICHD R01HD089511. J.K. was supported by The Sigrid Juselius Foundation, the Academy of Finland (297338 and 307247) and Novo Nordisk Foundation (NNF17OC0026062). C.M.L. was supported by the Li Ka Shing Foundation, NIHR Oxford Biomedical Research Centre, Oxford, NIH (1P50HD104224-01), Gates Foundation (INV-024200) and Wellcome Trust Investigator Award (221782/Z/20/Z). A.S. was supported by J. Willard and Alice S. Marriott Foundation, NIH NICHD R21 HD096358, NIH NICHD R01 HD094842. D.K.H. was supported by Wellbeing of Women (RG2137 and RG1073). C.H. was supported by MRC University Unit Programme Grant (MC_UU_00007/10—QTL in Health and Disease). D.C.W. was supported by NHMRC APP1155413, APP1185416, APP1073898 and APP1063061. M.N. acknowledge the Novo Nordisk Foundation (NNF21OC0071050). K.B. acknowledge the Novo Nordisk Foundation (NNF17OC0027594 and NNF14CC0001). TwinsUK receives funding from the Wellcome Trust (212904/Z/18/Z), Chronic Disease Research Foundation (CDRF) and European Union (H2020 contract 733100). TwinsUK and M.M. are supported by the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords
- Comorbidity
- Endometriosis/genetics
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Pain