General Gynecology · Pelvic Pain

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

Rahmioglu N, Mortlock S, Ghiasi M, Møller PL, Stefansdottir L, Galarneau G, Turman C, Danning R, Law MH, Sapkota Y, Christofidou P, Skarp S, Giri A, Banasik K, Krassowski M, Lepamets M, Marciniak B, Nõukas M, Perro D, Sliz E, Sobalska-Kwapis M, Thorleifsson G, Topbas-Selcuki NF, Vitonis A, Westergaard D, Arnadottir R, Burgdorf KS, Campbell A, Cheuk CSK, Clementi C, Cook J, De Vivo I, DiVasta A, Dorien O, Donoghue JF, Edwards T, Fontanillas P, Fung JN, Geirsson RT, Girling JE, Harkki P, Harris HR, Healey M, Heikinheimo O, Holdsworth-Carson S, Hostettler IC, Houlden H, Houshdaran S, Irwin JC, Jarvelin MR, Kamatani Y, Kennedy SH, Kepka E, Kettunen J, Kubo M, Kulig B, Kurra V, Laivuori H, Laufer MR, Lindgren CM, MacGregor S, Mangino M, Martin NG, Matalliotaki C, Matalliotakis M, Murray AD, Ndungu A, Nezhat C, Olsen CM, Opoku-Anane J, Padmanabhan S, Paranjpe M, Peters M, Polak G, Porteous DJ, Rabban J, Rexrode KM, Romanowicz H, Saare M, Saavalainen L, Schork AJ, Sen S, Shafrir AL, Siewierska-Górska A, Słomka M, Smith BH, Smolarz B, Szaflik T, Szyłło K, Takahashi A, Terry KL, Tomassetti C, Treloar SA, Vanhie A, Vincent K, Vo KC, Werring DJ, Zeggini E, Zervou MI, Adachi S, Buring JE, Ridker PM, D'Hooghe T, Goulielmos GN, Hapangama DK, Hayward C, Horne AW, Low SK, Martikainen H, Chasman DI, Rogers PAW, Saunders PT, Sirota M, Spector T, Strapagiel D, Tung JY, Whiteman DC, Giudice LC, Velez-Edwards DR, Uimari O, Kraft P, Salumets A, Nyholt DR, Mägi R, Stefansson K, Becker CM, Yurttas-Beim P, Steinthorsdottir V, Nyegaard M, Missmer SA, Montgomery GW, Morris AP, Zondervan KT

Published March 15, 2023 Nature Genetics, 55(3), 423-436
DOI 10.1038/s41588-023-01323-z PMID 36914876 PMC PMC10042257

RRM Academy Synopsis

Endometriosis shares genetic risk with migraine and chronic pain

Endometriosis shares inherited risk with migraine, back pain and other chronic pain conditions. A genetic study pooled 24 smaller studies: 60,674 women with endometriosis and 701,926 controls, mostly of European ancestry. It found 42 regions of DNA linked to the disease. Thirty-one were new.

Key Findings

  • The meta-analysis pooled 24 genome-wide association studies. It included 60,674 cases and 701,926 controls, 98% of European ancestry and 2% of East Asian ancestry (Japan).
  • The analysis found 42 genome-wide significant loci, which held 49 distinct association signals. Thirty-one of the 42 loci were new.
  • Lead variants at 38 of 42 loci had larger effects in stage III/IV than stage I/II disease. The 49 signals explained 5.01% of stage III/IV variance and 1.98% of overall variance.
  • Genetic correlation with endometriosis was 0.43 for multi-site chronic pain, 0.29 for migraine, 0.24 for osteoarthritis and 0.17 for asthma. Each passed the study's multiple-testing threshold.
  • Stage III/IV effect sizes tracked endometrioma most closely (r=0.73). Correlations were lower for deep lesions (r=0.42) and for superficial peritoneal lesions (r=0.15).

Interpretation

The study is a genome-wide association meta-analysis. It compares DNA variants between people with and without a condition. A genetic correlation means two conditions share inherited influences. The design cannot show that one condition causes the other. Together the signals explain 5.01% of disease variance at most. Nearly all participants had European ancestry. Links from variants to particular genes rest on statistical inference. Brain imaging analyses found no evidence of shared risk through brain structure, and the authors note low power.

RRM Context

The authors report a weak link between stage III/IV genetic effects and the number of pelvic pain symptoms. Restorative reproductive medicine looks for the disease behind a woman's pain, and excision removes the lesions. Pain in other parts of the body belongs in that picture.

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.

Topics

By this author

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General Gynecology › Pelvic Pain › Chronic Pelvic Pain
Nilufer Rahmioglu, Sally Mortlock, Marzieh Ghiasi, Peter L Møller, Lilja Stefansdottir, Geneviève Galarneau, Constance Turman, Rebecca Danning, Matthew H Law, Yadav Sapkota, Paraskevi Christofidou, Sini Skarp, Ayush Giri, Karina Banasik, Michal Krassowski, Maarja Lepamets, Błażej Marciniak, Margit Nõukas, Danielle Perro, Eeva Sliz, Marta Sobalska-Kwapis, Gudmar Thorleifsson, Nura F Topbas-Selcuki, Allison Vitonis, David Westergaard, Ragnheidur Arnadottir, Kristoffer S Burgdorf, Archie Campbell, Cecilia S K Cheuk, Caterina Clementi, James Cook, Immaculata De Vivo, Amy DiVasta, Jacqueline F Donoghue, Todd Edwards, Pierre Fontanillas, Jenny N Fung, Reynir T Geirsson, Jane E Girling, Paivi Harkki, Holly R Harris, Martin Healey, Oskari Heikinheimo, Sarah Holdsworth-Carson, Isabel C Hostettler, Henry Houlden, Sahar Houshdaran, Juan C Irwin, Marjo-Riitta Jarvelin, Yoichiro Kamatani, Stephen H Kennedy, Ewa Kepka, Johannes Kettunen, Michiaki Kubo, Bartosz Kulig, Venla Kurra, Hannele Laivuori, Marc R Laufer, Cecilia M Lindgren, Stuart MacGregor, Massimo Mangino, Nicholas G Martin, Charoula Matalliotaki, Michail Matalliotakis, Alison D Murray, Anne Ndungu, Camran Nezhat, Catherine M Olsen, Jessica Opoku-Anane, Sandosh Padmanabhan, Manish Paranjpe, Maire Peters, Grzegorz Polak, David J Porteous, Joseph Rabban, Kathyrn M Rexrode, Hanna Romanowicz, Merli Saare, Liisu Saavalainen, Andrew J Schork, Sushmita Sen, Amy L Shafrir, Anna Siewierska-Górska, Marcin Słomka, Blair H Smith, Beata Smolarz, Tomasz Szaflik, Krzysztof Szyłło, Atsushi Takahashi, Kathryn L Terry, Carla Tomassetti, Susan A Treloar, Arne Vanhie, Katy Vincent, Kim C Vo, David J Werring, Eleftheria Zeggini, Maria I Zervou, Sosuke Adachi, Julie E Buring, Paul M Ridker, Thomas D'Hooghe, George N Goulielmos, Dharani K Hapangama, Caroline Hayward, Andrew W Horne, Siew-Kee Low, Hannu Martikainen, Daniel I Chasman, Peter A W Rogers, Philippa T Saunders, Marina Sirota, Tim Spector, Dominik Strapagiel, Joyce Y Tung, David C Whiteman, Linda C Giudice, Digna R Velez-Edwards, Outi Uimari, Peter Kraft, Andres Salumets, Dale R Nyholt, Reedik Mägi, Kari Stefansson, Christian M Becker, Piraye Yurttas-Beim, Valgerdur Steinthorsdottir, Mette Nyegaard, Stacey A Missmer, Grant W Montgomery, Andrew P Morris, Krina T Zondervan
N Rahmioglu, S Mortlock, M Ghiasi, Pete Møller, P Møller, L Stefansdottir, G Galarneau, C Turman, Becky Danning, R Danning, Matt Law, M Law, Y Sapkota, P Christofidou, S Skarp, A Giri, K Banasik, M Krassowski, M Lepamets, B Marciniak, M Nõukas, D Perro, E Sliz, M Sobalska-Kwapis, G Thorleifsson, N Topbas-Selcuki, A Vitonis, Dave Westergaard, D Westergaard, R Arnadottir, K Burgdorf, A Campbell, C Cheuk, C Clementi, Jim Cook, Jimmy Cook, J Cook, I Vivo, A DiVasta, J Donoghue, T Edwards, P Fontanillas, Jennifer Fung, J Fung, R Geirsson, J Girling, P Harkki, H Harris, M Healey, O Heikinheimo, S Holdsworth-Carson, I Hostettler, H Houlden, S Houshdaran, J Irwin, M Jarvelin, Y Kamatani, Steve Kennedy, S Kennedy, E Kepka, J Kettunen, M Kubo, B Kulig, V Kurra, H Laivuori, M Laufer, C Lindgren, S MacGregor, M Mangino, Nick Martin, N Martin, C Matalliotaki, M Matalliotakis, A Murray, A Ndungu, C Nezhat, Cathy Olsen, Kate Olsen, C Olsen, Jess Opoku-Anane, J Opoku-Anane, S Padmanabhan, M Paranjpe, M Peters, G Polak, Dave Porteous, D Porteous, Joe Rabban, Joey Rabban, J Rabban, K Rexrode, H Romanowicz, M Saare, L Saavalainen, Andy Schork, Drew Schork, A Schork, S Sen, A Shafrir, A Siewierska-Górska, M Słomka, B Smith, B Smolarz, T Szaflik, K Szyłło, A Takahashi, Kathy Terry, Kate Terry, K Terry, C Tomassetti, Sue Treloar, S Treloar, A Vanhie, K Vincent, K Vo, Dave Werring, D Werring, E Zeggini, M Zervou, S Adachi, J Buring, P Ridker, Tom D'Hooghe, T D'Hooghe, G Goulielmos, D Hapangama, C Hayward, Andy Horne, Drew Horne, A Horne, S Low, H Martikainen, Dan Chasman, Danny Chasman, D Chasman, Pete Rogers, P Rogers, P Saunders, M Sirota, Timothy Spector, T Spector, D Strapagiel, J Tung, Dave Whiteman, D Whiteman, L Giudice, D Velez-Edwards, O Uimari, Pete Kraft, P Kraft, A Salumets, D Nyholt, R Mägi, K Stefansson, C Becker, P Yurttas-Beim, V Steinthorsdottir, M Nyegaard, S Missmer, G Montgomery, Andy Morris, Drew Morris, A Morris, K Zondervan
PMID 36914876 36914876 DOI 10.1038/s41588-023-01323-z 10.1038/s41588-023-01323-z Rahmioglu et al. 2023, Rahmioglu 2023