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1. Time for global health policy and research leaders to prioritize endometriosis

Author

Giudice, Linda C, Horne, Andrew W, and Missmer, Stacey A

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Health Sciences, Clinical Research, Infertility, Contraception/Reproduction, Pain Research, Endometriosis, Chronic Pain, Digestive Diseases, Good Health and Well Being, Female, Humans, Global Health, Health Policy
Abstract

Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.

Published
2023

2. Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function

Author

Mortlock, Sally, Houshdaran, Sahar, Kosti, Idit, Rahmioglu, Nilufer, Nezhat, Camran, Vitonis, Allison F, Andrews, Shan V, Grosjean, Parker, Paranjpe, Manish, Horne, Andrew W, Jacoby, Alison, Lager, Jeannette, Opoku-Anane, Jessica, Vo, Kim Chi, Manvelyan, Evelina, Sen, Sushmita, Ghukasyan, Zhanna, Collins, Frances, Santamaria, Xavier, Saunders, Philippa, Kober, Kord, McRae, Allan F, Terry, Kathryn L, Vallvé-Juanico, Júlia, Becker, Christian, Rogers, Peter AW, Irwin, Juan C, Zondervan, Krina, Montgomery, Grant W, Missmer, Stacey, Sirota, Marina, and Giudice, Linda

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Pain Research, Infertility, Contraception/Reproduction, Human Genome, Biotechnology, Endometriosis, Aetiology, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Good Health and Well Being, Female, Humans, DNA Methylation, Pain, Embryo Implantation, Biological sciences, Biomedical and clinical sciences
Abstract

Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.

Published
2023

3. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

Author

Dareng, Eileen O., Coetzee, Simon G., Tyrer, Jonathan P., Peng, Pei-Chen, Rosenow, Will, Chen, Stephanie, Davis, Brian D., Dezem, Felipe Segato, Seo, Ji-Heui, Nameki, Robbin, Reyes, Alberto L., Aben, Katja K.H., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Bandera, Elisa V., Beane Freeman, Laura E., Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bolton, Kelly L., Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Cai, Hui, Campbell, Ian, Cannioto, Rikki, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chenevix-Trench, Georgia, Chiew, Yoke-Eng, Cook, Linda S., DeFazio, Anna, Dennis, Joe, Doherty, Jennifer A., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Ene, Gabrielle, Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Fostira, Florentia, Gentry-Maharaj, Aleksandra, Giles, Graham G., Goodman, Marc T., Gronwald, Jacek, Haiman, Christopher A., Håkansson, Niclas, Heitz, Florian, Hildebrandt, Michelle A.T., Høgdall, Estrid, Høgdall, Claus K., Huang, Ruea-Yea, Jensen, Allan, Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony N., Kelemen, Linda E., Kennedy, Catherine J., Khusnutdinova, Elza K., Kiemeney, Lambertus A., Kjaer, Susanne K., Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Larson, Melissa C., Le, Nhu D., Lester, Jenny, Li, Lian, Lubiński, Jan, Lush, Michael, Marks, Jeffrey R., Matsuo, Keitaro, May, Taymaa, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Missmer, Stacey, Modugno, Francesmary, Moffitt, Melissa, Monteiro, Alvaro N., Moysich, Kirsten B., Narod, Steven A., Nguyen-Dumont, Tu, Odunsi, Kunle, Olsson, Håkan, Onland-Moret, N. Charlotte, Park, Sue K., Pejovic, Tanja, Permuth, Jennifer B., Piskorz, Anna, Prokofyeva, Darya, Riggan, Marjorie J., Risch, Harvey A., Rodríguez-Antona, Cristina, Rossing, Mary Anne, Sandler, Dale P., Setiawan, V. Wendy, Shan, Kang, Song, Honglin, Southey, Melissa C., Steed, Helen, Sutphen, Rebecca, Swerdlow, Anthony J., Teo, Soo Hwang, Terry, Kathryn L., Thompson, Pamela J., Vestrheim Thomsen, Liv Cecilie, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Webb, Penelope M., Weinberg, Clarice R., Weise, Rayna Matsuno, Wentzensen, Nicolas, White, Emily, Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zeinomar, Nur, Zheng, Wei, Ziogas, Argyrios, Berchuck, Andrew, Goode, Ellen L., Huntsman, David G., Pearce, Celeste L., Ramus, Susan J., Sellers, Thomas A., Freedman, Matthew L., Lawrenson, Kate, Schildkraut, Joellen M., Hazelett, Dennis, Plummer, Jasmine T., Kar, Siddhartha, Jones, Michelle R., Pharoah, Paul D.P., and Gayther, Simon A.

Published
2024
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5. Impact of Endometriosis on Life-Course Potential: A Narrative Review

Author

Missmer, Stacey A, Tu, Frank F, Agarwal, Sanjay K, Chapron, Charles, Soliman, Ahmed M, Chiuve, Stephanie, Eichner, Samantha, Flores-Caldera, Idhaliz, Horne, Andrew W, Kimball, Alexandra B, Laufer, Marc R, Leyland, Nicholas, Singh, Sukhbir S, Taylor, Hugh S, and As-Sanie, Sawsan

Subjects
Clinical Research, Pediatric, Endometriosis, Behavioral and Social Science, Management of diseases and conditions, 7.1 Individual care needs, Good Health and Well Being, endometriosis, health trajectory, life-course impairment, Clinical Sciences
Abstract

Endometriosis may exert a profound negative influence on the lives of individuals with the disorder, adversely affecting quality of life, participation in daily and social activities, physical and sexual functioning, relationships, educational and work productivity, mental health, and well-being. Over the course of a lifetime, these daily challenges may translate into limitations in achieving life goals such as pursuing or completing educational opportunities; making career choices or advancing in a chosen career; forming stable, fulfilling relationships; or starting a family, all of which ultimately alter one's life trajectory. The potential for endometriosis to impact the life course is considerable, as symptom onset generally occurs at a time of life (menarche through menopause, adolescence through middle age) when multiple life-changing and trajectory-defining decisions are made. Using a life-course approach, we examine how the known effects of endometriosis on life-domain satisfaction may impact health and well-being across the life course of affected individuals. We provide a quasi-systematic, narrative review of the literature as well as expert opinion on recommendations for clinical management and future research directions.

Published
2021

18. The relationship between surrounding greenness in childhood and adolescence and depressive symptoms in adolescence and early adulthood.

Author

Bezold, Carla, Banay, Rachel, Coull, Brent, Hart, Jaime, James, Peter, Kubzansky, Laura, Missmer, Stacey, and Laden, Francine

Subjects
Depression, Environment design, Mental health, Residence characteristics, Adolescent, Adult, Built Environment, Child, Cohort Studies, Depression, Environment, Environment Design, Female, Humans, Incidence, Male, Massachusetts, Mental Health, Population Density, Proportional Hazards Models, Prospective Studies, Residence Characteristics
Abstract

PURPOSE: Exposure to nature, particularly vegetation (greenness), may be beneficial for mental health. We investigated whether higher surrounding greenness in early life was associated with subsequent reduced risk of depressive symptoms and whether this association was modified by age, sex, or population density. METHODS: Participants from the Growing Up Today Study were included if they reported on depressive symptoms between 1999 and 2013. Greenness exposure was characterized as the cumulative average normalized difference vegetation index value (1000 m resolution) from 1989 until 2 years before outcome assessment or age 18 based on geocoded addresses. We defined high depressive symptoms as the top 10% of scores on the McKnight Risk Factor Survey or the Center for Epidemiologic Studies of Depression scale, depending on the questionnaire. Data were analyzed using Cox proportional hazards model adjusted for socioeconomic status and other confounders. RESULTS: There was a 6% lower incidence of high depressive symptoms associated with an interquartile range increase in greenness (95% confidence interval, 11%-0%). This relationship was stronger in higher population density areas (>1000 people/mi2, 8% lower incidence, 95% confidence interval 15%-1%). CONCLUSIONS: Living in an area with greater surrounding greenness during childhood may be beneficial for mental health, particularly in more urban areas.

Published
2018

19. Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study

Author

Ong, Jue-Sheng, Hwang, Liang-Dar, Cuellar-Partida, Gabriel, Martin, Nicholas G, Chenevix-Trench, Georgia, Quinn, Michael CJ, Cornelis, Marilyn C, Gharahkhani, Puya, Webb, Penelope M, MacGregor, Stuart, Bryne, Enda, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Swerdlow, Anthony J, Jones, Michael, Orr, Nicholas, Schoemaker, Minouk, Edwards, Digna Velez, Brenton, James, Benítez, Javier, García, María J, Rodriguez-Antona, Cristina, Rossing, Mary Anne, Fortner, Renée T, Riboli, Elio, Chang-Claude, Jenny, Eilber, Ursula, Wang-Gohrke, Shan, Yannoukakos, Drakoulis, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Duerst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Heitz, Florian, Karlan, Beth, Olsson, Håkan, Kjaer, Susanne K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Hildebrandt, Michelle AT, Liang, Dong, Wu, Xifeng, Le Marchand, Loic, Setiawan, V Wendy, Permuth, Jennifer B, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Willet, Walter, Missmer, Stacey, Bjorge, Line, Kopperud, Reidun K, Bischof, Katharina, Thomsen, Liv Cecilie Vestrheim, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, and Lissowska, Jolanta

Subjects
Epidemiology, Health Sciences, Clinical Research, Ovarian Cancer, Nutrition, Rare Diseases, Prevention, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Coffee, Female, Humans, Mendelian Randomization Analysis, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, Ovarian Cancer Association Consortium, Statistics, Public Health and Health Services, Public health
Abstract

BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.

Published
2018

22. Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry.

Author

Sapkota, Yadav, Vivo, Immaculata De, Steinthorsdottir, Valgerdur, Fassbender, Amelie, Bowdler, Lisa, Buring, Julie E, Edwards, Todd L, Jones, Sarah, O, Dorien, Peterse, Daniëlle, Rexrode, Kathryn M, Ridker, Paul M, Schork, Andrew J, Thorleifsson, Gudmar, Wallace, Leanne M, iPSYCH-SSI-Broad Group, Kraft, Peter, Morris, Andrew P, Nyholt, Dale R, Edwards, Digna R Velez, Nyegaard, Mette, D'Hooghe, Thomas, Chasman, Daniel I, Stefansson, Kari, Missmer, Stacey A, and Montgomery, Grant W

Subjects
iPSYCH-SSI-Broad Group, Humans, Endometriosis, Genetic Predisposition to Disease, Case-Control Studies, Chromosome Mapping, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Meta-Analysis as Topic, Genetic Variation, Genome-Wide Association Study, Exome, Biomarkers, Whole Exome Sequencing, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors
Abstract

Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10-9) in GREB1 at 2p25.1 - a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.

Published
2017

23. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.

Author

Sapkota, Yadav, Steinthorsdottir, Valgerdur, Morris, Andrew P, Fassbender, Amelie, Rahmioglu, Nilufer, De Vivo, Immaculata, Buring, Julie E, Zhang, Futao, Edwards, Todd L, Jones, Sarah, O, Dorien, Peterse, Daniëlle, Rexrode, Kathryn M, Ridker, Paul M, Schork, Andrew J, MacGregor, Stuart, Martin, Nicholas G, Becker, Christian M, Adachi, Sosuke, Yoshihara, Kosuke, Enomoto, Takayuki, Takahashi, Atsushi, Kamatani, Yoichiro, Matsuda, Koichi, Kubo, Michiaki, Thorleifsson, Gudmar, Geirsson, Reynir T, Thorsteinsdottir, Unnur, Wallace, Leanne M, iPSYCH-SSI-Broad Group, Yang, Jian, Velez Edwards, Digna R, Nyegaard, Mette, Low, Siew-Kee, Zondervan, Krina T, Missmer, Stacey A, D'Hooghe, Thomas, Montgomery, Grant W, Chasman, Daniel I, Stefansson, Kari, Tung, Joyce Y, and Nyholt, Dale R

Subjects
iPSYCH-SSI-Broad Group, Humans, Endometriosis, Genetic Predisposition to Disease, Gonadal Steroid Hormones, Estrogen Receptor alpha, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Metabolic Networks and Pathways, Genome-Wide Association Study, Genetic Loci, Genetics, Pain Research, Human Genome, Contraception/Reproduction, Clinical Research, Prevention, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning
Abstract

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P

Published
2017

24. Research Priorities for Endometriosis

Author

Rogers, Peter AW, Adamson, G David, Al-Jefout, Moamar, Becker, Christian M, D’Hooghe, Thomas M, Dunselman, Gerard AJ, Fazleabas, Asgerally, Giudice, Linda C, Horne, Andrew W, Hull, M Louise, Hummelshoj, Lone, Missmer, Stacey A, Montgomery, Grant W, Stratton, Pamela, Taylor, Robert N, Rombauts, Luk, Saunders, Philippa T, Vincent, Katy, and Zondervan, Krina T

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Endometriosis, Contraception/Reproduction, Consensus, Education, Female, Humans, Research, endometriosis, research priorities, international workshop, consensus report, WES/WERF Consortium for Research Priorities in Endometriosis, biological marker, Conference Paper, disease classification, embryo development, epigenetics, female infertility, genetics, genomics, health care policy, human, infertility therapy, lowest income group, oocyte, ovary follicle development, pain, pathogenesis, pathophysiology, pregnancy outcome, priority journal, prognosis, research priority, symptom assessment, workshop, consensus, education, female, research, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine, Reproductive medicine, Midwifery
Abstract

The 3rd International Consensus Workshop on Research Priorities in Endometriosis was held in São Paulo on May 4, 2014, following the 12th World Congress on Endometriosis. The workshop was attended by 60 participants from 19 countries and was divided into 5 main sessions covering pathogenesis/pathophysiology, symptoms, diagnosis/classification/prognosis, disease/symptom management, and research policy. This research priorities consensus statement builds on earlier efforts to develop research directions for endometriosis. Of the 56 research recommendations from the 2011 meeting in Montpellier, a total of 41 remained unchanged, 13 were updated, and 2 were deemed to be completed. Fifty-three new research recommendations were made at the 2014 meeting in Sao Paulo, which in addition to the 13 updated recommendations resulted in a total of 66 new recommendations for research. The research recommendations published herein, as well as those from the 2 previous papers from international consensus workshops, are an attempt to promote high-quality research in endometriosis by identifying and agreeing on key issues that require investigation. New areas included in the 2014 recommendations include infertility, patient stratification, and research in emerging nations, in addition to an increased focus on translational research. A revised and updated set of research priorities that builds on this document will be developed at the 13th World Congress on Endometriosis to be held on May 17-20, 2017, in Vancouver, British Columbia, Canada.

Published
2017

29. Differences in characteristics and use of complementary and alternative methods for coping with endometriosis-associated acyclic pelvic pain across adolescence and adulthood

Author

Mongiovi, Jennifer M., primary, Wallace, Britani, additional, Goodwin, McKenzie, additional, Vitonis, Allison F., additional, Karevicius, Sarah, additional, Shafrir, Amy L., additional, Sasamoto, Naoko, additional, DiVasta, Amy D., additional, Sieberg, Christine B., additional, Terry, Kathryn L., additional, and Missmer, Stacey A., additional

Published
2024
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31. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

Author

Ong, Jue-Sheng, Cuellar-Partida, Gabriel, Lu, Yi, Australian Ovarian Cancer Study, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Anne Doherty, Jennifer, Anne Rossing, Mary, Chang-Claude, Jenny, Eilber, Ursula, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle At, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja Kh, Kiemeney, Lambertus A, Massuger, Leon Fag, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, and Poole, Elizabeth M

Subjects
Australian Ovarian Cancer Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Vitamin D, Odds Ratio, Risk Factors, Polymorphism, Single Nucleotide, Female, Mendelian Randomization Analysis, Carcinoma, Ovarian Epithelial, Neoplasms, Glandular and Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Prevention, Rare Diseases, Nutrition, Clinical Research, Cancer, Ovarian Cancer, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundIn vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.MethodsWe employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).ResultsThe odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).ConclusionsGenetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Published
2016

32. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Author

Cuellar-Partida, Gabriel, Lu, Yi, Dixon, Suzanne C, Australian Ovarian Cancer Study, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Doherty, Jennifer Anne, Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Blake Gilks, C, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, Poole, Elizabeth M, and Morgan, Terry K

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Obesity, Women's Health, Cancer Genomics, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Female, Genotype, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Pathology, Molecular, Polymorphism, Single Nucleotide, Australian Ovarian Cancer Study, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Published
2016

37. Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: results from an Eastern Mediterranean population.

Author

Swift, Bethan, Taneri, Bahar, Becker, Christian M., Basarir, Hasan, Naci, Huseyin, Missmer, Stacey A., Zondervan, Krina T., and Rahmioglu, Nilufer

Subjects
DIAGNOSIS of endometriosis, CROSS-sectional method, HEALTH impact assessment, DESCRIPTIVE statistics, ENDOMETRIOSIS, ODDS ratio, QUALITY of life, DELAYED diagnosis, WOMEN'S health, COMPARATIVE studies, DATA analysis software, CONFIDENCE intervals, PELVIC pain, ECONOMIC aspects of diseases
Abstract

Background: There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an underrepresented region in Europe. Methods: Cyprus Women's Health Research Initiative, a cross-sectional study recruited 7646 women aged 18-55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n=2922) and without (n=4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. Results: Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9-5.9%, n=410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P<0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P=0.027) and asymptomatic (0.3%, P<0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03-2.38) higher than the symptomatic and 1.95 (95% CI: 1.30-2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P=0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811-$10 917) including healthcare, costs relating to absence and loss of productivity at work. Conclusion: Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain. [ABSTRACT FROM AUTHOR]

Published
2024
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38. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

Author

Mathieson, Iain, Day, Felix R., Barban, Nicola, Tropf, Felix C., Brazel, David M., van Heemst, Diana, Vaez, Ahmad, van Zuydam, Natalie, Bitarello, Bárbara D., Gardner, Eugene J., Akimova, Evelina T., Azad, Ajuna, Bergmann, Sven, Bielak, Lawrence F., Boomsma, Dorret I., Bosak, Kristina, Brumat, Marco, Buring, Julie E., Cesarini, David, Chasman, Daniel I., Chavarro, Jorge E., Cocca, Massimiliano, Concas, Maria Pina, Davey Smith, George, Davies, Gail, Deary, Ian J., Esko, Tõnu, Faul, Jessica D., Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J., Gelemanovic, Andrea, de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P., Hayward, Caroline, He, Chunyan, Hill, W. David, Hoffmann, Eva R., Homuth, Georg, Hottenga, Jouke Jan, Huang, Hongyang, Hyppӧnen, Elina, Ikram, M. Arfan, Jansen, Rick, Johannesson, Magnus, Kamali, Zoha, Kardia, Sharon L. R., Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Liew, Gerald, van der Most, Peter J., Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, Medland, Sarah E., Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Milani, Lili, Missmer, Stacey A., Mitchell, Paul, Møllegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, de Mutsert, Renée, Nauck, Matthias, Nolte, Ilja M., Noordam, Raymond, Penninx, Brenda W. J. H., Peters, Annette, Peyser, Patricia A., Polašek, Ozren, Power, Chris, Pribisalic, Ajka, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Shukla, Vallari, Smith, Jennifer A., Stankovic, Stasa, Stefánsson, Kári, Stöckl, Doris, Strauch, Konstantin, Swertz, Morris A., Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Uitterlinden, André G., Waldenberger, Melanie, Wareham, Nicholas J., Weir, David R., Willemsen, Gonneke, Zhao, Jing Hau, Zhao, Wei, Zhao, Yajie, Snieder, Harold, den Hoed, Marcel, Ong, Ken K., Mills, Melinda C., Perry, John R. B., Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Ageing & Vitality, AMS - Sports, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Epidemiology, Applied Economics, Internal Medicine, Mathieson, Iain, Day, Felix R, Barban, Nicola, Tropf, Felix C, Hyppӧnen, Elina, Perry, John RB, eQTLGen Consortium, BIOS Consortium, FinnGen Study, Lifelines Cohort Study, Brazel, David M, Vaez, Ahmad, van Zuydam, Natalie, Bitarello, Bárbara D, Gardner, Eugene J, Akimova, Evelina T, Azad, Ajuna, Bergmann, Sven, Bielak, Lawrence F, Boomsma, Dorret I, Bosak, Kristina, Brumat, Marco, Buring, Julie E, Cesarini, David, Chasman, Daniel I, Chavarro, Jorge E, Cocca, Massimiliano, Concas, Maria Pina, Davey Smith, George, Davies, Gail, Deary, Ian J, Esko, Tõnu, Faul, Jessica D, Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J, Gelemanovic, Andrea, de Geus, Eco J C, Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P, Hayward, Caroline, He, Chunyan, van Heemst, Diana, Hill, W David, Hoffmann, Eva R, Homuth, Georg, Hottenga, Jouke Jan, Huang, Hongyang, Ikram, M Arfan, Jansen, Rick, Johannesson, Magnu, Kamali, Zoha, Kardia, Sharon L R, Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Liew, Gerald, Lind, Penelope A, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K E, Mahajan, Anubha, Martin, Nicholas G, Mbarek, Hamdi, McCarthy, Mark I, McMahon, George, Medland, Sarah E, Meitinger, Thoma, Metspalu, Andre, Mihailov, Evelin, Milani, Lili, Missmer, Stacey A, Mitchell, Paul, Møllegaard, Stine, Mook-Kanamori, Dennis O, Morgan, Anna, van der Most, Peter J, de Mutsert, Renée, Nauck, Matthia, Nolte, Ilja M, Noordam, Raymond, Penninx, Brenda W J H, Peters, Annette, Peyser, Patricia A, Polašek, Ozren, Power, Chri, Pribisalic, Ajka, Redmond, Paul, Rich-Edwards, Janet W, Ridker, Paul M, Rietveld, Cornelius A, Ring, Susan M, Rose, Lynda M, Rueedi, Rico, Shukla, Vallari, Smith, Jennifer A, Stankovic, Stasa, Stefánsson, Kári, Stöckl, Dori, Strauch, Konstantin, Swertz, Morris A, Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A Roy, Timpson, Nicholas J, Turman, Constance, Uitterlinden, André G, Waldenberger, Melanie, Wareham, Nicholas J, Weir, David R, Willemsen, Gonneke, Zhao, Jing Hau, Zhao, Wei, Zhao, Yajie, Snieder, Harold, den Hoed, Marcel, Ong, Ken K, Mills, Melinda C, Perry, John R B, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
Behavioral Neuroscience, Endocrine reproductive disorders Genome-wide association studies, Social Psychology, genome-wide association studies, TERM BALANCING SELECTION, QUALITY-CONTROL, ASSOCIATION, VARIANTS, GWAS, HERITABILITY, METAANALYSIS, ADAPTATION, SIGNATURES, EQTL, endocrine reproductive disorders, Experimental and Cognitive Psychology, Bristol Population Health Science Institute
Abstract

Refereed/Peer-reviewed Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Published
2023

44. Clinical profiling of specific diagnostic subgroups of women with chronic pelvic pain

Author

Demetriou, Lysia, primary, Krassowski, Michal, additional, Abreu Mendes, Pedro, additional, Garbutt, Kurtis, additional, Vitonis, Allison F., additional, Wilkins, Elizabeth, additional, Coxon, Lydia, additional, Arendt-Nielsen, Lars, additional, Aziz, Qasim, additional, Birch, Judy, additional, Horne, Andrew W., additional, Hoffman, Anja, additional, Hummelshoj, Lone, additional, Lunde, Claire E., additional, Meijlink, Jane, additional, Perro, Danielle, additional, Rahmioglu, Nilufer, additional, Terry, Kathryn L., additional, Pogatzki-Zahn, Esther, additional, Sieberg, Christine B., additional, Treede, Rolf-Detlef, additional, Becker, Christian M., additional, Cruz, Francisco, additional, Missmer, Stacey A., additional, Zondervan, Krina T., additional, Nagel, Jens, additional, and Vincent, Katy, additional

Published
2023
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46. Comprehensive quantitative sensory testing shows altered sensory function in women with chronic pelvic pain:results from the Translational Research in Pelvic Pain (TRiPP) Study

Author

Coxon, Lydia, Vollert, Jan, Perro, Danielle, Lunde, Claire E, Ferreira-Gomes, Joana, Charrua, Ana, Abreu-Mendes, Pedro, Krassowski, Michal, Birch, Judy, Meijlink, Jane, Hummelshoj, Lone, Hoffmann, Anja, Aziz, Qasim, Arendt-Nielsen, Lars, Pogatzki-Zahn, Esther, Evans, Emma, Demetriou, Lysia, McMahon, Stephen B, Missmer, Stacey A, Becker, Christian M, Zondervan, Krina T, Horne, Andrew W, Cruz, Francisco, Sieberg, Christine B, Treede, Rolf-Detlef, Nagel, Jens, and Vincent, Katy

Abstract

Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in

Published
2023

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

Author

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

Subjects
genome-wide association studies, gene expression, genomics, Genetics, Humans, Pain, Female, Genetic Predisposition to Disease, Comorbidity, reproductive disorders, Article, Endometriosis/genetics, Genome-Wide Association Study
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.

Published
2023

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