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

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

doi:10.1038/s42003-023-05070-z

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

Commun Biol. 2023 Aug 16;6(1):780. doi: 10.1038/s42003-023-05070-z.

Authors

Sally Mortlock^#¹, Sahar Houshdaran^#², Idit Kosti^#³, Nilufer Rahmioglu^#^{4

5}, Camran Nezhat^{6

7

8}, Allison F Vitonis⁹, Shan V Andrews³, Parker Grosjean³, Manish Paranjpe³, Andrew W Horne¹⁰, Alison Jacoby², Jeannette Lager², Jessica Opoku-Anane², Kim Chi Vo², Evelina Manvelyan², Sushmita Sen², Zhanna Ghukasyan², Frances Collins¹⁰, Xavier Santamaria^{11

12}, Philippa Saunders¹³, Kord Kober^{3

14}, Allan F McRae¹⁵, Kathryn L Terry^{9

16

17}, Júlia Vallvé-Juanico^{2

12}, Christian Becker⁵, Peter A W Rogers¹⁸, Juan C Irwin², Krina Zondervan^{4

5}, Grant W Montgomery¹⁵, Stacey Missmer^{16

17

19

20}, Marina Sirota^{3

21}, Linda Giudice²²

Affiliations

¹ The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia. s.mortlock@imb.uq.edu.au.
² Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA.
³ Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA, USA.
⁴ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁵ Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁶ Stanford University Medical Center, Palo Alto, CA, USA.
⁷ University of California San Francisco, San Francisco, CA, USA.
⁸ Camran Nezhat Institute, Center for Special Minimally Invasive and Robotic Surgery, Woodside, CA, USA.
⁹ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ MRC Centre for Reproductive Health, University of Edinburgh, QMRI, Edinburgh, UK.
¹¹ Carlos Simon Foundation, Health Research Institute, Valencia, Spain.
¹² Group of Biomedical Research in Gynecology, Vall d'Hebron Research Institute, Barcelona, Spain.
¹³ Centre for Inflammation Research, Institute for Regeneration and Repair University of Edinburgh, Edinburgh, UK.
¹⁴ Department of Physiological Nursing, University of California San Francisco, San Francisco, CA, USA.
¹⁵ The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
¹⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁷ Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA, USA.
¹⁸ University of Melbourne Department of Obstetrics and Gynaecology, Royal Women's Hospital, Melbourne, Australia.
¹⁹ Division of Adolescent and Young Adult Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
²⁰ Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
²¹ Department of Pediatrics, Division of Neonatology, University of California San Francisco, San Francisco, CA, USA.
²² Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA. Linda.Giudice@ucsf.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation
Embryo Implantation
Endometriosis* / genetics
Female
Humans
Pain

Abstract

Publication types

MeSH terms

Grants and funding