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; Julia  Vallve-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

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 SaundersKord Kober, Allan F. McRae, Kathryn L Terry, Julia Vallve-Juanico, Christian Becker, Peter A.W. Rogers, Juan C. Irwin, Krina Zondervan, Grant W Montgomery, Stacey Missmer, Marina Sirota, Linda Giudice

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Abstract

Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Identifying biologic and genetic effects on DNA methylation (DNAm) in endometrium increases understanding of mechanisms that influence gene regulation predisposing to endometriosis and offers an opportunity for novel therapeutic target discovery. Herein, we characterize variation in endometrial DNAm and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genome-wide genotype data and methylation at 759,345 DNAm sites in endometrial samples from 984 deeply-phenotyped participants. We identify significant differences in DNAm profiles between menstrual cycle phases and at four DNAm sites between stage III/IV endometriosis and controls. We estimate that 15.4% of the variation in endometriosis is captured by DNAm, and identify DNAm networks associated with endometriosis. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTL including some tissue-specific effects. We find significant differences in DNAm profiles between endometriosis sub-phenotypes and a significant association between genetic regulation of methylation in endometrium and disease risk, providing functional evidence for genomic targets contributing to endometriosis risk and pathogenesis.

Original language	English
Article number	780
Journal	Communications Biology
Volume	6
DOIs	https://doi.org/10.1038/s42003-023-05070-z
Publication status	Published - 16 Aug 2023

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Mortlock , S., Houshdaran, S., Kosti, I., Rahmioglu, N., Nezhat, C., Vitonis, A. F., Andrews, S. V., Grosjean, P., Paranjpe, M., Horne, A. W., Jacoby, A., Lager, J., Opoku-Anane, J., Chi Vo, K., Manvelyan, E., Sen, S., Ghukasyan, Z., Collins, F., Santamaria, X., ... Giudice, L. (2023). Global Endometrial DNA Methylation Analysis Reveals Insights into mQTL Regulation and Associated Endometriosis Disease Risk and Endometrial Function. Communications Biology, 6, Article 780. https://doi.org/10.1038/s42003-023-05070-z

@article{0f57d39fb81c421eade1172934ce4246,

title = "Global Endometrial DNA Methylation Analysis Reveals Insights into mQTL Regulation and Associated Endometriosis Disease Risk and Endometrial Function",

abstract = "Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Identifying biologic and genetic effects on DNA methylation (DNAm) in endometrium increases understanding of mechanisms that influence gene regulation predisposing to endometriosis and offers an opportunity for novel therapeutic target discovery. Herein, we characterize variation in endometrial DNAm and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genome-wide genotype data and methylation at 759,345 DNAm sites in endometrial samples from 984 deeply-phenotyped participants. We identify significant differences in DNAm profiles between menstrual cycle phases and at four DNAm sites between stage III/IV endometriosis and controls. We estimate that 15.4\% of the variation in endometriosis is captured by DNAm, and identify DNAm networks associated with endometriosis. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTL including some tissue-specific effects. We find significant differences in DNAm profiles between endometriosis sub-phenotypes and a significant association between genetic regulation of methylation in endometrium and disease risk, providing functional evidence for genomic targets contributing to endometriosis risk and pathogenesis. ",

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

note = "Funding Information: This work has been supported by the National Institutes of Health (NIH) NICHD R01 HD089511. It was also supported, in part, by funding from Wellbeing of Women (through sponsorship from PwC) (R42533) and the Medical Research Council (MR/N024524/1 and MR/N022556/1) and NIH HD094842 (Harvard/MSU). K.K. was supported by NIH NCI R37 CA233774. A.F.M. was supported by an Australian Research Council Future Fellowship (FT200100837). G.W.M. was supported by NHMRC Fellowship (GNT1177194). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = aug,

day = "16",

doi = "10.1038/s42003-023-05070-z",

language = "English",

volume = "6",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

}

Mortlock , S, Houshdaran, S, Kosti, I, Rahmioglu, N, Nezhat, C, Vitonis, AF, Andrews, SV, Grosjean, P, Paranjpe, M, Horne, AW, Jacoby, A, Lager, J, Opoku-Anane, J, Chi Vo, K, Manvelyan, E, Sen, S, Ghukasyan, Z, Collins, F, Santamaria, X, Saunders, P, Kober, K, McRae, AF, Terry, KL, Vallve-Juanico, J, Becker, C, Rogers, PAW, Irwin, JC, Zondervan, K, Montgomery, GW, Missmer, S, Sirota, M & Giudice, L 2023, 'Global Endometrial DNA Methylation Analysis Reveals Insights into mQTL Regulation and Associated Endometriosis Disease Risk and Endometrial Function', Communications Biology, vol. 6, 780. https://doi.org/10.1038/s42003-023-05070-z

TY - JOUR

T1 - Global Endometrial DNA Methylation Analysis Reveals Insights into mQTL Regulation and Associated Endometriosis Disease Risk and Endometrial Function

AU - Mortlock , Sally

AU - Houshdaran, Sahar

AU - Kosti, Idit

AU - Rahmioglu, Nilufer

AU - Nezhat, Camran

AU - Vitonis, Allison F

AU - Andrews, Shan V

AU - Grosjean, Parker

AU - Paranjpe, Manish

AU - Horne, Andrew W

AU - Jacoby, Alison

AU - Lager, Jeannette

AU - Opoku-Anane, Jessica

AU - Chi Vo, Kim

AU - Manvelyan, Evelina

AU - Sen, Sushmita

AU - Ghukasyan, Zhanna

AU - Collins, Frances

AU - Santamaria, Xavier

AU - Saunders, Philippa

AU - Kober, Kord

AU - McRae, Allan F.

AU - Terry, Kathryn L

AU - Vallve-Juanico, Julia

AU - Becker, Christian

AU - Rogers, Peter A.W.

AU - Irwin, Juan C.

AU - Zondervan, Krina

AU - Montgomery, Grant W

AU - Missmer, Stacey

AU - Sirota, Marina

AU - Giudice, Linda

N1 - Funding Information: This work has been supported by the National Institutes of Health (NIH) NICHD R01 HD089511. It was also supported, in part, by funding from Wellbeing of Women (through sponsorship from PwC) (R42533) and the Medical Research Council (MR/N024524/1 and MR/N022556/1) and NIH HD094842 (Harvard/MSU). K.K. was supported by NIH NCI R37 CA233774. A.F.M. was supported by an Australian Research Council Future Fellowship (FT200100837). G.W.M. was supported by NHMRC Fellowship (GNT1177194). Publisher Copyright: © 2023, The Author(s).

PY - 2023/8/16

Y1 - 2023/8/16

N2 - Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Identifying biologic and genetic effects on DNA methylation (DNAm) in endometrium increases understanding of mechanisms that influence gene regulation predisposing to endometriosis and offers an opportunity for novel therapeutic target discovery. Herein, we characterize variation in endometrial DNAm and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genome-wide genotype data and methylation at 759,345 DNAm sites in endometrial samples from 984 deeply-phenotyped participants. We identify significant differences in DNAm profiles between menstrual cycle phases and at four DNAm sites between stage III/IV endometriosis and controls. We estimate that 15.4% of the variation in endometriosis is captured by DNAm, and identify DNAm networks associated with endometriosis. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTL including some tissue-specific effects. We find significant differences in DNAm profiles between endometriosis sub-phenotypes and a significant association between genetic regulation of methylation in endometrium and disease risk, providing functional evidence for genomic targets contributing to endometriosis risk and pathogenesis.

AB - Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Identifying biologic and genetic effects on DNA methylation (DNAm) in endometrium increases understanding of mechanisms that influence gene regulation predisposing to endometriosis and offers an opportunity for novel therapeutic target discovery. Herein, we characterize variation in endometrial DNAm and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genome-wide genotype data and methylation at 759,345 DNAm sites in endometrial samples from 984 deeply-phenotyped participants. We identify significant differences in DNAm profiles between menstrual cycle phases and at four DNAm sites between stage III/IV endometriosis and controls. We estimate that 15.4% of the variation in endometriosis is captured by DNAm, and identify DNAm networks associated with endometriosis. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTL including some tissue-specific effects. We find significant differences in DNAm profiles between endometriosis sub-phenotypes and a significant association between genetic regulation of methylation in endometrium and disease risk, providing functional evidence for genomic targets contributing to endometriosis risk and pathogenesis.

U2 - 10.1038/s42003-023-05070-z

DO - 10.1038/s42003-023-05070-z

M3 - Article

SN - 2399-3642

VL - 6

JO - Communications Biology

JF - Communications Biology

M1 - 780

ER -

Global Endometrial DNA Methylation Analysis Reveals Insights into mQTL Regulation and Associated Endometriosis Disease Risk and Endometrial Function

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