Global Endometrial DNA Multi-omics Analysis Reveals Insights into mQTL Regulation and Associated Endometriosis Disease Risk

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 independentcis-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.

Endometriosis in the era of precision medicine and impact on sexual and reproductive health across the lifespan and in diverse populations

“…As endometrium is the origin of pelvic endometriosis and has cellular features and molecular pathways that differ in patients with and without disease at the transcriptional and epigenetic levels, 3 it has been mined for possible disease diagnosis and staging classifiers-e.g., the EndoMarker TM protocol for sampling endometrium and concomitant blood, all cycle phases 131 and specific machine learning classifiers for transcriptomics and methylomics. 132 Endometrial gene expression (oligonucleotide microarrays, bulk RNA-sequencing, scRNAseq, Q-RT-PCR), 89,[133][134][135] and endometrial whole DNA methylome and candidate gene DNA methylation signatures [136][137][138][139][140] have identified genes involved with steroid hormone dependence and abnormalities in patients with versus without endometriosis. However, most results fail to be replicated due to limited sample size, cellular heterogeneity in bulk tissue, poor cycle phase assignments, and limited clinical metadata.…”

From morphology to methylome: epigenetic studies of Müllerian mesonephric‐like adenocarcinoma reveal similarities to cervical mesonephric adenocarcinoma†

“…Additionally, while the study by Kommoss et al [5] compared MLAs with NSMP endometrial carcinomas, it is important to note that the NSMP group comprises a heterogeneous group of tumors. Further research evaluating ER/PR-negative NSMP tumors compared with MLAs are needed, since hormonal status greatly influences epigenetic features including global methylation profiles [10].…”