Dataset Information

Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases.

ABSTRACT: BACKGROUND:Major challenges in understanding the functional consequences of genetic risk factors for human disease are which tissues and cell types are affected and the limited availability of suitable tissue. The aim of this study was to evaluate tissue-specific genotype-epigenetic characteristics in DNA samples from both endometrium and blood collected from women at different stages of the menstrual cycle and relate results to genetic risk factors for reproductive traits and diseases. RESULTS:We analysed DNA methylation (DNAm) data from endometrium and blood samples from 66 European women. Methylation profiles were compared between stages of the menstrual cycle, and changes in methylation overlaid with changes in transcription and genotypes. We observed large changes in methylation (27,262 DNAm probes) across the menstrual cycle in endometrium that were not observed in blood. Individual genotype data was tested for association with methylation at 443,016 and 443,101 DNAm probes in endometrium and blood respectively to identify methylation quantitative trait loci (mQTLs). A total of 4546 sentinel cis-mQTLs (P?

SUBMITTER: Mortlock S

PROVIDER: S-EPMC6416889 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases.

Mortlock Sally S Restuadi Restuadi R Levien Rupert R Girling Jane E JE Holdsworth-Carson Sarah J SJ Healey Martin M Zhu Zhihong Z Qi Ting T Wu Yang Y Lukowski Samuel W SW Rogers Peter A W PAW Yang Jian J McRae Allan F AF Fung Jenny N JN Montgomery Grant W GW

Clinical epigenetics 20190314 1

<h4>Background</h4>Major challenges in understanding the functional consequences of genetic risk factors for human disease are which tissues and cell types are affected and the limited availability of suitable tissue. The aim of this study was to evaluate tissue-specific genotype-epigenetic characteristics in DNA samples from both endometrium and blood collected from women at different stages of the menstrual cycle and relate results to genetic risk factors for reproductive traits and diseases.< ...[more]

PMID: 30871624

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Project description:The endometrium is a complex and dynamic tissue essential for fertility and implicated in many reproductive disorders. The tissue consists of glandular epithelium and vascularised stroma and is unique because it is constantly shed and regrown with each menstrual cycle, generating up to 10 mm of new mucosa. Consequently, there are marked changes in cell composition and gene expression across the menstrual cycle. Recent evidence shows expression of many genes is influenced by genetic variation between individuals. We and others have reported evidence for genetic effects on hundreds of genes in endometrium. The genetic factors influencing endometrial gene expression are highly correlated with the genetic effects on expression in other reproductive (e.g., in uterus and ovary) and digestive tissues (e.g., salivary gland and stomach), supporting a shared genetic regulation of gene expression in biologically similar tissues. There is also increasing evidence for cell specific genetic effects for some genes. Sample size for studies in endometrium are modest and results from the larger studies of gene expression in blood report genetic effects for a much higher proportion of genes than currently reported for endometrium. There is also emerging evidence for the importance of genetic variation on RNA splicing. Gene mapping studies for common disease, including diseases associated with endometrium, show most variation maps to intergenic regulatory regions. It is likely that genetic risk factors for disease function through modifying the program of cell specific gene expression. The emerging evidence from our gene mapping studies coupled with tissue specific studies, and the GTEx, eQTLGen and EpiMap projects, show we need to expand our understanding of the complex regulation of gene expression. These data also help to link disease genetic risk factors to specific target genes. Combining our data on genetic regulation of gene expression in endometrium, and cell types within the endometrium with gene mapping data for endometriosis and related diseases is beginning to uncover the specific genes and pathways responsible for increased risk of these diseases.

Dataset Information

Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases.

Publications

Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases.

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