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 charact...
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2019-03-01
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Series: | Clinical Epigenetics |
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Online Access: | http://link.springer.com/article/10.1186/s13148-019-0648-7 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sally Mortlock Restuadi Restuadi Rupert Levien Jane E. Girling Sarah J. Holdsworth-Carson Martin Healey Zhihong Zhu Ting Qi Yang Wu Samuel W. Lukowski Peter A. W. Rogers Jian Yang Allan F. McRae Jenny N. Fung Grant W. Montgomery |
spellingShingle |
Sally Mortlock Restuadi Restuadi Rupert Levien Jane E. Girling Sarah J. Holdsworth-Carson Martin Healey Zhihong Zhu Ting Qi Yang Wu Samuel W. Lukowski Peter A. W. Rogers Jian Yang Allan F. McRae Jenny N. Fung Grant W. Montgomery Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases Clinical Epigenetics DNA methylation DNA methylation quantitative trait loci (mQTL) Endometrium Blood Menstrual cycle Endometriosis |
author_facet |
Sally Mortlock Restuadi Restuadi Rupert Levien Jane E. Girling Sarah J. Holdsworth-Carson Martin Healey Zhihong Zhu Ting Qi Yang Wu Samuel W. Lukowski Peter A. W. Rogers Jian Yang Allan F. McRae Jenny N. Fung Grant W. Montgomery |
author_sort |
Sally Mortlock |
title |
Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases |
title_short |
Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases |
title_full |
Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases |
title_fullStr |
Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases |
title_full_unstemmed |
Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases |
title_sort |
genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases |
publisher |
BMC |
series |
Clinical Epigenetics |
issn |
1868-7075 1868-7083 |
publishDate |
2019-03-01 |
description |
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 < 1.13 × 10−10) and 434 sentinel trans-mQTLs (P < 2.29 × 10−12) were detected in endometrium and 6615 sentinel cis-mQTLs (P < 1.13 × 10−10) and 590 sentinel trans-mQTLs (P < 2.29 × 10−12) were detected in blood. Following secondary analyses, conducted to test for overlap between mQTLs in the two tissues, we found that 62% of endometrial cis-mQTLs were also observed in blood and the genetic effects between tissues were highly correlated. A number of mQTL SNPs were associated with reproductive traits and diseases, including one mQTL located in a known risk region for endometriosis (near GREB1). Conclusions We report novel findings characterising genetic regulation of methylation in endometrium and the association of endometrial mQTLs with endometriosis risk and other reproductive traits and diseases. The high correlation of genetic effects between tissues highlights the potential to exploit the power of large mQTL datasets in endometrial research and identify target genes for functional studies. However, tissue-specific methylation profiles and genetic effects also highlight the importance of also using disease-relevant tissues when investigating molecular mechanisms of disease risk. |
topic |
DNA methylation DNA methylation quantitative trait loci (mQTL) Endometrium Blood Menstrual cycle Endometriosis |
url |
http://link.springer.com/article/10.1186/s13148-019-0648-7 |
work_keys_str_mv |
AT sallymortlock geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT restuadirestuadi geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT rupertlevien geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT janeegirling geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT sarahjholdsworthcarson geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT martinhealey geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT zhihongzhu geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT tingqi geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT yangwu geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT samuelwlukowski geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT peterawrogers geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT jianyang geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT allanfmcrae geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT jennynfung geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases AT grantwmontgomery geneticregulationofmethylationinhumanendometriumandbloodandgenetargetsforreproductivediseases |
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doaj-60b8eb5419064806af1dfba2a6c969442020-11-24T21:36:28ZengBMCClinical Epigenetics1868-70751868-70832019-03-0111111910.1186/s13148-019-0648-7Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseasesSally Mortlock0Restuadi Restuadi1Rupert Levien2Jane E. Girling3Sarah J. Holdsworth-Carson4Martin Healey5Zhihong Zhu6Ting Qi7Yang Wu8Samuel W. Lukowski9Peter A. W. Rogers10Jian Yang11Allan F. McRae12Jenny N. Fung13Grant W. Montgomery14Institute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandDepartment of Obstetrics and Gynaecology, and Gynaecology Research Centre, University of Melbourne, Royal Women’s HospitalDepartment of Obstetrics and Gynaecology, and Gynaecology Research Centre, University of Melbourne, Royal Women’s HospitalDepartment of Obstetrics and Gynaecology, and Gynaecology Research Centre, University of Melbourne, Royal Women’s HospitalInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandDepartment of Obstetrics and Gynaecology, and Gynaecology Research Centre, University of Melbourne, Royal Women’s HospitalInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandAbstract 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 < 1.13 × 10−10) and 434 sentinel trans-mQTLs (P < 2.29 × 10−12) were detected in endometrium and 6615 sentinel cis-mQTLs (P < 1.13 × 10−10) and 590 sentinel trans-mQTLs (P < 2.29 × 10−12) were detected in blood. Following secondary analyses, conducted to test for overlap between mQTLs in the two tissues, we found that 62% of endometrial cis-mQTLs were also observed in blood and the genetic effects between tissues were highly correlated. A number of mQTL SNPs were associated with reproductive traits and diseases, including one mQTL located in a known risk region for endometriosis (near GREB1). Conclusions We report novel findings characterising genetic regulation of methylation in endometrium and the association of endometrial mQTLs with endometriosis risk and other reproductive traits and diseases. The high correlation of genetic effects between tissues highlights the potential to exploit the power of large mQTL datasets in endometrial research and identify target genes for functional studies. However, tissue-specific methylation profiles and genetic effects also highlight the importance of also using disease-relevant tissues when investigating molecular mechanisms of disease risk.http://link.springer.com/article/10.1186/s13148-019-0648-7DNA methylationDNA methylation quantitative trait loci (mQTL)EndometriumBloodMenstrual cycleEndometriosis |