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Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome
BACKGROUND: parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understandin...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654798/ https://www.ncbi.nlm.nih.gov/pubmed/34883445 http://dx.doi.org/10.1016/j.ebiom.2021.103730 |
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author | Zeng, Yanni Amador, Carmen Gao, Chenhao Walker, Rosie M. Morris, Stewart W. Campbell, Archie Frkatović, Azra Madden, Rebecca A Adams, Mark J. He, Shuai Bretherick, Andrew D. Hayward, Caroline Porteous, David J. Wilson, James F. Evans, Kathryn L. McIntosh, Andrew M. Navarro, Pau Haley, Chris S. |
author_facet | Zeng, Yanni Amador, Carmen Gao, Chenhao Walker, Rosie M. Morris, Stewart W. Campbell, Archie Frkatović, Azra Madden, Rebecca A Adams, Mark J. He, Shuai Bretherick, Andrew D. Hayward, Caroline Porteous, David J. Wilson, James F. Evans, Kathryn L. McIntosh, Andrew M. Navarro, Pau Haley, Chris S. |
author_sort | Zeng, Yanni |
collection | PubMed |
description | BACKGROUND: parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing modifiable POE exist. METHODS: in order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as ‘predicted mRNA expression levels’ of DNA methylation/imprinting machinery genes and environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315). FINDINGS: a set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, ‘lifetime smoking status’ and ‘predicted mRNA expression levels’ of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs. INTERPRETATION: the modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases. FUNDING: NSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH. |
format | Online Article Text |
id | pubmed-8654798 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-86547982021-12-20 Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome Zeng, Yanni Amador, Carmen Gao, Chenhao Walker, Rosie M. Morris, Stewart W. Campbell, Archie Frkatović, Azra Madden, Rebecca A Adams, Mark J. He, Shuai Bretherick, Andrew D. Hayward, Caroline Porteous, David J. Wilson, James F. Evans, Kathryn L. McIntosh, Andrew M. Navarro, Pau Haley, Chris S. EBioMedicine Research paper BACKGROUND: parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing modifiable POE exist. METHODS: in order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as ‘predicted mRNA expression levels’ of DNA methylation/imprinting machinery genes and environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315). FINDINGS: a set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, ‘lifetime smoking status’ and ‘predicted mRNA expression levels’ of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs. INTERPRETATION: the modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases. FUNDING: NSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH. Elsevier 2021-12-06 /pmc/articles/PMC8654798/ /pubmed/34883445 http://dx.doi.org/10.1016/j.ebiom.2021.103730 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research paper Zeng, Yanni Amador, Carmen Gao, Chenhao Walker, Rosie M. Morris, Stewart W. Campbell, Archie Frkatović, Azra Madden, Rebecca A Adams, Mark J. He, Shuai Bretherick, Andrew D. Hayward, Caroline Porteous, David J. Wilson, James F. Evans, Kathryn L. McIntosh, Andrew M. Navarro, Pau Haley, Chris S. Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome |
title | Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome |
title_full | Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome |
title_fullStr | Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome |
title_full_unstemmed | Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome |
title_short | Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome |
title_sort | lifestyle and genetic factors modify parent-of-origin effects on the human methylome |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654798/ https://www.ncbi.nlm.nih.gov/pubmed/34883445 http://dx.doi.org/10.1016/j.ebiom.2021.103730 |
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