Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome
Yanni Zeng,
Carmen Amador,
Chenhao Gao,
Rosie M. Walker,
Stewart W. Morris,
Archie Campbell,
Azra Frkatović,
Rebecca A Madden,
Mark J. Adams,
Shuai He,
Andrew D. Bretherick,
Caroline Hayward,
David J. Porteous,
James F. Wilson,
Kathryn L. Evans,
Andrew M. McIntosh,
Pau Navarro,
Chris S. Haley
Affiliations
Yanni Zeng
Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Corresponding authors: Yanni Zeng, Pau Navarro, Chris S. Haley
Carmen Amador
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Chenhao Gao
Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
Rosie M. Walker
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, Chancellor's Building, The University of Edinburgh, Edinburgh, UK
Stewart W. Morris
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Archie Campbell
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Azra Frkatović
Genos Glycoscience Research Laboratory, Borongajska cesta 83h, 10000 Zagreb, Croatia
Rebecca A Madden
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
Mark J. Adams
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
Shuai He
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China
Andrew D. Bretherick
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Caroline Hayward
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
David J. Porteous
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
James F. Wilson
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK
Kathryn L. Evans
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Andrew M. McIntosh
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
Pau Navarro
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Corresponding authors: Yanni Zeng, Pau Navarro, Chris S. Haley
Chris S. Haley
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK; Corresponding authors: Yanni Zeng, Pau Navarro, Chris S. Haley
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.
