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Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome

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Cheung, WA 
Shao, X 
Morin, A 
Siroux, V 
Kwan, T 



The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples.


We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases.


Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome.



Alleles, Chromosomal Position Effects, CpG Islands, DNA Methylation, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Genome, Human, Genotype, High-Throughput Nucleotide Sequencing, Humans, Organ Specificity, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci

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Genome Biology

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BioMed Central
Medical Research Council (MR/L003120/1)
Medical Research Council (G0800270)
British Heart Foundation (None)
Medical Research Council (G0800270/1)
This work was supported by a Canadian Institute of Health Research (CIHR) team grant awarded to E.G. and M.L. (TEC-128093) and the CIHR funded Epigenome Mapping Centre at McGill University (EP1-120608) awarded to T.P. and M.L. The work was also supported in part by a grant to M.L. from Génome Québec, le Ministère de l’Enseignement supérieur, de la Recherche, de la Science et de la Technologie Québec (MESRST), and McGill University as well as by the RESERt-AID grant (ANR-15-EPIG-0004-05) awarded to T.P and F.D. and by a grant from the French national clinical research program (PHRC) awarded to I.P. which also covered salary support to D.A. and X.S. E.G. is Tier 2 Canada Research Chair in Disease Genomics and Epigenomics, T.P. is Tier 2 Canada Research Chair in Human Genomics, and M.-C.V. is Tier 1 Canada Research Chair in Genomics Applied to Nutrition and Health. W.C. and A.M. are supported by a fellowship from the Fonds de Recherche du Quebec (FRSQ-32203 and FRSQ-27644). X.S. is supported by a fellowship from the Research Institute of the MUHC (McGill University Health Centre). D.S.P. and The Cardiovascular Epidemiology Unit are supported by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and NIHR Cambridge Biomedical Research Centre.