Warren A. Cheung, Xiaojian Shao, Andréanne Morin, Valérie Siroux, Tony Kwan, Bing Ge, Dylan Aïssi, Lu Chen, Louella Vasquez, Fiona Allum, Frédéric Guénard, Emmanuelle Bouzigon, Marie-Michelle Simon, Elodie Boulier, Adriana Redensek, Stephen Watt, Avik Datta, Laura Clarke, Paul Flicek, Daniel Mead, Dirk S. Paul, Stephan Beck, Guillaume Bourque, Mark Lathrop, André Tchernof, Marie-Claude Vohl, Florence Demenais, Isabelle Pin, Kate Downes, Hendrick G. Stunnenberg, Nicole Soranzo, Tomi Pastinen, Elin Grundberg, Paul, Dirk [0000-0002-8230-0116], Downes, Kate [0000-0003-0366-1579], Soranzo, Nicole [0000-0003-1095-3852], and Apollo - University of Cambridge Repository
Background 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1173-7) contains supplementary material, which is available to authorized users.