TY - JOUR
T1 - Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome
AU - Cheung, Warren A.
AU - Shao, Xiaojian
AU - Morin, Andréanne
AU - Siroux, Valérie
AU - Kwan, Tony
AU - Ge, Bing
AU - Aïssi, Dylan
AU - Chen, Lu
AU - Vasquez, Louella
AU - Allum, Fiona
AU - Guénard, Frédéric
AU - Bouzigon, Emmanuelle
AU - Simon, Marie Michelle
AU - Boulier, Elodie
AU - Redensek, Adriana
AU - Watt, Stephen
AU - Datta, Avik
AU - Clarke, Laura
AU - Flicek, Paul
AU - Mead, Daniel
AU - Paul, Dirk S.
AU - Beck, Stephan
AU - Bourque, Guillaume
AU - Lathrop, Mark
AU - Tchernof, André
AU - Vohl, Marie Claude
AU - Demenais, Florence
AU - Pin, Isabelle
AU - Downes, Kate
AU - Stunnenberg, Hendrick G.
AU - Soranzo, Nicole
AU - Pastinen, Tomi
AU - Grundberg, Elin
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/3/10
Y1 - 2017/3/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014936699&partnerID=8YFLogxK
U2 - 10.1186/s13059-017-1173-7
DO - 10.1186/s13059-017-1173-7
M3 - Article
C2 - 28283040
AN - SCOPUS:85014936699
SN - 1474-7596
VL - 18
JO - Genome Biology
JF - Genome Biology
IS - 1
M1 - 50
ER -