title: Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation.
abstract: Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders. Targeted bis-seq confirmed hap-ASM in 12/13 loci tested, including CCDC155, CD69, FRMD1, IRF1, KBTBD11, and S100A(∗)-ILF2, associated with immune phenotypes, MYT1L, PTPRN2, CMTM8 and CELF2, associated with neurological disorders, NGFR and HLA-DRB6, associated with both immunological and brain disorders, and ZFP57, a trans-acting regulator of genomic imprinting. Polymorphic CTCF and transcription factor (TF) binding sites were over-represented among hap-ASM DMRs and mQTLs, and analysis of the human data, supplemented by cross-species comparisons to macaques, indicated that CTCF and TF binding likelihood predicts the strength and direction of the allelic methylation asymmetry. These results show that hap-ASM is highly tissue specific; an important trans-acting regulator of genomic imprinting is regulated by this phenomenon; and variation in CTCF and TF binding sites is an underlying mechanism, and maps of hap-ASM and mQTLs reveal regulatory sequences underlying supra- and sub-threshold GWAS peaks in immunological and neurological disorders.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA. Electronic address: cd2695@columbia.edu.
authors.forename: Catherine
authors.initials: C
authors.lastname: Do
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lang
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lin
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Huferesh
authors.initials: H
authors.lastname: Darbary
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Izabela
authors.initials: I
authors.lastname: Krupska
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Obstetrics and Gynecology, Vienna Medical University, Vienna 1090, Austria.
authors.forename: Aulona
authors.initials: A
authors.lastname: Gaba
authors.affiliation: Departments of Epidemiology and Dermatology, Columbia University, New York, NY 10032, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Petukhova
authors.affiliation: Departments of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.affiliation: Division of Pediatric Endocrinology, Diabetes and Metabolism, Columbia University, New York, NY 10032, USA.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Gallagher
authors.affiliation: Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA.
authors.forename: Robin S
authors.initials: RS
authors.lastname: Goland
authors.affiliation: Departments of Pathology, Medicine, and Dermatology, Columbia University, New York, NY 10032, USA.
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Clynes
authors.affiliation: Departments of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dwork
authors.affiliation: Departments of Surgery, Medicine, and Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Kral
authors.affiliation: Departments of Psychiatry and Behavioral Medicine and Obstetrics and Gynecology, Columbia University, New York, NY 10032, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Monk
authors.affiliation: Departments of Dermatology, Genetics, and Development, Columbia University, New York, NY 10032, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Departments of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: bt12@columbia.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
mesh_terms: D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics; D008253:Macaca mulatta; D008255:Macaca radiata; D009422:Nervous System Diseases / Q000235:genetics; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy; D040641:Quantitative Trait Loci; D013045:Species Specificity; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D015534:Trans-Activators