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Am J Hum Genet. 2016 May 5;98(5):934-955. doi: 10.1016/j.ajhg.2016.03.027.

Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA. Electronic address: cd2695@columbia.edu.
2
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
3
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Obstetrics and Gynecology, Vienna Medical University, Vienna 1090, Austria.
4
Departments of Epidemiology and Dermatology, Columbia University, New York, NY 10032, USA.
5
Departments of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
6
Division of Pediatric Endocrinology, Diabetes and Metabolism, Columbia University, New York, NY 10032, USA.
7
Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA.
8
Departments of Pathology, Medicine, and Dermatology, Columbia University, New York, NY 10032, USA.
9
Departments of Surgery, Medicine, and Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
10
Departments of Psychiatry and Behavioral Medicine and Obstetrics and Gynecology, Columbia University, New York, NY 10032, USA.
11
Departments of Dermatology, Genetics, and Development, Columbia University, New York, NY 10032, USA.
12
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.

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.

PMID:
27153397
PMCID:
PMC4863666
DOI:
10.1016/j.ajhg.2016.03.027
[Indexed for MEDLINE]
Free PMC Article

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