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PMID: 23263488 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Chromatin marks identify critical cell types for fine mapping complex trait variants.

Nature genetics ·Vol. 45 ·No. 2 ·2013-02-00 ·Pages 124-30

Trynka G, Sandor C, Han B, Xu H, Stranger BE, Liu XS, Raychaudhuri S

Abstract

If trait-associated variants alter regulatory regions, then they should fall within chromatin marks in relevant cell types. However, it is unclear which of the many marks are most useful in defining cell types associated with disease and fine mapping variants. We hypothesized that informative marks are phenotypically cell type specific; that is, SNPs associated with the same trait likely overlap marks in the same cell type. We examined 15 chromatin marks and found that those highlighting active gene regulation were phenotypically cell type specific. Trimethylation of histone H3 at lysine 4 (H3K4me3) was the most phenotypically cell type specific (P < 1 × 10(-6)), driven by colocalization of variants and marks rather than gene proximity (P < 0.001). H3K4me3 peaks overlapped with 37 SNPs for plasma low-density lipoprotein concentration in the liver (P < 7 × 10(-5)), 31 SNPs for rheumatoid arthritis within CD4(+) regulatory T cells (P = 1 × 10(-4)), 67 SNPs for type 2 diabetes in pancreatic islet cells (P = 0.003) and the liver (P = 0.003), and 14 SNPs for neuropsychiatric disease in neuronal tissues (P = 0.007). We show how cell type-specific H3K4me3 peaks can inform the fine mapping of associated SNPs to identify causal variation.

MeSH Terms
Arthritis, Rheumatoid/genetics Chromatin/genetics Databases, Genetic Diabetes Mellitus, Type 2/genetics Genetic Markers/genetics Histones/genetics Humans Nervous System Diseases/genetics Phenotype Polymorphism, Single Nucleotide/genetics Software
Chemicals
Chromatin Genetic Markers Histones
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Trynka Gosia
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Sandor Cynthia
Han Buhm
Xu Han
Stranger Barbara E
Liu X Shirley
Raychaudhuri Soumya
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2504
Published
2013-02-00
Epub
2012-00-23
Pages
124-30
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3826950
Subset
IM
Grants
NHGRI NIH HHS · U01 HG007033 · United States
NIAMS NIH HHS · K08AR055688 · United States
NIAMS NIH HHS · UH2 AR067677 · United States
NHGRI NIH HHS · R01 HG004069 · United States
NHGRI NIH HHS · U01HG0070033 · United States
NIAMS NIH HHS · K08 AR055688 · United States
External Links
PubMed source DOI: 10.1038/ng.2504 PMC Full Text View journal details
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