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

By G. Trynka, C. Sandor, B. Han, Han Xu, B. Stranger, X. S. Liu, Soumya Raychaudhuri. Nature Genetics, 2012

604 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/685d8063be1344476a718e74f9e07101de5fb82e

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Citations in the corpus

Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia (2016, background): “The patterns of results should be different for “trans-eQTLs”, i.e., SNPs correlated with expression of a gene beyond 1 Mb of its genomic location.”
An expanded view of complex traits: from polygenic to omnigenic (2017, background): “In partic- ular, many groups have shown that disease-associated SNPs are enriched in active chromatin and particularly in chromatin that is active in cell types relevant to disease (Trynka et al., 2013; Farh et al., 2015; Finucane et al., 2015; Kundaje et al., 2015).”
Functionally-informed fine-mapping and polygenic localization of complex trait heritability (2019, background): “6 and Supplementary Table 15); 118 pleiotropic SNPs resided in coding regions and 93 were nonsynonymous (Supplementary Table 15).”