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PLoS Genet. 2018 Feb 26;14(2):e1007240. doi: 10.1371/journal.pgen.1007240. eCollection 2018 Feb.

Methods for fine-mapping with chromatin and expression data.

Author information

1
Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California, United States of America.
2
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
3
Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
4
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
5
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.

Abstract

Recent studies have identified thousands of regions in the genome associated with chromatin modifications, which may in turn be affecting gene expression. Existing works have used heuristic methods to investigate the relationships between genome, epigenome, and gene expression, but, to our knowledge, none have explicitly modeled the chain of causality whereby genetic variants impact chromatin, which impacts gene expression. In this work we introduce a new hierarchical fine-mapping framework that integrates information across all three levels of data to better identify the causal variant and chromatin mark that are concordantly influencing gene expression. In simulations we show that our method is more accurate than existing approaches at identifying the causal mark influencing expression. We analyze empirical genetic, chromatin, and gene expression data from 65 African-ancestry and 47 European-ancestry individuals and show that many of the paths prioritized by our method are consistent with the proposed causal model and often lie in likely functional regions.

PMID:
29481575
PMCID:
PMC5843356
DOI:
10.1371/journal.pgen.1007240
[Indexed for MEDLINE]
Free PMC Article

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