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PLoS One. 2017 Nov 21;12(11):e0186518. doi: 10.1371/journal.pone.0186518. eCollection 2017.

Enrichment of colorectal cancer associations in functional regions: Insight for using epigenomics data in the analysis of whole genome sequence-imputed GWAS data.

Author information

1
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
2
Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America.
3
Biomedical Informatics Program, Stanford University, Stanford, California, United States of America.
4
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America.
5
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
6
Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
7
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
9
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
11
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
12
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
13
Centre for Epidemiology and Biostatistics, Melbourne School of Population Health, The University of Melbourne, Melbourne, Victoria, Australia.
14
Division of Cancer Epidemiology C020, German Cancer Research Center (DKFZ), Heidelberg, Germany.
15
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
16
Division of Medical Oncology, Stanford School of Medicine, Stanford, California, United States of America.
17
Department of Molecular and Human Genetics, Baylor College of Medicine Center for Statistical Genetics, Houston, Texas, United States of America.
18
Ontario Institute for Cancer Research, MaRS Centre, South Tower, Toronto, Ontario, Canada.
19
Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.
20
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
21
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, United States of America.
22
Department Genome Sciences, University of Washington, Seattle, Washington, United States of America.
23
University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
24
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
25
Division of Hematology, University of Ottawa, Ottawa, Ontario, Canada.
26
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
27
Department of Genetics, Stanford University, Stanford, California, United States of America.
28
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.

Abstract

BACKGROUND:

The evaluation of less frequent genetic variants and their effect on complex disease pose new challenges for genomic research. To investigate whether epigenetic data can be used to inform aggregate rare-variant association methods (RVAM), we assessed whether variants more significantly associated with colorectal cancer (CRC) were preferentially located in non-coding regulatory regions, and whether enrichment was specific to colorectal tissues.

METHODS:

Active regulatory elements (ARE) were mapped using data from 127 tissues and cell-types from NIH Roadmap Epigenomics and Encyclopedia of DNA Elements (ENCODE) projects. We investigated whether CRC association p-values were more significant for common variants inside versus outside AREs, or 2) inside colorectal (CR) AREs versus AREs of other tissues and cell-types. We employed an integrative epigenomic RVAM for variants with allele frequency <1%. Gene sets were defined as ARE variants within 200 kilobases of a transcription start site (TSS) using either CR ARE or ARE from non-digestive tissues. CRC-set association p-values were used to evaluate enrichment of less frequent variant associations in CR ARE versus non-digestive ARE.

RESULTS:

ARE from 126/127 tissues and cell-types were significantly enriched for stronger CRC-variant associations. Strongest enrichment was observed for digestive tissues and immune cell types. CR-specific ARE were also enriched for stronger CRC-variant associations compared to ARE combined across non-digestive tissues (p-value = 9.6 × 10-4). Additionally, we found enrichment of stronger CRC association p-values for rare variant sets of CR ARE compared to non-digestive ARE (p-value = 0.029).

CONCLUSIONS:

Integrative epigenomic RVAM may enable discovery of less frequent variants associated with CRC, and ARE of digestive and immune tissues are most informative. Although distance-based aggregation of less frequent variants in CR ARE surrounding TSS showed modest enrichment, future association studies would likely benefit from joint analysis of transcriptomes and epigenomes to better link regulatory variation with target genes.

PMID:
29161273
PMCID:
PMC5697874
DOI:
10.1371/journal.pone.0186518
[Indexed for MEDLINE]
Free PMC Article

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