Dataset Information

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

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.

SUBMITTER: Bien SA

PROVIDER: S-EPMC5697874 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Bien Stephanie A SA Auer Paul L PL Harrison Tabitha A TA Qu Conghui C Connolly Charles M CM Greenside Peyton G PG Chen Sai S Berndt Sonja I SI Bézieau Stéphane S Kang Hyun M HM Huyghe Jeroen J Brenner Hermann H Casey Graham G Chan Andrew T AT Hopper John L JL Banbury Barbara L BL Chang-Claude Jenny J Chanock Stephen J SJ Haile Robert W RW Hoffmeister Michael M Fuchsberger Christian C Jenkins Mark A MA Leal Suzanne M SM Lemire Mathieu M Newcomb Polly A PA Gallinger Steven S Potter John D JD Schoen Robert E RE Slattery Martha L ML Smith Joshua D JD Le Marchand Loic L White Emily E Zanke Brent W BW Abeçasis Goncalo R GR Carlson Christopher S CS Peters Ulrike U Nickerson Deborah A DA Kundaje Anshul A Hsu Li L

PloS one 20171121 11

<h4>Background</h4>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.<h4>Methods</h4>Active regulatory ...[more]

PMID: 29161273

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Dataset Information

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

Publications

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

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