TY - JOUR
T1 - Enrichment of colorectal cancer associations in functional regions
T2 - Insight for using epigenomics data in the analysis of whole genome sequence-imputed GWAS data
AU - GECCO
AU - CCFR
AU - Bien, Stephanie A.
AU - Auer, Paul L.
AU - Harrison, Tabitha A.
AU - Qu, Conghui
AU - Connolly, Charles M.
AU - Greenside, Peyton G.
AU - Chen, Sai
AU - Berndt, Sonja I.
AU - Bézieau, Stéphane
AU - Kang, Hyun M.
AU - Huyghe, Jeroen
AU - Brenner, Hermann
AU - Casey, Graham
AU - Chan, Andrew T.
AU - Hopper, John L.
AU - Banbury, Barbara L.
AU - Chang-Claude, Jenny
AU - Chanock, Stephen J.
AU - Haile, Robert W.
AU - Hoffmeister, Michael
AU - Fuchsberger, Christian
AU - Jenkins, Mark A.
AU - Leal, Suzanne M.
AU - Lemire, Mathieu
AU - Newcomb, Polly A.
AU - Gallinger, Steven
AU - Potter, John D.
AU - Schoen, Robert E.
AU - Slattery, Martha L.
AU - Smith, Joshua D.
AU - Le Marchand, Loic
AU - White, Emily
AU - Zanke, Brent W.
AU - Abeçasis, Goncalo R.
AU - Carlson, Christopher S.
AU - Peters, Ulrike
AU - Nickerson, Deborah A.
AU - Kundaje, Anshul
AU - Hsu, Li
N1 - Publisher Copyright:
© 2017 Bien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85034777436&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0186518
DO - 10.1371/journal.pone.0186518
M3 - Article
C2 - 29161273
AN - SCOPUS:85034777436
SN - 1932-6203
VL - 12
JO - PLoS ONE
JF - PLoS ONE
IS - 11
M1 - e0186518
ER -