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Your search keyword '"Connolly, Charles M."' showing total 2 results
Start Over Author "Connolly, Charles M." Topic gene expression
2 results on '"Connolly, Charles M."'

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

Author

Bien, Stephanie A., Auer, Paul L., Harrison, Tabitha A., Qu, Conghui, Connolly, Charles M., Greenside, Peyton G., Chen, Sai, Berndt, Sonja I., Bézieau, Stéphane, Kang, Hyun M., Huyghe, Jeroen, Brenner, Hermann, Casey, Graham, Chan, Andrew T., Hopper, John L., Banbury, Barbara L., Chang-Claude, Jenny, Chanock, Stephen J., Haile, Robert W., and Hoffmeister, Michael

Subjects
COLON cancer risk factors, NUCLEOTIDE sequencing, CIS-regulatory elements (Genetics), GENETICS of colon cancer, EPIGENOMICS
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. [ABSTRACT FROM AUTHOR]

Published
2017
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2. Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Author

Bien, Stephanie A, Su, Yu-Ru, Conti, David V, Harrison, Tabitha A, Qu, Conghui, Guo, Xingyi, Lu, Yingchang, Albanes, Demetrius, Auer, Paul L, Banbury, Barbara L, Berndt, Sonja I, Bézieau, Stéphane, Brenner, Hermann, Buchanan, Daniel D, Caan, Bette J, Campbell, Peter T, Carlson, Christopher S, Chan, Andrew T, Chang-Claude, Jenny, Chen, Sai, Connolly, Charles M, Easton, Douglas F, Feskens, Edith JM, Gallinger, Steven, Giles, Graham G, Gunter, Marc J, Hampe, Jochen, Huyghe, Jeroen R, Hoffmeister, Michael, Hudson, Thomas J, Jacobs, Eric J, Jenkins, Mark A, Kampman, Ellen, Kang, Hyun Min, Kühn, Tilman, Küry, Sébastien, Lejbkowicz, Flavio, Le Marchand, Loic, Milne, Roger L, Li, Li, Li, Christopher I, Lindblom, Annika, Lindor, Noralane M, Martín, Vicente, McNeil, Caroline E, Melas, Marilena, Moreno, Victor, Newcomb, Polly A, Offit, Kenneth, Pharaoh, Paul DP, Potter, John D, Qu, Chenxu, Riboli, Elio, Rennert, Gad, Sala, Núria, Schafmayer, Clemens, Scacheri, Peter C, Schmit, Stephanie L, Severi, Gianluca, Slattery, Martha L, Smith, Joshua D, Trichopoulou, Antonia, Tumino, Rosario, Ulrich, Cornelia M, Van Duijnhoven, Fränzel JB, Van Guelpen, Bethany, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Casey, Graham, Nickerson, Deborah A, Gruber, Stephen B, Hsu, Li, Zheng, Wei, and Peters, Ulrike

Subjects
Gene Expression Regulation, Neoplastic, Gene Frequency, Predictive Value of Tests, Risk Factors, Case-Control Studies, Gene Expression, Humans, Genetic Predisposition to Disease, Colorectal Neoplasms, Prognosis, Polymorphism, Single Nucleotide, 3. Good health, Genome-Wide Association Study
Abstract

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.

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