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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA;Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA.
Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA;Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA.
Univ Southern Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA;Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA;Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA.
Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA;Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA.
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2019 (English)In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 138, no 4, p. 307-326Article in journal (Refereed) Published
Abstract [en]

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 FDR0.2 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=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-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.

Place, publisher, year, edition, pages
2019. Vol. 138, no 4, p. 307-326
National Category
Medical Genetics Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-383482DOI: 10.1007/s00439-019-01989-8ISI: 000465974800002PubMedID: 30820706OAI: oai:DiVA.org:uu-383482DiVA, id: diva2:1316193
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 312057Swedish Research Council, K2015-55X-22674-01-4Swedish Research Council, K2008-55X-20157-03-3Swedish Research Council, K2006-72X-20157-01-2EU, European Research Council
Note

Correction in: HUMAN GENETICS, Volume: 138, Issue: 7, Pages: 789-791, DOI: 10.1007/s00439-019-02030-8

Available from: 2019-05-16 Created: 2019-05-16 Last updated: 2019-08-16Bibliographically approved

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