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000143007 0247_ $$2ISSN$$a0340-6717
000143007 0247_ $$2ISSN$$a1432-1203
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000143007 041__ $$aeng
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000143007 1001_ $$aBien, Stephanie A$$b0
000143007 245__ $$aGenetic variant predictors of gene expression provide new insight into risk of colorectal cancer.
000143007 260__ $$aHeidelberg$$bSpringer$$c2019
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000143007 520__ $$aGenome-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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000143007 7001_ $$aSu, Yu-Ru$$b1
000143007 7001_ $$aConti, David V$$b2
000143007 7001_ $$aHarrison, Tabitha A$$b3
000143007 7001_ $$aQu, Conghui$$b4
000143007 7001_ $$aGuo, Xingyi$$b5
000143007 7001_ $$aLu, Yingchang$$b6
000143007 7001_ $$aAlbanes, Demetrius$$b7
000143007 7001_ $$aAuer, Paul L$$b8
000143007 7001_ $$aBanbury, Barbara L$$b9
000143007 7001_ $$aBerndt, Sonja I$$b10
000143007 7001_ $$aBézieau, Stéphane$$b11
000143007 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b12$$udkfz
000143007 7001_ $$aBuchanan, Daniel D$$b13
000143007 7001_ $$aCaan, Bette J$$b14
000143007 7001_ $$aCampbell, Peter T$$b15
000143007 7001_ $$aCarlson, Christopher S$$b16
000143007 7001_ $$aChan, Andrew T$$b17
000143007 7001_ $$0P:(DE-He78)c259d6cc99edf5c7bc7ce22c7f87c253$$aChang-Claude, Jenny$$b18$$udkfz
000143007 7001_ $$aChen, Sai$$b19
000143007 7001_ $$aConnolly, Charles M$$b20
000143007 7001_ $$aEaston, Douglas F$$b21
000143007 7001_ $$aFeskens, Edith J M$$b22
000143007 7001_ $$aGallinger, Steven$$b23
000143007 7001_ $$aGiles, Graham G$$b24
000143007 7001_ $$aGunter, Marc J$$b25
000143007 7001_ $$aHampe, Jochen$$b26
000143007 7001_ $$aHuyghe, Jeroen R$$b27
000143007 7001_ $$0P:(DE-He78)6c5d058b7552d071a7fa4c5e943fff0f$$aHoffmeister, Michael$$b28$$udkfz
000143007 7001_ $$aHudson, Thomas J$$b29
000143007 7001_ $$aJacobs, Eric J$$b30
000143007 7001_ $$aJenkins, Mark A$$b31
000143007 7001_ $$aKampman, Ellen$$b32
000143007 7001_ $$aKang, Hyun Min$$b33
000143007 7001_ $$0P:(DE-He78)0907a10ba1dc8f53f04907f54f6fdcfe$$aKühn, Tilman$$b34$$udkfz
000143007 7001_ $$aKüry, Sébastien$$b35
000143007 7001_ $$aLejbkowicz, Flavio$$b36
000143007 7001_ $$aLe Marchand, Loic$$b37
000143007 7001_ $$aMilne, Roger L$$b38
000143007 7001_ $$aLi, Li$$b39
000143007 7001_ $$aLi, Christopher I$$b40
000143007 7001_ $$aLindblom, Annika$$b41
000143007 7001_ $$aLindor, Noralane M$$b42
000143007 7001_ $$aMartín, Vicente$$b43
000143007 7001_ $$aMcNeil, Caroline E$$b44
000143007 7001_ $$aMelas, Marilena$$b45
000143007 7001_ $$aMoreno, Victor$$b46
000143007 7001_ $$aNewcomb, Polly A$$b47
000143007 7001_ $$aOffit, Kenneth$$b48
000143007 7001_ $$aPharaoh, Paul D P$$b49
000143007 7001_ $$aPotter, John D$$b50
000143007 7001_ $$aQu, Chenxu$$b51
000143007 7001_ $$aRiboli, Elio$$b52
000143007 7001_ $$aRennert, Gad$$b53
000143007 7001_ $$aSala, Núria$$b54
000143007 7001_ $$aSchafmayer, Clemens$$b55
000143007 7001_ $$aScacheri, Peter C$$b56
000143007 7001_ $$aSchmit, Stephanie L$$b57
000143007 7001_ $$aSeveri, Gianluca$$b58
000143007 7001_ $$aSlattery, Martha L$$b59
000143007 7001_ $$aSmith, Joshua D$$b60
000143007 7001_ $$aTrichopoulou, Antonia$$b61
000143007 7001_ $$aTumino, Rosario$$b62
000143007 7001_ $$aUlrich, Cornelia M$$b63
000143007 7001_ $$avan Duijnhoven, Fränzel J B$$b64
000143007 7001_ $$aVan Guelpen, Bethany$$b65
000143007 7001_ $$aWeinstein, Stephanie J$$b66
000143007 7001_ $$aWhite, Emily$$b67
000143007 7001_ $$aWolk, Alicja$$b68
000143007 7001_ $$aWoods, Michael O$$b69
000143007 7001_ $$aWu, Anna H$$b70
000143007 7001_ $$aAbecasis, Goncalo R$$b71
000143007 7001_ $$aCasey, Graham$$b72
000143007 7001_ $$aNickerson, Deborah A$$b73
000143007 7001_ $$aGruber, Stephen B$$b74
000143007 7001_ $$aHsu, Li$$b75
000143007 7001_ $$aZheng, Wei$$b76
000143007 7001_ $$aPeters, Ulrike$$b77
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