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000164059 1001_ $$aGuo, Xingyi$$b0
000164059 245__ $$aIdentifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects.
000164059 260__ $$aPhiladelphia, Pa. [u.a.]$$bSaunders$$c2021
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000164059 520__ $$aSusceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (TCGA, n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in four novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In nine known GWAS-identified loci, we uncovered nine genes that have not been previously reported, whereas four genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < 0.01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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000164059 7001_ $$aLin, Weiqiang$$b1
000164059 7001_ $$aWen, Wanqing$$b2
000164059 7001_ $$aHuyghe, Jeroen$$b3
000164059 7001_ $$aBien, Stephanie$$b4
000164059 7001_ $$aCai, Qiuyin$$b5
000164059 7001_ $$aHarrison, Tabitha$$b6
000164059 7001_ $$aChen, Zhishan$$b7
000164059 7001_ $$aQu, Conghui$$b8
000164059 7001_ $$aBao, Jiandong$$b9
000164059 7001_ $$aLong, Jirong$$b10
000164059 7001_ $$aYuan, Yuan$$b11
000164059 7001_ $$aWang, Fangqin$$b12
000164059 7001_ $$aBai, Mengqiu$$b13
000164059 7001_ $$aAbecasis, Goncalo R$$b14
000164059 7001_ $$aAlbanes, Demetrius$$b15
000164059 7001_ $$aBerndt, Sonja I$$b16
000164059 7001_ $$aBézieau, Stéphane$$b17
000164059 7001_ $$aBishop, D Timothy$$b18
000164059 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b19$$udkfz
000164059 7001_ $$aBuch, Stephan$$b20
000164059 7001_ $$aBurnett-Hartman, Andrea$$b21
000164059 7001_ $$aCampbell, Peter T$$b22
000164059 7001_ $$aCastellví-Bel, Sergi$$b23
000164059 7001_ $$aChan, Andrew T$$b24
000164059 7001_ $$0P:(DE-He78)c259d6cc99edf5c7bc7ce22c7f87c253$$aChang-Claude, Jenny$$b25$$udkfz
000164059 7001_ $$aChanock, Stephen J$$b26
000164059 7001_ $$aCho, Sang Hee$$b27
000164059 7001_ $$aConti, David V$$b28
000164059 7001_ $$ade la Chapelle, Albert$$b29
000164059 7001_ $$aFeskens, Edith Jm$$b30
000164059 7001_ $$aGallinger, Steven J$$b31
000164059 7001_ $$aGiles, Graham G$$b32
000164059 7001_ $$aGoodman, Phyllis J$$b33
000164059 7001_ $$aGsur, Andrea$$b34
000164059 7001_ $$aGuinter, Mark$$b35
000164059 7001_ $$aGunter, Marc J$$b36
000164059 7001_ $$aHampe, Jochen$$b37
000164059 7001_ $$aHampel, Heather$$b38
000164059 7001_ $$aHayes, Richard B$$b39
000164059 7001_ $$0P:(DE-He78)6c5d058b7552d071a7fa4c5e943fff0f$$aHoffmeister, Michael$$b40$$udkfz
000164059 7001_ $$aKampman, Ellen$$b41
000164059 7001_ $$aKang, Hyun Min$$b42
000164059 7001_ $$aKeku, Temitope O$$b43
000164059 7001_ $$aKim, Hyeong Rok$$b44
000164059 7001_ $$aLe Marchand, Loic$$b45
000164059 7001_ $$aLee, Soo Chin$$b46
000164059 7001_ $$aLi, Christopher I$$b47
000164059 7001_ $$aLi, Li$$b48
000164059 7001_ $$aLindblom, Annika$$b49
000164059 7001_ $$aLindor, Noralane$$b50
000164059 7001_ $$aMilne, Roger L$$b51
000164059 7001_ $$aMoreno, Victor$$b52
000164059 7001_ $$aMurphy, Neil$$b53
000164059 7001_ $$aNewcomb, Polly A$$b54
000164059 7001_ $$aNickerson, Deborah A$$b55
000164059 7001_ $$aOffit, Kenneth$$b56
000164059 7001_ $$aPearlman, Rachel$$b57
000164059 7001_ $$aPharoah, Paul D P$$b58
000164059 7001_ $$aPlatz, Elizabeth A$$b59
000164059 7001_ $$aPotter, John D$$b60
000164059 7001_ $$aRennert, Gad$$b61
000164059 7001_ $$aSakoda, Lori C$$b62
000164059 7001_ $$aSchafmayer, Clemens$$b63
000164059 7001_ $$aSchmit, Stephanie L$$b64
000164059 7001_ $$aSchoen, Robert E$$b65
000164059 7001_ $$aSchumacher, Fredrick R$$b66
000164059 7001_ $$aSlattery, Martha L$$b67
000164059 7001_ $$aSu, Yu-Ru$$b68
000164059 7001_ $$aTangen, Catherine M$$b69
000164059 7001_ $$aUlrich, Cornelia M$$b70
000164059 7001_ $$avan Duijnhoven, Franzel Jb$$b71
000164059 7001_ $$aVan Guelpen, Bethany$$b72
000164059 7001_ $$aVisvanathan, Kala$$b73
000164059 7001_ $$aVodicka, Pavel$$b74
000164059 7001_ $$aVodickova, Ludmila$$b75
000164059 7001_ $$aVymetalkova, Veronika$$b76
000164059 7001_ $$aWang, Xiaolong$$b77
000164059 7001_ $$aWhite, Emily$$b78
000164059 7001_ $$aWolk, Alicja$$b79
000164059 7001_ $$aWoods, Michael O$$b80
000164059 7001_ $$aCasey, Graham$$b81
000164059 7001_ $$aHsu, Li$$b82
000164059 7001_ $$aJenkins, Mark A$$b83
000164059 7001_ $$aGruber, Stephen B$$b84
000164059 7001_ $$aPeters, Ulrike$$b85
000164059 7001_ $$aZheng, Wei$$b86
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