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000282345 041__ $$aEnglish
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000282345 1001_ $$aChen, Zhishan$$b0
000282345 245__ $$aNovel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.
000282345 260__ $$aOxford$$bOxford Univ. Press$$c2024
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000282345 500__ $$a2024 Jan 10;116(1):127-137
000282345 520__ $$aTranscriptome-wide association studies (TWAS) have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large TWAS and an alternative splicing-TWAS (sp-TWAS) in CRC using improved genetic prediction models and performed in-depth functional investigations.We analyzed RNA-sequencing (RNA-seq) data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing, and evaluated model performance using independent RNA-seq data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58,131 CRC cases and 67,347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for three selected genes in multiple CRC cell lines.We identified a total of 57 putative CRC susceptibility genes, which included the 48 genes from TWAS and 15 genes from sp-TWAS, at Bonferroni-corrected P < 0.05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for two unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166.This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.
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000282345 650_7 $$2Other$$aAlternative splicing
000282345 650_7 $$2Other$$aColorectal cancer
000282345 650_7 $$2Other$$aTWAS
000282345 650_7 $$2Other$$asusceptibility genes
000282345 7001_ $$aSong, Wenqiang$$b1
000282345 7001_ $$aShu, Xiao-Ou$$b2
000282345 7001_ $$aWen, Wanqing$$b3
000282345 7001_ $$aDevall, Matthew$$b4
000282345 7001_ $$aDampier, Christopher$$b5
000282345 7001_ $$aMoratalla-Navarro, Ferran$$b6
000282345 7001_ $$aCai, Qiuyin$$b7
000282345 7001_ $$aLong, Jirong$$b8
000282345 7001_ $$aVan Kaer, Luc$$b9
000282345 7001_ $$aWu, Lan$$b10
000282345 7001_ $$aHuyghe, Jeroen R$$b11
000282345 7001_ $$aThomas, Minta$$b12
000282345 7001_ $$aHsu, Li$$b13
000282345 7001_ $$aWoods, Michael O$$b14
000282345 7001_ $$aAlbanes, Demetrius$$b15
000282345 7001_ $$aBuchanan, Daniel D$$b16
000282345 7001_ $$aGsur, Andrea$$b17
000282345 7001_ $$0P:(DE-He78)6c5d058b7552d071a7fa4c5e943fff0f$$aHoffmeister, Michael$$b18$$udkfz
000282345 7001_ $$aVodicka, Pavel$$b19
000282345 7001_ $$aWolk, Alicja$$b20
000282345 7001_ $$aMarchand, Loic Le$$b21
000282345 7001_ $$aWu, Anna H$$b22
000282345 7001_ $$aPhipps, Amanda I$$b23
000282345 7001_ $$aMoreno, Victor$$b24
000282345 7001_ $$aUlrike, Peters$$b25
000282345 7001_ $$aZheng, Wei$$b26
000282345 7001_ $$aCasey, Graham$$b27
000282345 7001_ $$aGuo, Xingyi$$b28
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