TY  - JOUR
AU  - Guo, Xingyi
AU  - Lin, Weiqiang
AU  - Wen, Wanqing
AU  - Huyghe, Jeroen
AU  - Bien, Stephanie
AU  - Cai, Qiuyin
AU  - Harrison, Tabitha
AU  - Chen, Zhishan
AU  - Qu, Conghui
AU  - Bao, Jiandong
AU  - Long, Jirong
AU  - Yuan, Yuan
AU  - Wang, Fangqin
AU  - Bai, Mengqiu
AU  - Abecasis, Goncalo R
AU  - Albanes, Demetrius
AU  - Berndt, Sonja I
AU  - Bézieau, Stéphane
AU  - Bishop, D Timothy
AU  - Brenner, Hermann
AU  - Buch, Stephan
AU  - Burnett-Hartman, Andrea
AU  - Campbell, Peter T
AU  - Castellví-Bel, Sergi
AU  - Chan, Andrew T
AU  - Chang-Claude, Jenny
AU  - Chanock, Stephen J
AU  - Cho, Sang Hee
AU  - Conti, David V
AU  - de la Chapelle, Albert
AU  - Feskens, Edith Jm
AU  - Gallinger, Steven J
AU  - Giles, Graham G
AU  - Goodman, Phyllis J
AU  - Gsur, Andrea
AU  - Guinter, Mark
AU  - Gunter, Marc J
AU  - Hampe, Jochen
AU  - Hampel, Heather
AU  - Hayes, Richard B
AU  - Hoffmeister, Michael
AU  - Kampman, Ellen
AU  - Kang, Hyun Min
AU  - Keku, Temitope O
AU  - Kim, Hyeong Rok
AU  - Le Marchand, Loic
AU  - Lee, Soo Chin
AU  - Li, Christopher I
AU  - Li, Li
AU  - Lindblom, Annika
AU  - Lindor, Noralane
AU  - Milne, Roger L
AU  - Moreno, Victor
AU  - Murphy, Neil
AU  - Newcomb, Polly A
AU  - Nickerson, Deborah A
AU  - Offit, Kenneth
AU  - Pearlman, Rachel
AU  - Pharoah, Paul D P
AU  - Platz, Elizabeth A
AU  - Potter, John D
AU  - Rennert, Gad
AU  - Sakoda, Lori C
AU  - Schafmayer, Clemens
AU  - Schmit, Stephanie L
AU  - Schoen, Robert E
AU  - Schumacher, Fredrick R
AU  - Slattery, Martha L
AU  - Su, Yu-Ru
AU  - Tangen, Catherine M
AU  - Ulrich, Cornelia M
AU  - van Duijnhoven, Franzel Jb
AU  - Van Guelpen, Bethany
AU  - Visvanathan, Kala
AU  - Vodicka, Pavel
AU  - Vodickova, Ludmila
AU  - Vymetalkova, Veronika
AU  - Wang, Xiaolong
AU  - White, Emily
AU  - Wolk, Alicja
AU  - Woods, Michael O
AU  - Casey, Graham
AU  - Hsu, Li
AU  - Jenkins, Mark A
AU  - Gruber, Stephen B
AU  - Peters, Ulrike
AU  - Zheng, Wei
TI  - Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects.
JO  - Gastroenterology
VL  - 160
IS  - 4
SN  - 0016-5085
CY  - Philadelphia, Pa. [u.a.]
PB  - Saunders
M1  - DKFZ-2020-02227
SP  - 1164-1178.e6
PY  - 2021
N1  - 2021 Mar;160(4):1164-1178.e6
AB  - Susceptibility 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:33058866
DO  - DOI:10.1053/j.gastro.2020.08.062
UR  - https://inrepo02.dkfz.de/record/164059
ER  -