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@ARTICLE{Guo:164059,
author = {X. Guo and W. Lin and W. Wen and J. Huyghe and S. Bien and
Q. Cai and T. Harrison and Z. Chen and C. Qu and J. Bao and
J. Long and Y. Yuan and F. Wang and M. Bai and G. R.
Abecasis and D. Albanes and S. I. Berndt and S. Bézieau and
D. T. Bishop and H. Brenner$^*$ and S. Buch and A.
Burnett-Hartman and P. T. Campbell and S. Castellví-Bel and
A. T. Chan and J. Chang-Claude$^*$ and S. J. Chanock and S.
H. Cho and D. V. Conti and A. de la Chapelle and E. J.
Feskens and S. J. Gallinger and G. G. Giles and P. J.
Goodman and A. Gsur and M. Guinter and M. J. Gunter and J.
Hampe and H. Hampel and R. B. Hayes and M. Hoffmeister$^*$
and E. Kampman and H. M. Kang and T. O. Keku and H. R. Kim
and L. Le Marchand and S. C. Lee and C. I. Li and L. Li and
A. Lindblom and N. Lindor and R. L. Milne and V. Moreno and
N. Murphy and P. A. Newcomb and D. A. Nickerson and K. Offit
and R. Pearlman and P. D. P. Pharoah and E. A. Platz and J.
D. Potter and G. Rennert and L. C. Sakoda and C. Schafmayer
and S. L. Schmit and R. E. Schoen and F. R. Schumacher and
M. L. Slattery and Y.-R. Su and C. M. Tangen and C. M.
Ulrich and F. J. van Duijnhoven and B. Van Guelpen and K.
Visvanathan and P. Vodicka and L. Vodickova and V.
Vymetalkova and X. Wang and E. White and A. Wolk and M. O.
Woods and G. Casey and L. Hsu and M. A. Jenkins and S. B.
Gruber and U. Peters and W. Zheng},
title = {{I}dentifying novel susceptibility genes for colorectal
cancer risk from a transcriptome-wide association study of
125,478 subjects.},
journal = {Gastroenterology},
volume = {160},
number = {4},
issn = {0016-5085},
address = {Philadelphia, Pa. [u.a.]},
publisher = {Saunders},
reportid = {DKFZ-2020-02227},
pages = {1164-1178.e6},
year = {2021},
note = {2021 Mar;160(4):1164-1178.e6},
abstract = {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.},
cin = {C070 / C120 / C020},
ddc = {610},
cid = {I:(DE-He78)C070-20160331 / I:(DE-He78)C120-20160331 /
I:(DE-He78)C020-20160331},
pnm = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
pid = {G:(DE-HGF)POF4-313},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:33058866},
doi = {10.1053/j.gastro.2020.08.062},
url = {https://inrepo02.dkfz.de/record/164059},
}