Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378041%3A_____%2F21%3A00552827" target="_blank" >RIV/68378041:_____/21:00552827 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11110/21:10434752
Result on the web
<a href="https://www.gastrojournal.org/article/S0016-5085(20)35243-4/fulltext" target="_blank" >https://www.gastrojournal.org/article/S0016-5085(20)35243-4/fulltext</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1053/j.gastro.2020.08.062" target="_blank" >10.1053/j.gastro.2020.08.062</a>
Alternative languages
Result language
angličtina
Original language name
Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects
Original language description
BACKGROUND AND AIMS: 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. METHODS: 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 (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. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P<9.1 x 10(-6), including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 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<.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. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10603 - Genetics and heredity (medical genetics to be 3)
Result continuities
Project
<a href="/en/project/EF16_019%2F0000787" target="_blank" >EF16_019/0000787: Fighting INfectious Diseases</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Gastroenterology
ISSN
0016-5085
e-ISSN
1528-0012
Volume of the periodical
160
Issue of the periodical within the volume
4
Country of publishing house
US - UNITED STATES
Number of pages
21
Pages from-to
"1164"-"1178.e6"
UT code for WoS article
000627499000038
EID of the result in the Scopus database
2-s2.0-85100525451