Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11110/21:10434752

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10603 - Genetics and heredity (medical genetics to be 3)

Projekt

<a href="/cs/project/EF16_019%2F0000787" target="_blank" >EF16_019/0000787: Centrum výzkumu infekčních onemocnění</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Gastroenterology

ISSN

0016-5085

e-ISSN

1528-0012

Svazek periodika

160

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

21

Strana od-do

"1164"-"1178.e6"

Kód UT WoS článku

000627499000038

EID výsledku v databázi Scopus

2-s2.0-85100525451