Dataset Information

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

ABSTRACT:

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 × 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.

SUBMITTER: Guo X

PROVIDER: S-EPMC7956223 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

Guo Xingyi X Lin Weiqiang W Wen Wanqing W Huyghe Jeroen J Bien Stephanie S Cai Qiuyin Q Harrison Tabitha T Chen Zhishan Z Qu Conghui C Bao Jiandong J Long Jirong J Yuan Yuan Y Wang Fangqin F Bai Mengqiu M Abecasis Goncalo R GR Albanes Demetrius D Berndt Sonja I SI Bézieau Stéphane S Bishop D Timothy DT Brenner Hermann H Buch Stephan S Burnett-Hartman Andrea A Campbell Peter T PT Castellví-Bel Sergi S Chan Andrew T AT Chang-Claude Jenny J Chanock Stephen J SJ Cho Sang Hee SH Conti David V DV Chapelle Albert de la A Feskens Edith J M EJM Gallinger Steven J SJ Giles Graham G GG Goodman Phyllis J PJ Gsur Andrea A Guinter Mark M Gunter Marc J MJ Hampe Jochen J Hampel Heather H Hayes Richard B RB Hoffmeister Michael M Kampman Ellen E Kang Hyun Min HM Keku Temitope O TO Kim Hyeong Rok HR Le Marchand Loic L Lee Soo Chin SC Li Christopher I CI Li Li L Lindblom Annika A Lindor Noralane N Milne Roger L RL Moreno Victor V Murphy Neil N Newcomb Polly A PA Nickerson Deborah A DA Offit Kenneth K Pearlman Rachel R Pharoah Paul D P PDP Platz Elizabeth A EA Potter John D JD Rennert Gad G Sakoda Lori C LC Schafmayer Clemens C Schmit Stephanie L SL Schoen Robert E RE Schumacher Fredrick R FR Slattery Martha L ML Su Yu-Ru YR Tangen Catherine M CM Ulrich Cornelia M CM van Duijnhoven Franzel J B FJB Van Guelpen Bethany B Visvanathan Kala K Vodicka Pavel P Vodickova Ludmila L Vymetalkova Veronika V Wang Xiaoliang X White Emily E Wolk Alicja A Woods Michael O MO Casey Graham G Hsu Li L Jenkins Mark A MA Gruber Stephen B SB Peters Ulrike U Zheng Wei W

Gastroenterology 20201012 4

<h4>Background and aims</h4>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.<h4>Methods</h4>Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Geno ...[more]

PMID: 33058866

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Project description:BackgroundGenetic risk factors substantially contributed to the development of coronary atherosclerosis. Genome-wide association study (GWAS) has identified many risk loci for coronary atherosclerosis, but the translation of these loci into therapeutic targets is limited for their location in non-coding regions. Here, we aimed to screen the potential coronary atherosclerosis pathogenic genes expressed though TWAS (transcriptome wide association study) and explore the underlying mechanism association.MethodsFour TWAS approaches (PrediXcan, JTI, UTMOST, and FUSION) were used to screen genes associated with coronary atherosclerosis. Enrichment analysis of TWAS-identified genes was applied through the Metascape website. The summary-data-based Mendelian randomization (SMR) analysis was conducted to provide the evidence of causal relationship between the candidate genes and coronary atherosclerosis. At last, the cell type-specific expression of the intersection genes was examined by using human coronary artery single-cell RNA-seq, interrogating the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.ResultsWe identified 19 genes by at least three approaches and 1 gene (NBEAL1) by four approaches. Enrichment analysis enriching the genes identified at least by two TWAS approaches, suggesting that these genes were markedly enriched in asthma and leukocyte mediated immunity reaction. Further, the summary-data-based Mendelian randomization (SMR) analysis provided the evidence of causal relationship between NBEAL1 gene and coronary atherosclerosis, confirming the protecting effects of NBEAL1 gene and coronary atherosclerosis. At last, the single cell cluster analysis demonstrated that NBEAL1 gene has differential expressions in macrophages, plasma cells and endothelial cells.ConclusionOur study identified the novel genes associated with coronary atherosclerosis and suggested the potential biological function for these genes, providing insightful guidance for further biological investigation and therapeutic approaches development in atherosclerosis-related diseases.

Project description:IntroductionCataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression.MethodsWe performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database.ResultsAcross tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data.DiscussionOur results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue.

Dataset Information

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

Background and aims

Methods

Results

Conclusions

Publications

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

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