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

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

doi:10.1053/j.gastro.2020.08.062

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

Xingyi Guo, Weiqiang Lin, Wanqing Wen, Jeroen Huyghe, Stephanie Bien, Qiuyin Cai, Tabitha Harrison, Zhishan Chen, Conghui Qu, Jiandong Bao, Jirong Long, Yuan Yuan, Fangqin Wang, Mengqiu Bai, Goncalo R. Abecasis, Demetrius Albanes, Sonja I. Berndt, Stéphane Bézieau, D. Timothy Bishop, Hermann BrennerStephan Buch, Andrea Burnett-Hartman, Peter T. Campbell, Sergi Castellví-Bel, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Sang Hee Cho, David V. Conti, Albert de la Chapelle, Edith J.M. Feskens, Steven J. Gallinger, Graham G. Giles, Phyllis J. Goodman, Andrea Gsur, Mark Guinter, Marc J. Gunter, Jochen Hampe, Heather Hampel, Richard B. Hayes, Michael Hoffmeister, Ellen Kampman, Hyun Min Kang, Temitope O. Keku, Hyeong Rok Kim, Loic Le Marchand, Soo Chin Lee, Christopher I. Li, Li Li, Annika Lindblom, Noralane Lindor, Roger L. Milne, Victor Moreno, Neil Murphy, Polly A. Newcomb, Deborah A. Nickerson, Kenneth Offit, Rachel Pearlman, Paul D.P. Pharoah, Elizabeth A. Platz, John D. Potter, Gad Rennert, Lori C. Sakoda, Clemens Schafmayer, Stephanie L. Schmit, Robert E. Schoen, Fredrick R. Schumacher, Martha L. Slattery, Yu Ru Su, Catherine M. Tangen, Cornelia M. Ulrich, Franzel J.B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Xiaoliang Wang, Emily White, Alicja Wolk, Michael O. Woods, Graham Casey, Li Hsu, Mark A. Jenkins, Stephen B. Gruber, Ulrike Peters, Wei Zheng

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1164-1178.e6
Journal	Gastroenterology
Volume	160
Issue number	4
DOIs	https://doi.org/10.1053/j.gastro.2020.08.062
State	Published - Mar 2021
Externally published	Yes

Keywords

CABLES2
Colorectal Cancer
Susceptibility Genes
TWAS

ASJC Scopus subject areas

Hepatology
Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1053/j.gastro.2020.08.062

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Guo, X., Lin, W., Wen, W., Huyghe, J., Bien, S., Cai, Q., Harrison, T., Chen, Z., Qu, C., Bao, J., Long, J., Yuan, Y., Wang, F., Bai, M., Abecasis, G. R., Albanes, D., Berndt, S. I., Bézieau, S., Bishop, D. T., ... Zheng, W. (2021). Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects. Gastroenterology, 160(4), 1164-1178.e6. https://doi.org/10.1053/j.gastro.2020.08.062

Guo, X, Lin, W, Wen, W, Huyghe, J, Bien, S, Cai, Q, Harrison, T, Chen, Z, Qu, C, Bao, J, Long, J, Yuan, Y, Wang, F, Bai, M, Abecasis, GR, Albanes, D, Berndt, SI, Bézieau, S, Bishop, DT, Brenner, H, Buch, S, Burnett-Hartman, A, Campbell, PT, Castellví-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Cho, SH, Conti, DV, Chapelle, ADL, Feskens, EJM, Gallinger, SJ, Giles, GG, Goodman, PJ, Gsur, A, Guinter, M, Gunter, MJ, Hampe, J, Hampel, H, Hayes, RB, Hoffmeister, M, Kampman, E, Kang, HM, Keku, TO, Kim, HR, Le Marchand, L, Lee, SC, Li, CI, Li, L, Lindblom, A, Lindor, N, Milne, RL, Moreno, V, Murphy, N, Newcomb, PA, Nickerson, DA, Offit, K, Pearlman, R, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Sakoda, LC, Schafmayer, C, Schmit, SL, Schoen, RE, Schumacher, FR, Slattery, ML, Su, YR, Tangen, CM, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Wang, X, White, E, Wolk, A, Woods, MO, Casey, G, Hsu, L, Jenkins, MA, Gruber, SB, Peters, U & Zheng, W 2021, 'Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects', Gastroenterology, vol. 160, no. 4, pp. 1164-1178.e6. https://doi.org/10.1053/j.gastro.2020.08.062

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title = "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.",

keywords = "CABLES2, Colorectal Cancer, Susceptibility Genes, TWAS",

author = "Xingyi Guo and Weiqiang Lin and Wanqing Wen and Jeroen Huyghe and Stephanie Bien and Qiuyin Cai and Tabitha Harrison and Zhishan Chen and Conghui Qu and Jiandong Bao and Jirong Long and Yuan Yuan and Fangqin Wang and Mengqiu Bai and Abecasis, {Goncalo R.} and Demetrius Albanes and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Bishop, {D. Timothy} and Hermann Brenner and Stephan Buch and Andrea Burnett-Hartman and Campbell, {Peter T.} and Sergi Castellv{\'i}-Bel and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Cho, {Sang Hee} and Conti, {David V.} and Chapelle, {Albert de la} and Feskens, {Edith J.M.} and Gallinger, {Steven J.} and Giles, {Graham G.} and Goodman, {Phyllis J.} and Andrea Gsur and Mark Guinter and Gunter, {Marc J.} and Jochen Hampe and Heather Hampel and Hayes, {Richard B.} and Michael Hoffmeister and Ellen Kampman and Kang, {Hyun Min} and Keku, {Temitope O.} and Kim, {Hyeong Rok} and {Le Marchand}, Loic and Lee, {Soo Chin} and Li, {Christopher I.} and Li Li and Annika Lindblom and Noralane Lindor and Milne, {Roger L.} and Victor Moreno and Neil Murphy and Newcomb, {Polly A.} and Nickerson, {Deborah A.} and Kenneth Offit and Rachel Pearlman and Pharoah, {Paul D.P.} and Platz, {Elizabeth A.} and Potter, {John D.} and Gad Rennert and Sakoda, {Lori C.} and Clemens Schafmayer and Schmit, {Stephanie L.} and Schoen, {Robert E.} and Schumacher, {Fredrick R.} and Slattery, {Martha L.} and Su, {Yu Ru} and Tangen, {Catherine M.} and Ulrich, {Cornelia M.} and {van Duijnhoven}, {Franzel J.B.} and {Van Guelpen}, Bethany and Kala Visvanathan and Pavel Vodicka and Ludmila Vodickova and Veronika Vymetalkova and Xiaoliang Wang and Emily White and Alicja Wolk and Woods, {Michael O.} and Graham Casey and Li Hsu and Jenkins, {Mark A.} and Gruber, {Stephen B.} and Ulrike Peters and Wei Zheng",

note = "Publisher Copyright: {\textcopyright} 2021 AGA Institute",

year = "2021",

month = mar,

doi = "10.1053/j.gastro.2020.08.062",

language = "English (US)",

volume = "160",

pages = "1164--1178.e6",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "4",

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TY - JOUR

T1 - Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects

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 - Chapelle, Albert de la

AU - Feskens, Edith J.M.

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 J.B.

AU - Van Guelpen, Bethany

AU - Visvanathan, Kala

AU - Vodicka, Pavel

AU - Vodickova, Ludmila

AU - Vymetalkova, Veronika

AU - Wang, Xiaoliang

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

PY - 2021/3

Y1 - 2021/3

N2 - 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.

AB - 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.

KW - CABLES2

KW - Colorectal Cancer

KW - Susceptibility Genes

KW - TWAS

UR - http://www.scopus.com/inward/record.url?scp=85100525451&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85100525451&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2020.08.062

DO - 10.1053/j.gastro.2020.08.062

M3 - Article

C2 - 33058866

AN - SCOPUS:85100525451

SN - 0016-5085

VL - 160

SP - 1164-1178.e6

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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