Novel common genetic susceptibility loci for colorectal cancer

Stephanie L. Schmit; Christopher K. Edlund; Fredrick R. Schumacher; Jian Gong; Tabitha A. Harrison; Jeroen R. Huyghe; Chenxu Qu; Marilena Melas; David J. Van Den Berg; Hansong Wang; Stephanie Tring; Sarah J. Plummer; Demetrius Albanes; M. Henar Alonso; Christopher I. Amos; Kristen Anton; Aaron K. Aragaki; Volker Arndt; Elizabeth L. Barry; Sonja I. Berndt; Stéphane Bezieau; Stephanie Bien; Amanda Bloomer; Juergen Boehm; Marie Christine Boutron-Ruault; Hermann Brenner; Stefanie Brezina; Daniel D. Buchanan; Katja Butterbach; Bette J. Caan; Peter T. Campbell; Christopher S. Carlson; Jose E. Castelao; Andrew T. Chan; Jenny Chang-Claude; Stephen J. Chanock; Iona Cheng; Ya Wen Cheng; Lee Soo Chin; James M. Church; Timothy Church; Gerhard A. Coetzee; Michelle Cotterchio; Marcia Cruz Correa; Keith R. Curtis; David Duggan; Douglas F. Easton; Dallas English; Edith J.M. Feskens; Rocky Fischer; Liesel M. FitzGerald; Barbara K. Fortini; Lars G. Fritsche; Charles S. Fuchs; Manuela Gago-Dominguez; Manish Gala; Steven J. Gallinger; W. James Gauderman; Graham G. Giles; Edward L. Giovannucci; Stephanie M. Gogarten; Clicerio Gonzalez-Villalpando; Elena M. Gonzalez-Villalpando; William M. Grady; Joel K. Greenson; Andrea Gsur; Marc Gunter; Christopher A. Haiman; Jochen Hampe; Sophia Harlid; John F. Harju; Richard B. Hayes; Philipp Hofer; Michael Hoffmeister; John L. Hopper; Shu Chen Huang; Jose Maria Huerta; Thomas J. Hudson; David J. Hunter; Gregory E. Idos; Motoki Iwasaki; Rebecca D. Jackson; Eric J. Jacobs; Sun Ha Jee; Mark A. Jenkins; Wei Hua Jia; Shuo Jiao; Amit D. Joshi; Laurence N. Kolonel; Suminori Kono; Charles Kooperberg; Vittorio Krogh; Tilman Kuehn; Sébastien Küry; Andrea LaCroix; Cecelia A. Laurie; Flavio Lejbkowicz; Mathieu Lemire; Heinz Josef Lenz; David Levine; Christopher I. Li; Li Li; Wolfgang Lieb; Yi Lin; Noralane M. Lindor; Yun Ru Liu; Fotios Loupakis; Yingchang Lu; Frank Luh; Jing Ma; Christoph Mancao; Frank J. Manion; Sanford D. Markowitz; Vicente Martin; Koichi Matsuda; Keitaro Matsuo; Kevin J. McDonnell; Caroline E. McNeil; Roger Milne; Antonio J. Molina; Bhramar Mukherjee; Neil Murphy; Polly A. Newcomb; Kenneth Offit; Hanane Omichessan; Domenico Palli; Jesus P. Paredes Cotoré; Julyann Pérez-Mayoral; Paul D. Pharoah; John D. Potter; Conghui Qu; Leon Raskin; Gad Rennert; Hedy S. Rennert; Bridget M. Riggs; Clemens Schafmayer; Robert E. Schoen; Thomas A. Sellers; Daniela Seminara; Gianluca Severi; Wei Shi; David Shibata; Xiao Ou Shu; Erin M. Siegel; Martha L. Slattery; Melissa Southey; Zsofia K. Stadler; Mariana C. Stern; Sebastian Stintzing; Darin Taverna; Stephen N. Thibodeau; Duncan C. Thomas; Antonia Trichopoulou; Shoichiro Tsugane; Cornelia M. Ulrich; Franzel J.B. Van Duijnhoven; Bethany Van Guelpan; Joseph Vijai; Jarmo Virtamo; Stephanie J. Weinstein; Emily White; Aung Ko Win; Alicja Wolk; Michael Woods; Anna H. Wu; Kana Wu; Yong Bing Xiang; Yun Yen; Brent W. Zanke; Yi Xin Zeng; Ben Zhang; Niha Zubair; Sun Seog Kweon; Jane C. Figueiredo; Wei Zheng; Loic Le Marchand; Annika Lindblom; Victor Moreno; Ulrike Peters; Graham Casey; Li Hsu; David V. Conti; Stephen B. Gruber

doi:10.1093/jnci/djy099

Novel common genetic susceptibility loci for colorectal cancer

Stephanie L. Schmit, Christopher K. Edlund, Fredrick R. Schumacher, Jian Gong, Tabitha A. Harrison, Jeroen R. Huyghe, Chenxu Qu, Marilena Melas, David J. Van Den Berg, Hansong Wang, Stephanie Tring, Sarah J. Plummer, Demetrius Albanes, M. Henar Alonso, Christopher I. Amos, Kristen Anton, Aaron K. Aragaki, Volker Arndt, Elizabeth L. Barry, Sonja I. BerndtStéphane Bezieau, Stephanie Bien, Amanda Bloomer, Juergen Boehm, Marie Christine Boutron-Ruault, Hermann Brenner, Stefanie Brezina, Daniel D. Buchanan, Katja Butterbach, Bette J. Caan, Peter T. Campbell, Christopher S. Carlson, Jose E. Castelao, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Iona Cheng, Ya Wen Cheng, Lee Soo Chin, James M. Church, Timothy Church, Gerhard A. Coetzee, Michelle Cotterchio, Marcia Cruz Correa, Keith R. Curtis, David Duggan, Douglas F. Easton, Dallas English, Edith J.M. Feskens, Rocky Fischer, Liesel M. FitzGerald, Barbara K. Fortini, Lars G. Fritsche, Charles S. Fuchs, Manuela Gago-Dominguez, Manish Gala, Steven J. Gallinger, W. James Gauderman, Graham G. Giles, Edward L. Giovannucci, Stephanie M. Gogarten, Clicerio Gonzalez-Villalpando, Elena M. Gonzalez-Villalpando, William M. Grady, Joel K. Greenson, Andrea Gsur, Marc Gunter, Christopher A. Haiman, Jochen Hampe, Sophia Harlid, John F. Harju, Richard B. Hayes, Philipp Hofer, Michael Hoffmeister, John L. Hopper, Shu Chen Huang, Jose Maria Huerta, Thomas J. Hudson, David J. Hunter, Gregory E. Idos, Motoki Iwasaki, Rebecca D. Jackson, Eric J. Jacobs, Sun Ha Jee, Mark A. Jenkins, Wei Hua Jia, Shuo Jiao, Amit D. Joshi, Laurence N. Kolonel, Suminori Kono, Charles Kooperberg, Vittorio Krogh, Tilman Kuehn, Sébastien Küry, Andrea LaCroix, Cecelia A. Laurie, Flavio Lejbkowicz, Mathieu Lemire, Heinz Josef Lenz, David Levine, Christopher I. Li, Li Li, Wolfgang Lieb, Yi Lin, Noralane M. Lindor, Yun Ru Liu, Fotios Loupakis, Yingchang Lu, Frank Luh, Jing Ma, Christoph Mancao, Frank J. Manion, Sanford D. Markowitz, Vicente Martin, Koichi Matsuda, Keitaro Matsuo, Kevin J. McDonnell, Caroline E. McNeil, Roger Milne, Antonio J. Molina, Bhramar Mukherjee, Neil Murphy, Polly A. Newcomb, Kenneth Offit, Hanane Omichessan, Domenico Palli, Jesus P. Paredes Cotoré, Julyann Pérez-Mayoral, Paul D. Pharoah, John D. Potter, Conghui Qu, Leon Raskin, Gad Rennert, Hedy S. Rennert, Bridget M. Riggs, Clemens Schafmayer, Robert E. Schoen, Thomas A. Sellers, Daniela Seminara, Gianluca Severi, Wei Shi, David Shibata, Xiao Ou Shu, Erin M. Siegel, Martha L. Slattery, Melissa Southey, Zsofia K. Stadler, Mariana C. Stern, Sebastian Stintzing, Darin Taverna, Stephen N. Thibodeau, Duncan C. Thomas, Antonia Trichopoulou, Shoichiro Tsugane, Cornelia M. Ulrich, Franzel J.B. Van Duijnhoven, Bethany Van Guelpan, Joseph Vijai, Jarmo Virtamo, Stephanie J. Weinstein, Emily White, Aung Ko Win, Alicja Wolk, Michael Woods, Anna H. Wu, Kana Wu, Yong Bing Xiang, Yun Yen, Brent W. Zanke, Yi Xin Zeng, Ben Zhang, Niha Zubair, Sun Seog Kweon, Jane C. Figueiredo, Wei Zheng, Loic Le Marchand, Annika Lindblom, Victor Moreno, Ulrike Peters, Graham Casey, Li Hsu, David V. Conti, Stephen B. Gruber

Environmental Health Sciences

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

110 Scopus citations

Abstract

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10^-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10^-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10^-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Original language	English (US)
Pages (from-to)	146-157
Number of pages	12
Journal	Journal of the National Cancer Institute
Volume	111
Issue number	2
DOIs	https://doi.org/10.1093/jnci/djy099
State	Published - Feb 1 2019

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© The Author(s) 2018. Published by Oxford University Press. All rights reserved.

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10.1093/jnci/djy099

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555904

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Schmit, S. L., Edlund, C. K., Schumacher, F. R., Gong, J., Harrison, T. A., Huyghe, J. R., Qu, C., Melas, M., Van Den Berg, D. J., Wang, H., Tring, S., Plummer, S. J., Albanes, D., Alonso, M. H., Amos, C. I., Anton, K., Aragaki, A. K., Arndt, V., Barry, E. L., ... Gruber, S. B. (2019). Novel common genetic susceptibility loci for colorectal cancer. Journal of the National Cancer Institute, 111(2), 146-157. https://doi.org/10.1093/jnci/djy099

Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van Den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, MC, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, YW, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, SC, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, WH, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Küry, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, HJ, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, YR, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Paredes Cotoré, JP, Pérez-Mayoral, J, Pharoah, PD, Potter, JD, Qu, C, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, XO, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, Van Duijnhoven, FJB, Van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, YB, Yen, Y, Zanke, BW, Zeng, YX, Zhang, B, Zubair, N, Kweon, SS, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV & Gruber, SB 2019, 'Novel common genetic susceptibility loci for colorectal cancer', Journal of the National Cancer Institute, vol. 111, no. 2, pp. 146-157. https://doi.org/10.1093/jnci/djy099

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title = "Novel common genetic susceptibility loci for colorectal cancer",

abstract = "Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.",

author = "Schmit, {Stephanie L.} and Edlund, {Christopher K.} and Schumacher, {Fredrick R.} and Jian Gong and Harrison, {Tabitha A.} and Huyghe, {Jeroen R.} and Chenxu Qu and Marilena Melas and {Van Den Berg}, {David J.} and Hansong Wang and Stephanie Tring and Plummer, {Sarah J.} and Demetrius Albanes and Alonso, {M. Henar} and Amos, {Christopher I.} and Kristen Anton and Aragaki, {Aaron K.} and Volker Arndt and Barry, {Elizabeth L.} and Berndt, {Sonja I.} and St{\'e}phane Bezieau and Stephanie Bien and Amanda Bloomer and Juergen Boehm and Boutron-Ruault, {Marie Christine} and Hermann Brenner and Stefanie Brezina and Buchanan, {Daniel D.} and Katja Butterbach and Caan, {Bette J.} and Campbell, {Peter T.} and Carlson, {Christopher S.} and Castelao, {Jose E.} and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Iona Cheng and Cheng, {Ya Wen} and Chin, {Lee Soo} and Church, {James M.} and Timothy Church and Coetzee, {Gerhard A.} and Michelle Cotterchio and Correa, {Marcia Cruz} and Curtis, {Keith R.} and David Duggan and Easton, {Douglas F.} and Dallas English and Feskens, {Edith J.M.} and Rocky Fischer and FitzGerald, {Liesel M.} and Fortini, {Barbara K.} and Fritsche, {Lars G.} and Fuchs, {Charles S.} and Manuela Gago-Dominguez and Manish Gala and Gallinger, {Steven J.} and Gauderman, {W. James} and Giles, {Graham G.} and Giovannucci, {Edward L.} and Gogarten, {Stephanie M.} and Clicerio Gonzalez-Villalpando and Gonzalez-Villalpando, {Elena M.} and Grady, {William M.} and Greenson, {Joel K.} and Andrea Gsur and Marc Gunter and Haiman, {Christopher A.} and Jochen Hampe and Sophia Harlid and Harju, {John F.} and Hayes, {Richard B.} and Philipp Hofer and Michael Hoffmeister and Hopper, {John L.} and Huang, {Shu Chen} and Huerta, {Jose Maria} and Hudson, {Thomas J.} and Hunter, {David J.} and Idos, {Gregory E.} and Motoki Iwasaki and Jackson, {Rebecca D.} and Jacobs, {Eric J.} and Jee, {Sun Ha} and Jenkins, {Mark A.} and Jia, {Wei Hua} and Shuo Jiao and Joshi, {Amit D.} and Kolonel, {Laurence N.} and Suminori Kono and Charles Kooperberg and Vittorio Krogh and Tilman Kuehn and S{\'e}bastien K{\"u}ry and Andrea LaCroix and Laurie, {Cecelia A.} and Flavio Lejbkowicz and Mathieu Lemire and Lenz, {Heinz Josef} and David Levine and Li, {Christopher I.} and Li Li and Wolfgang Lieb and Yi Lin and Lindor, {Noralane M.} and Liu, {Yun Ru} and Fotios Loupakis and Yingchang Lu and Frank Luh and Jing Ma and Christoph Mancao and Manion, {Frank J.} and Markowitz, {Sanford D.} and Vicente Martin and Koichi Matsuda and Keitaro Matsuo and McDonnell, {Kevin J.} and McNeil, {Caroline E.} and Roger Milne and Molina, {Antonio J.} and Bhramar Mukherjee and Neil Murphy and Newcomb, {Polly A.} and Kenneth Offit and Hanane Omichessan and Domenico Palli and {Paredes Cotor{\'e}}, {Jesus P.} and Julyann P{\'e}rez-Mayoral and Pharoah, {Paul D.} and Potter, {John D.} and Conghui Qu and Leon Raskin and Gad Rennert and Rennert, {Hedy S.} and Riggs, {Bridget M.} and Clemens Schafmayer and Schoen, {Robert E.} and Sellers, {Thomas A.} and Daniela Seminara and Gianluca Severi and Wei Shi and David Shibata and Shu, {Xiao Ou} and Siegel, {Erin M.} and Slattery, {Martha L.} and Melissa Southey and Stadler, {Zsofia K.} and Stern, {Mariana C.} and Sebastian Stintzing and Darin Taverna and Thibodeau, {Stephen N.} and Thomas, {Duncan C.} and Antonia Trichopoulou and Shoichiro Tsugane and Ulrich, {Cornelia M.} and {Van Duijnhoven}, {Franzel J.B.} and {Van Guelpan}, Bethany and Joseph Vijai and Jarmo Virtamo and Weinstein, {Stephanie J.} and Emily White and Win, {Aung Ko} and Alicja Wolk and Michael Woods and Wu, {Anna H.} and Kana Wu and Xiang, {Yong Bing} and Yun Yen and Zanke, {Brent W.} and Zeng, {Yi Xin} and Ben Zhang and Niha Zubair and Kweon, {Sun Seog} and Figueiredo, {Jane C.} and Wei Zheng and {Le Marchand}, Loic and Annika Lindblom and Victor Moreno and Ulrike Peters and Graham Casey and Li Hsu and Conti, {David V.} and Gruber, {Stephen B.}",

year = "2019",

month = feb,

day = "1",

doi = "10.1093/jnci/djy099",

language = "English (US)",

volume = "111",

pages = "146--157",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "2",

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TY - JOUR

T1 - Novel common genetic susceptibility loci for colorectal cancer

AU - Schmit, Stephanie L.

AU - Edlund, Christopher K.

AU - Schumacher, Fredrick R.

AU - Gong, Jian

AU - Harrison, Tabitha A.

AU - Huyghe, Jeroen R.

AU - Qu, Chenxu

AU - Melas, Marilena

AU - Van Den Berg, David J.

AU - Wang, Hansong

AU - Tring, Stephanie

AU - Plummer, Sarah J.

AU - Albanes, Demetrius

AU - Alonso, M. Henar

AU - Amos, Christopher I.

AU - Anton, Kristen

AU - Aragaki, Aaron K.

AU - Arndt, Volker

AU - Barry, Elizabeth L.

AU - Berndt, Sonja I.

AU - Bezieau, Stéphane

AU - Bien, Stephanie

AU - Bloomer, Amanda

AU - Boehm, Juergen

AU - Boutron-Ruault, Marie Christine

AU - Brenner, Hermann

AU - Brezina, Stefanie

AU - Buchanan, Daniel D.

AU - Butterbach, Katja

AU - Caan, Bette J.

AU - Campbell, Peter T.

AU - Carlson, Christopher S.

AU - Castelao, Jose E.

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Cheng, Iona

AU - Cheng, Ya Wen

AU - Chin, Lee Soo

AU - Church, James M.

AU - Church, Timothy

AU - Coetzee, Gerhard A.

AU - Cotterchio, Michelle

AU - Correa, Marcia Cruz

AU - Curtis, Keith R.

AU - Duggan, David

AU - Easton, Douglas F.

AU - English, Dallas

AU - Feskens, Edith J.M.

AU - Fischer, Rocky

AU - FitzGerald, Liesel M.

AU - Fortini, Barbara K.

AU - Fritsche, Lars G.

AU - Fuchs, Charles S.

AU - Gago-Dominguez, Manuela

AU - Gala, Manish

AU - Gallinger, Steven J.

AU - Gauderman, W. James

AU - Giles, Graham G.

AU - Giovannucci, Edward L.

AU - Gogarten, Stephanie M.

AU - Gonzalez-Villalpando, Clicerio

AU - Gonzalez-Villalpando, Elena M.

AU - Grady, William M.

AU - Greenson, Joel K.

AU - Gsur, Andrea

AU - Gunter, Marc

AU - Haiman, Christopher A.

AU - Hampe, Jochen

AU - Harlid, Sophia

AU - Harju, John F.

AU - Hayes, Richard B.

AU - Hofer, Philipp

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Huang, Shu Chen

AU - Huerta, Jose Maria

AU - Hudson, Thomas J.

AU - Hunter, David J.

AU - Idos, Gregory E.

AU - Iwasaki, Motoki

AU - Jackson, Rebecca D.

AU - Jacobs, Eric J.

AU - Jee, Sun Ha

AU - Jenkins, Mark A.

AU - Jia, Wei Hua

AU - Jiao, Shuo

AU - Joshi, Amit D.

AU - Kolonel, Laurence N.

AU - Kono, Suminori

AU - Kooperberg, Charles

AU - Krogh, Vittorio

AU - Kuehn, Tilman

AU - Küry, Sébastien

AU - LaCroix, Andrea

AU - Laurie, Cecelia A.

AU - Lejbkowicz, Flavio

AU - Lemire, Mathieu

AU - Lenz, Heinz Josef

AU - Levine, David

AU - Li, Christopher I.

AU - Li, Li

AU - Lieb, Wolfgang

AU - Lin, Yi

AU - Lindor, Noralane M.

AU - Liu, Yun Ru

AU - Loupakis, Fotios

AU - Lu, Yingchang

AU - Luh, Frank

AU - Ma, Jing

AU - Mancao, Christoph

AU - Manion, Frank J.

AU - Markowitz, Sanford D.

AU - Martin, Vicente

AU - Matsuda, Koichi

AU - Matsuo, Keitaro

AU - McDonnell, Kevin J.

AU - McNeil, Caroline E.

AU - Milne, Roger

AU - Molina, Antonio J.

AU - Mukherjee, Bhramar

AU - Murphy, Neil

AU - Newcomb, Polly A.

AU - Offit, Kenneth

AU - Omichessan, Hanane

AU - Palli, Domenico

AU - Paredes Cotoré, Jesus P.

AU - Pérez-Mayoral, Julyann

AU - Pharoah, Paul D.

AU - Potter, John D.

AU - Qu, Conghui

AU - Raskin, Leon

AU - Rennert, Gad

AU - Rennert, Hedy S.

AU - Riggs, Bridget M.

AU - Schafmayer, Clemens

AU - Schoen, Robert E.

AU - Sellers, Thomas A.

AU - Seminara, Daniela

AU - Severi, Gianluca

AU - Shi, Wei

AU - Shibata, David

AU - Shu, Xiao Ou

AU - Siegel, Erin M.

AU - Slattery, Martha L.

AU - Southey, Melissa

AU - Stadler, Zsofia K.

AU - Stern, Mariana C.

AU - Stintzing, Sebastian

AU - Taverna, Darin

AU - Thibodeau, Stephen N.

AU - Thomas, Duncan C.

AU - Trichopoulou, Antonia

AU - Tsugane, Shoichiro

AU - Ulrich, Cornelia M.

AU - Van Duijnhoven, Franzel J.B.

AU - Van Guelpan, Bethany

AU - Vijai, Joseph

AU - Virtamo, Jarmo

AU - Weinstein, Stephanie J.

AU - White, Emily

AU - Win, Aung Ko

AU - Wolk, Alicja

AU - Woods, Michael

AU - Wu, Anna H.

AU - Wu, Kana

AU - Xiang, Yong Bing

AU - Yen, Yun

AU - Zanke, Brent W.

AU - Zeng, Yi Xin

AU - Zhang, Ben

AU - Zubair, Niha

AU - Kweon, Sun Seog

AU - Figueiredo, Jane C.

AU - Zheng, Wei

AU - Le Marchand, Loic

AU - Lindblom, Annika

AU - Moreno, Victor

AU - Peters, Ulrike

AU - Casey, Graham

AU - Hsu, Li

AU - Conti, David V.

AU - Gruber, Stephen B.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

AB - Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

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U2 - 10.1093/jnci/djy099

DO - 10.1093/jnci/djy099

M3 - Article

C2 - 29917119

AN - SCOPUS:85060758530

SN - 0027-8874

VL - 111

SP - 146

EP - 157

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 2

ER -

Novel common genetic susceptibility loci for colorectal cancer

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