Discovery of common and rare genetic risk variants for colorectal cancer

Jeroen R. Huyghe; Stephanie A. Bien; Tabitha A. Harrison; Hyun Min Kang; Sai Chen; Stephanie L. Schmit; David V. Conti; Conghui Qu; Jihyoun Jeon; Christopher K. Edlund; Peyton Greenside; Michael Wainberg; Fredrick R. Schumacher; Joshua D. Smith; David M. Levine; Sarah C. Nelson; Nasa A. Sinnott-Armstrong; Demetrius Albanes; M. Henar Alonso; Kristin Anderson; Coral Arnau-Collell; Volker Arndt; Christina Bamia; Barbara L. Banbury; John A. Baron; Sonja I. Berndt; Stéphane Bézieau; D. Timothy Bishop; Juergen Boehm; Heiner Boeing; Hermann Brenner; Stefanie Brezina; Stephan Buch; Daniel D. Buchanan; Andrea Burnett-Hartman; Katja Butterbach; Bette J. Caan; Peter T. Campbell; Christopher S. Carlson; Sergi Castellví-Bel; Andrew T. Chan; Jenny Chang-Claude; Stephen J. Chanock; Maria-Dolores Chirlaque; Sang Hee Cho; Charles M. Connolly; Amanda J. Cross; Katarina Cuk; Keith R. Curtis; Albert de la Chapelle; Kimberly F. Doheny; David Duggan; Douglas F. Easton; Sjoerd G. Elias; Faye Elliott; Dallas R. English; Edith J. M. Feskens; Jane C. Figueiredo; Rocky Fischer; Liesel M. FitzGerald; David Forman; Manish Gala; Steven Gallinger; W. James Gauderman; Graham G. Giles; Elizabeth Gillanders; Jian Gong; Phyllis J. Goodman; William M. Grady; John S. Grove; Andrea Gsur; Marc J. Gunter; Robert W. Haile; Jochen Hampe; Heather Hampel; Sophia Harlid; Richard B. Hayes; Philipp Hofer; Michael Hoffmeister; John L. Hopper; Wan-Ling Hsu; Wen-Yi Huang; Thomas J. Hudson; David J. Hunter; Gemma Ibañez-Sanz; Gregory E. Idos; Roxann Ingersoll; Rebecca D. Jackson; Eric J. Jacobs; Mark A. Jenkins; Amit D. Joshi; Corinne E. Joshu; Temitope O. Keku; Timothy J. Key; Hyeong Rok Kim; Emiko Kobayashi; Laurence N. Kolonel; Charles Kooperberg; Tilman Kühn; Sébastien Küry; Sun-Seog Kweon; Susanna C. Larsson; Cecelia A. Laurie; Loic Le Marchand; Suzanne M. Leal; Soo Chin Lee; Flavio Lejbkowicz; Mathieu Lemire; Christopher I. Li; Li Li; Wolfgang Lieb; Yi Lin; Annika Lindblom; Noralane M. Lindor; Hua Ling; Tin L. Louie; Satu Männistö; Sanford D. Markowitz; Vicente Martín; Giovanna Masala; Caroline E. McNeil; Marilena Melas; Roger L. Milne; Lorena Moreno; Neil Murphy; Robin Myte; Alessio Naccarati; Polly A. Newcomb; Kenneth Offit; Shuji Ogino; N. Charlotte Onland-Moret; Barbara Pardini; Patrick S. Parfrey; Rachel Pearlman; Vittorio Perduca; Paul D. P. Pharoah; Mila Pinchev; Elizabeth A. Platz; Ross L. Prentice; Elizabeth Pugh; Leon Raskin; Gad Rennert; Hedy S. Rennert; Elio Riboli; Miguel Rodríguez-Barranco; Jane Romm; Lori C. Sakoda; Clemens Schafmayer; Robert E. Schoen; Daniela Seminara; Mitul Shah; Tameka Shelford; Min-Ho Shin; Katerina Shulman; Sabina Sieri; Martha L. Slattery; Melissa C. Southey; Zsofia K. Stadler; Christa Stegmaier; Yu-Ru Su; Catherine M. Tangen; Stephen N. Thibodeau; Duncan C. Thomas; Sushma S. Thomas; Amanda E. Toland; Antonia Trichopoulou; Cornelia M. Ulrich; David J. Van Den Berg; Franzel J. B. van Duijnhoven; Bethany Van Guelpen; Henk van Kranen; Joseph Vijai; Kala Visvanathan; Pavel Vodicka; Ludmila Vodickova; Veronika Vymetalkova; Korbinian Weigl; Stephanie J. Weinstein; Emily White; Aung Ko Win; C. Roland Wolf; Alicja Wolk; Michael O. Woods; Anna H. Wu; Syed H. Zaidi; Brent W. Zanke; Qing Zhang; Wei Zheng; Peter C. Scacheri; John D. Potter; Michael C. Bassik; Anshul Kundaje; Graham Casey; Victor Moreno; Goncalo R. Abecasis; Deborah A. Nickerson; Stephen B. Gruber; Li Hsu; Ulrike Peters

doi:10.1038/s41588-018-0286-6

Discovery of common and rare genetic risk variants for colorectal cancer

Jeroen R. Huyghe, Stephanie A. Bien, Tabitha A. Harrison, Hyun Min Kang, Sai Chen, Stephanie L. Schmit, David V. Conti, Conghui Qu, Jihyoun Jeon, Christopher K. Edlund, Peyton Greenside, Michael Wainberg, Fredrick R. Schumacher, Joshua D. Smith, David M. Levine, Sarah C. Nelson, Nasa A. Sinnott-Armstrong, Demetrius Albanes, M. Henar Alonso, Kristin AndersonCoral Arnau-Collell, Volker Arndt, Christina Bamia, Barbara L. Banbury, John A. Baron, Sonja I. Berndt, Stéphane Bézieau, D. Timothy Bishop, Juergen Boehm, Heiner Boeing, Hermann Brenner, Stefanie Brezina, Stephan Buch, Daniel D. Buchanan, Andrea Burnett-Hartman, Katja Butterbach, Bette J. Caan, Peter T. Campbell, Christopher S. Carlson, Sergi Castellví-Bel, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Maria-Dolores Chirlaque, Sang Hee Cho, Charles M. Connolly, Amanda J. Cross, Katarina Cuk, Keith R. Curtis, Albert de la Chapelle, Kimberly F. Doheny, David Duggan, Douglas F. Easton, Sjoerd G. Elias, Faye Elliott, Dallas R. English, Edith J. M. Feskens, Jane C. Figueiredo, Rocky Fischer, Liesel M. FitzGerald, David Forman, Manish Gala, Steven Gallinger, W. James Gauderman, Graham G. Giles, Elizabeth Gillanders, Jian Gong, Phyllis J. Goodman, William M. Grady, John S. Grove, Andrea Gsur, Marc J. Gunter, Robert W. Haile, Jochen Hampe, Heather Hampel, Sophia Harlid, Richard B. Hayes, Philipp Hofer, Michael Hoffmeister, John L. Hopper, Wan-Ling Hsu, Wen-Yi Huang, Thomas J. Hudson, David J. Hunter, Gemma Ibañez-Sanz, Gregory E. Idos, Roxann Ingersoll, Rebecca D. Jackson, Eric J. Jacobs, Mark A. Jenkins, Amit D. Joshi, Corinne E. Joshu, Temitope O. Keku, Timothy J. Key, Hyeong Rok Kim, Emiko Kobayashi, Laurence N. Kolonel, Charles Kooperberg, Tilman Kühn, Sébastien Küry, Sun-Seog Kweon, Susanna C. Larsson, Cecelia A. Laurie, Loic Le Marchand, Suzanne M. Leal, Soo Chin Lee, Flavio Lejbkowicz, Mathieu Lemire, Christopher I. Li, Li Li, Wolfgang Lieb, Yi Lin, Annika Lindblom, Noralane M. Lindor, Hua Ling, Tin L. Louie, Satu Männistö, Sanford D. Markowitz, Vicente Martín, Giovanna Masala, Caroline E. McNeil, Marilena Melas, Roger L. Milne, Lorena Moreno, Neil Murphy, Robin Myte, Alessio Naccarati, Polly A. Newcomb, Kenneth Offit, Shuji Ogino, N. Charlotte Onland-Moret, Barbara Pardini, Patrick S. Parfrey, Rachel Pearlman, Vittorio Perduca, Paul D. P. Pharoah, Mila Pinchev, Elizabeth A. Platz, Ross L. Prentice, Elizabeth Pugh, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elio Riboli, Miguel Rodríguez-Barranco, Jane Romm, Lori C. Sakoda, Clemens Schafmayer, Robert E. Schoen, Daniela Seminara, Mitul Shah, Tameka Shelford, Min-Ho Shin, Katerina Shulman, Sabina Sieri, Martha L. Slattery, Melissa C. Southey, Zsofia K. Stadler, Christa Stegmaier, Yu-Ru Su, Catherine M. Tangen, Stephen N. Thibodeau, Duncan C. Thomas, Sushma S. Thomas, Amanda E. Toland, Antonia Trichopoulou, Cornelia M. Ulrich, David J. Van Den Berg, Franzel J. B. van Duijnhoven, Bethany Van Guelpen, Henk van Kranen, Joseph Vijai, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Korbinian Weigl, Stephanie J. Weinstein, Emily White, Aung Ko Win, C. Roland Wolf, Alicja Wolk, Michael O. Woods, Anna H. Wu, Syed H. Zaidi, Brent W. Zanke, Qing Zhang, Wei Zheng, Peter C. Scacheri, John D. Potter, Michael C. Bassik, Anshul Kundaje, Graham Casey, Victor Moreno, Goncalo R. Abecasis, Deborah A. Nickerson, Stephen B. Gruber, Li Hsu, Ulrike Peters (Lead / Corresponding author)

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

360 Citations (Scopus)

333 Downloads (Pure)

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 ⁻⁸, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Original language	English
Pages (from-to)	76-87
Number of pages	12
Journal	Nature Genetics
Volume	51
Issue number	1
Early online date	3 Dec 2018
DOIs	https://doi.org/10.1038/s41588-018-0286-6
Publication status	Published - 1 Jan 2019

Keywords

Aged
Case-Control Studies
Colorectal Neoplasms/genetics
Female
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study/methods
Genotype
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide/genetics
RNA, Long Noncoding/genetics
Risk Factors
Signal Transduction/genetics

ASJC Scopus subject areas

Genetics

UN SDGs

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

Access to Document

10.1038/s41588-018-0286-6

Author Accepted ManuscriptAccepted author manuscript, 1.64 MB

Cite this

Huyghe, J. R., Bien, S. A., Harrison, T. A., Kang, H. M., Chen, S., Schmit, S. L., Conti, D. V., Qu, C., Jeon, J., Edlund, C. K., Greenside, P., Wainberg, M., Schumacher, F. R., Smith, J. D., Levine, D. M., Nelson, S. C., Sinnott-Armstrong, N. A., Albanes, D., Alonso, M. H., ... Peters, U. (2019). Discovery of common and rare genetic risk variants for colorectal cancer. Nature Genetics, 51(1), 76-87. https://doi.org/10.1038/s41588-018-0286-6

@article{e8fdb275e78449e0b97ff8544e04782a,

title = "Discovery of common and rare genetic risk variants for colorectal cancer",

abstract = "To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 −8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Kr{\"u}ppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development. ",

keywords = "Aged, Case-Control Studies, Colorectal Neoplasms/genetics, Female, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide/genetics, RNA, Long Noncoding/genetics, Risk Factors, Signal Transduction/genetics",

author = "Huyghe, {Jeroen R.} and Bien, {Stephanie A.} and Harrison, {Tabitha A.} and Kang, {Hyun Min} and Sai Chen and Schmit, {Stephanie L.} and Conti, {David V.} and Conghui Qu and Jihyoun Jeon and Edlund, {Christopher K.} and Peyton Greenside and Michael Wainberg and Schumacher, {Fredrick R.} and Smith, {Joshua D.} and Levine, {David M.} and Nelson, {Sarah C.} and Sinnott-Armstrong, {Nasa A.} and Demetrius Albanes and Alonso, {M. Henar} and Kristin Anderson and Coral Arnau-Collell and Volker Arndt and Christina Bamia and Banbury, {Barbara L.} and Baron, {John A.} and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Bishop, {D. Timothy} and Juergen Boehm and Heiner Boeing and Hermann Brenner and Stefanie Brezina and Stephan Buch and Buchanan, {Daniel D.} and Andrea Burnett-Hartman and Katja Butterbach and Caan, {Bette J.} and Campbell, {Peter T.} and Carlson, {Christopher S.} and Sergi Castellv{\'i}-Bel and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Maria-Dolores Chirlaque and Cho, {Sang Hee} and Connolly, {Charles M.} and Cross, {Amanda J.} and Katarina Cuk and Curtis, {Keith R.} and {de la Chapelle}, Albert and Doheny, {Kimberly F.} and David Duggan and Easton, {Douglas F.} and Elias, {Sjoerd G.} and Faye Elliott and English, {Dallas R.} and Feskens, {Edith J. M.} and Figueiredo, {Jane C.} and Rocky Fischer and FitzGerald, {Liesel M.} and David Forman and Manish Gala and Steven Gallinger and Gauderman, {W. James} and Giles, {Graham G.} and Elizabeth Gillanders and Jian Gong and Goodman, {Phyllis J.} and Grady, {William M.} and Grove, {John S.} and Andrea Gsur and Gunter, {Marc J.} and Haile, {Robert W.} and Jochen Hampe and Heather Hampel and Sophia Harlid and Hayes, {Richard B.} and Philipp Hofer and Michael Hoffmeister and Hopper, {John L.} and Wan-Ling Hsu and Wen-Yi Huang and Hudson, {Thomas J.} and Hunter, {David J.} and Gemma Iba{\~n}ez-Sanz and Idos, {Gregory E.} and Roxann Ingersoll and Jackson, {Rebecca D.} and Jacobs, {Eric J.} and Jenkins, {Mark A.} and Joshi, {Amit D.} and Joshu, {Corinne E.} and Keku, {Temitope O.} and Key, {Timothy J.} and Kim, {Hyeong Rok} and Emiko Kobayashi and Kolonel, {Laurence N.} and Charles Kooperberg and Tilman K{\"u}hn and S{\'e}bastien K{\"u}ry and Sun-Seog Kweon and Larsson, {Susanna C.} and Laurie, {Cecelia A.} and {Le Marchand}, Loic and Leal, {Suzanne M.} and Lee, {Soo Chin} and Flavio Lejbkowicz and Mathieu Lemire and Li, {Christopher I.} and Li Li and Wolfgang Lieb and Yi Lin and Annika Lindblom and Lindor, {Noralane M.} and Hua Ling and Louie, {Tin L.} and Satu M{\"a}nnist{\"o} and Markowitz, {Sanford D.} and Vicente Mart{\'i}n and Giovanna Masala and McNeil, {Caroline E.} and Marilena Melas and Milne, {Roger L.} and Lorena Moreno and Neil Murphy and Robin Myte and Alessio Naccarati and Newcomb, {Polly A.} and Kenneth Offit and Shuji Ogino and Onland-Moret, {N. Charlotte} and Barbara Pardini and Parfrey, {Patrick S.} and Rachel Pearlman and Vittorio Perduca and Pharoah, {Paul D. P.} and Mila Pinchev and Platz, {Elizabeth A.} and Prentice, {Ross L.} and Elizabeth Pugh and Leon Raskin and Gad Rennert and Rennert, {Hedy S.} and Elio Riboli and Miguel Rodr{\'i}guez-Barranco and Jane Romm and Sakoda, {Lori C.} and Clemens Schafmayer and Schoen, {Robert E.} and Daniela Seminara and Mitul Shah and Tameka Shelford and Min-Ho Shin and Katerina Shulman and Sabina Sieri and Slattery, {Martha L.} and Southey, {Melissa C.} and Stadler, {Zsofia K.} and Christa Stegmaier and Yu-Ru Su and Tangen, {Catherine M.} and Thibodeau, {Stephen N.} and Thomas, {Duncan C.} and Thomas, {Sushma S.} and Toland, {Amanda E.} and Antonia Trichopoulou and Ulrich, {Cornelia M.} and {Van Den Berg}, {David J.} and {van Duijnhoven}, {Franzel J. B.} and {Van Guelpen}, Bethany and {van Kranen}, Henk and Joseph Vijai and Kala Visvanathan and Pavel Vodicka and Ludmila Vodickova and Veronika Vymetalkova and Korbinian Weigl and Weinstein, {Stephanie J.} and Emily White and Win, {Aung Ko} and Wolf, {C. Roland} and Alicja Wolk and Woods, {Michael O.} and Wu, {Anna H.} and Zaidi, {Syed H.} and Zanke, {Brent W.} and Qing Zhang and Wei Zheng and Scacheri, {Peter C.} and Potter, {John D.} and Bassik, {Michael C.} and Anshul Kundaje and Graham Casey and Victor Moreno and Abecasis, {Goncalo R.} and Nickerson, {Deborah A.} and Gruber, {Stephen B.} and Li Hsu and Ulrike Peters",

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Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bézieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellví-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibañez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kühn, T, Küry, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Männistö, S, Markowitz, SD, Martín, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodríguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van Den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L & Peters, U 2019, 'Discovery of common and rare genetic risk variants for colorectal cancer', Nature Genetics, vol. 51, no. 1, pp. 76-87. https://doi.org/10.1038/s41588-018-0286-6

TY - JOUR

T1 - Discovery of common and rare genetic risk variants for colorectal cancer

AU - Huyghe, Jeroen R.

AU - Bien, Stephanie A.

AU - Harrison, Tabitha A.

AU - Kang, Hyun Min

AU - Chen, Sai

AU - Schmit, Stephanie L.

AU - Conti, David V.

AU - Qu, Conghui

AU - Jeon, Jihyoun

AU - Edlund, Christopher K.

AU - Greenside, Peyton

AU - Wainberg, Michael

AU - Schumacher, Fredrick R.

AU - Smith, Joshua D.

AU - Levine, David M.

AU - Nelson, Sarah C.

AU - Sinnott-Armstrong, Nasa A.

AU - Albanes, Demetrius

AU - Alonso, M. Henar

AU - Anderson, Kristin

AU - Arnau-Collell, Coral

AU - Arndt, Volker

AU - Bamia, Christina

AU - Banbury, Barbara L.

AU - Baron, John A.

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

AU - Bishop, D. Timothy

AU - Boehm, Juergen

AU - Boeing, Heiner

AU - Brenner, Hermann

AU - Brezina, Stefanie

AU - Buch, Stephan

AU - Buchanan, Daniel D.

AU - Burnett-Hartman, Andrea

AU - Butterbach, Katja

AU - Caan, Bette J.

AU - Campbell, Peter T.

AU - Carlson, Christopher S.

AU - Castellví-Bel, Sergi

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Chirlaque, Maria-Dolores

AU - Cho, Sang Hee

AU - Connolly, Charles M.

AU - Cross, Amanda J.

AU - Cuk, Katarina

AU - Curtis, Keith R.

AU - de la Chapelle, Albert

AU - Doheny, Kimberly F.

AU - Duggan, David

AU - Easton, Douglas F.

AU - Elias, Sjoerd G.

AU - Elliott, Faye

AU - English, Dallas R.

AU - Feskens, Edith J. M.

AU - Figueiredo, Jane C.

AU - Fischer, Rocky

AU - FitzGerald, Liesel M.

AU - Forman, David

AU - Gala, Manish

AU - Gallinger, Steven

AU - Gauderman, W. James

AU - Giles, Graham G.

AU - Gillanders, Elizabeth

AU - Gong, Jian

AU - Goodman, Phyllis J.

AU - Grady, William M.

AU - Grove, John S.

AU - Gsur, Andrea

AU - Gunter, Marc J.

AU - Haile, Robert W.

AU - Hampe, Jochen

AU - Hampel, Heather

AU - Harlid, Sophia

AU - Hayes, Richard B.

AU - Hofer, Philipp

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Hsu, Wan-Ling

AU - Huang, Wen-Yi

AU - Hudson, Thomas J.

AU - Hunter, David J.

AU - Ibañez-Sanz, Gemma

AU - Idos, Gregory E.

AU - Ingersoll, Roxann

AU - Jackson, Rebecca D.

AU - Jacobs, Eric J.

AU - Jenkins, Mark A.

AU - Joshi, Amit D.

AU - Joshu, Corinne E.

AU - Keku, Temitope O.

AU - Key, Timothy J.

AU - Kim, Hyeong Rok

AU - Kobayashi, Emiko

AU - Kolonel, Laurence N.

AU - Kooperberg, Charles

AU - Kühn, Tilman

AU - Küry, Sébastien

AU - Kweon, Sun-Seog

AU - Larsson, Susanna C.

AU - Laurie, Cecelia A.

AU - Le Marchand, Loic

AU - Leal, Suzanne M.

AU - Lee, Soo Chin

AU - Lejbkowicz, Flavio

AU - Lemire, Mathieu

AU - Li, Christopher I.

AU - Li, Li

AU - Lieb, Wolfgang

AU - Lin, Yi

AU - Lindblom, Annika

AU - Lindor, Noralane M.

AU - Ling, Hua

AU - Louie, Tin L.

AU - Männistö, Satu

AU - Markowitz, Sanford D.

AU - Martín, Vicente

AU - Masala, Giovanna

AU - McNeil, Caroline E.

AU - Melas, Marilena

AU - Milne, Roger L.

AU - Moreno, Lorena

AU - Murphy, Neil

AU - Myte, Robin

AU - Naccarati, Alessio

AU - Newcomb, Polly A.

AU - Offit, Kenneth

AU - Ogino, Shuji

AU - Onland-Moret, N. Charlotte

AU - Pardini, Barbara

AU - Parfrey, Patrick S.

AU - Pearlman, Rachel

AU - Perduca, Vittorio

AU - Pharoah, Paul D. P.

AU - Pinchev, Mila

AU - Platz, Elizabeth A.

AU - Prentice, Ross L.

AU - Pugh, Elizabeth

AU - Raskin, Leon

AU - Rennert, Gad

AU - Rennert, Hedy S.

AU - Riboli, Elio

AU - Rodríguez-Barranco, Miguel

AU - Romm, Jane

AU - Sakoda, Lori C.

AU - Schafmayer, Clemens

AU - Schoen, Robert E.

AU - Seminara, Daniela

AU - Shah, Mitul

AU - Shelford, Tameka

AU - Shin, Min-Ho

AU - Shulman, Katerina

AU - Sieri, Sabina

AU - Slattery, Martha L.

AU - Southey, Melissa C.

AU - Stadler, Zsofia K.

AU - Stegmaier, Christa

AU - Su, Yu-Ru

AU - Tangen, Catherine M.

AU - Thibodeau, Stephen N.

AU - Thomas, Duncan C.

AU - Thomas, Sushma S.

AU - Toland, Amanda E.

AU - Trichopoulou, Antonia

AU - Ulrich, Cornelia M.

AU - Van Den Berg, David J.

AU - van Duijnhoven, Franzel J. B.

AU - Van Guelpen, Bethany

AU - van Kranen, Henk

AU - Vijai, Joseph

AU - Visvanathan, Kala

AU - Vodicka, Pavel

AU - Vodickova, Ludmila

AU - Vymetalkova, Veronika

AU - Weigl, Korbinian

AU - Weinstein, Stephanie J.

AU - White, Emily

AU - Win, Aung Ko

AU - Wolf, C. Roland

AU - Wolk, Alicja

AU - Woods, Michael O.

AU - Wu, Anna H.

AU - Zaidi, Syed H.

AU - Zanke, Brent W.

AU - Zhang, Qing

AU - Zheng, Wei

AU - Scacheri, Peter C.

AU - Potter, John D.

AU - Bassik, Michael C.

AU - Kundaje, Anshul

AU - Casey, Graham

AU - Moreno, Victor

AU - Abecasis, Goncalo R.

AU - Nickerson, Deborah A.

AU - Gruber, Stephen B.

AU - Hsu, Li

AU - Peters, Ulrike

PY - 2019/1/1

Y1 - 2019/1/1

N2 - To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 −8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

AB - To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 −8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

KW - Aged

KW - Case-Control Studies

KW - Colorectal Neoplasms/genetics

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study/methods

KW - Genotype

KW - Humans

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide/genetics

KW - RNA, Long Noncoding/genetics

KW - Risk Factors

KW - Signal Transduction/genetics

UR - http://www.scopus.com/inward/record.url?scp=85058017067&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0286-6

DO - 10.1038/s41588-018-0286-6

M3 - Article

C2 - 30510241

SN - 1061-4036

VL - 51

SP - 76

EP - 87

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Discovery of common and rare genetic risk variants for colorectal cancer

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