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, 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

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.

Conflict of interest statement

Competing Interests Statement

Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest.

Figures

Figure 1. Conditionally independent association signals at…
Figure 1. Conditionally independent association signals at the BMP2 locus.
Regional association plot showing the unconditional −log10(P-value) for the association with CRC risk in the combined meta-analysis of up to 125,478 individuals, as a function of genomic position (Build 37) for each variant in the region. The lead variants are indicated by a diamond symbol and its positions are indicated by dashed vertical lines. The color-labeling and shape of all other variants indicate the lead variant with which they are in strongest LD. The two new genome-wide significant signals are indicated by an asterisk.
Figure 2. Functional genomic annotation of new…
Figure 2. Functional genomic annotation of new CRC risk locus overlapping KLF5 super-enhancer.
Top: Regional association plot showing the unconditional −log10(P-value) for the association with CRC risk in the combined meta-analysis of up to 125,478 individuals, as a function of genomic position (Build 37) for each variant in the region. The lead variants are indicated by a diamond symbol and its positions are indicated by dashed vertical lines. The color-labeling and shape of all other variants indicate the lead variant with which they are in strongest LD. Bottom: UCSC genome browser annotations for region overlapping the super-enhancer flanked by KLF5 and KLF12, and spanning variants in LD with rs78341008, and with two conditionally independent association signals indexed by rs45597035 and rs1924816. The region is annotated with the following tracks (from top to bottom): UCSC gene annotations; epigenomic profiles showing MACS2 peak calls as transparent overlays for different samples taken from non-diseased colonic crypt cells or colon tissue (purple) and from different primary CRC cell lines or tumor samples (teal); position of the lead variants and variants in LD with the lead; variants in the 99% credible set; the union of super-enhancers called using the ROSE package; gray bars highlight the targeted enhancers (e1,e3, and e4) previously shown by Zhang et al. to have combinatorial effects on KLF5 expression. ATAC-seq data newly generated for this study show high resolution annotation of putative binding regions within the active super-enhancer further fine-mapping putative causal variants at each of the three signals.
Figure 3. Recommended age to start CRC…
Figure 3. Recommended age to start CRC screening based on a polygenic risk score (PRS).
The PRS was constructed using the 95 known and newly discovered variants. The horizontal lines represent the recommended age for the first endoscopy for an average-risk person in the current screening guideline for CRC. The risk threshold to determine the age for the first screening was set as the average of 10-year CRC risks for a 50-year-old man (1.25%) and woman (0.68%), i.e. (1.25%+0.68%)/2 = 0.97%, who have not previously received an endoscopy. Details are given in the Online Methods.

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