Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Ceres Fernandez-Rozadilla; Maria Timofeeva; Zhishan Chen; Philip Law; Minta Thomas; Stephanie Schmit; Virginia Díez-Obrero; Li Hsu; Juan Fernandez-Tajes; Claire Palles; Kitty Sherwood; Sarah Briggs; Victoria Svinti; Kevin Donnelly; Susan Farrington; James Blackmur; Peter Vaughan-Shaw; Xiao ou Shu; Jirong Long; Qiuyin Cai; Xingyi Guo; Yingchang Lu; Peter Broderick; James Studd; Jeroen Huyghe; Tabitha Harrison; David Conti; Christopher Dampier; Mathew Devall; Fredrick Schumacher; Marilena Melas; Gad Rennert; Mireia Obón-Santacana; Vicente Martín-Sánchez; Ferran Moratalla-Navarro; Jae Hwan Oh; Jeongseon Kim; Sun Ha Jee; Keum Ji Jung; Sun Seog Kweon; Min Ho Shin; Aesun Shin; Yoon Ok Ahn; Dong Hyun Kim; Isao Oze; Wanqing Wen; Keitaro Matsuo; Koichi Matsuda; Chizu Tanikawa; Zefang Ren; Yu Tang Gao; Wei Hua Jia; John Hopper; Mark Jenkins; Aung Ko Win; Rish Pai; Jane Figueiredo; Robert Haile; Steven Gallinger; Michael Woods; Polly Newcomb; David Duggan; Jeremy Cheadle; Richard Kaplan; Timothy Maughan; Rachel Kerr; David Kerr; Iva Kirac; Jan Böhm; Lukka Pekka Mecklin; Pekka Jousilahti; Paul Knekt; Lauri Aaltonen; Harri Rissanen; Eero Pukkala; Johan Eriksson; Tatiana Cajuso; Ulrika Hänninen; Johanna Kondelin; Kimmo Palin; Tomas Tanskanen; Laura Renkonen-Sinisalo; Brent Zanke; Satu Männistö; Demetrius Albanes; Stephanie Weinstein; Edward Ruiz-Narvaez; Julie Palmer; Daniel Buchanan; Elizabeth Platz; Kala Visvanathan; Cornelia Ulrich; Erin Siegel; Stefanie Brezina; Andrea Gsur; Peter Campbell; Jenny Chang-Claude; Michael Hoffmeister; Hermann Brenner; Martha Slattery; John Potter; Konstantinos Tsilidis; Matthias Schulze; Marc Gunter; Neil Murphy; Antoni Castells; Sergi Castellví-Bel; Leticia Moreira; Volker Arndt; Anna Shcherbina; Mariana Stern; Bens Pardamean; Timothy Bishop; Graham Giles; Melissa Southey; Gregory Idos; Kevin McDonnell; Zomoroda Abu-Ful; Joel Greenson; Katerina Shulman; Flavio Lejbkowicz; Kenneth Offit; Yu Ru Su; Robert Steinfelder; Temitope Keku; Bethany van Guelpen; Thomas Hudson; Heather Hampel; Rachel Pearlman; Sonja Berndt; Richard Hayes; Marie Elena Martinez; Sushma Thomas; Douglas Corley; Paul Pharoah; Susanna Larsson; Yun Yen; Heinz Josef Lenz; Emily White; Li Li; Kimberly Doheny; Elizabeth Pugh; Tameka Shelford; Andrew Chan; Marcia Cruz-Correa; Annika Lindblom; David Hunter; Amit Joshi; Clemens Schafmayer; Peter Scacheri; Anshul Kundaje; Deborah Nickerson; Robert Schoen; Jochen Hampe; Zsofia Stadler; Pavel Vodicka; Ludmila Vodickova; Veronika Vymetalkova; Nickolas Papadopoulos; Chistopher Edlund; William Gauderman; Duncan Thomas; David Shibata; Amanda Toland; Sanford Markowitz; Andre Kim; Stephen Chanock; Franzel van Duijnhoven; Edith Feskens; Lori Sakoda; Manuela Gago-Dominguez; Alicja Wolk; Alessio Naccarati; Barbara Pardini; Liesel FitzGerald; Soo Chin Lee; Shuji Ogino; Stephanie Bien; Charles Kooperberg; Christopher Li; Yi Lin; Ross Prentice; Conghui Qu; Stéphane Bézieau; Catherine Tangen; Elaine Mardis; Taiki Yamaji; Norie Sawada; Motoki Iwasaki; Christopher Haiman; Loic Le Marchand; Anna Wu; Chenxu Qu; Caroline McNeil; Gerhard Coetzee; Caroline Hayward; Ian Deary; Sarah Harris; Evropi Theodoratou; Stuart Reid; Marion Walker; Li Yin Ooi; Victor Moreno; Graham Casey; Stephen Gruber; Ian Tomlinson; Wei Zheng; Malcolm Dunlop; Richard Houlston; Ulrike Peters

doi:10.1038/s41588-022-01222-9

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Ceres Fernandez-Rozadilla, Maria Timofeeva, Zhishan Chen, Philip Law, Minta Thomas, Stephanie Schmit, Virginia Díez-Obrero, Li Hsu, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah Briggs, Victoria Svinti, Kevin Donnelly, Susan Farrington, James Blackmur, Peter Vaughan-Shaw, Xiao ou Shu, Jirong Long, Qiuyin CaiXingyi Guo, Yingchang Lu, Peter Broderick, James Studd, Jeroen Huyghe, Tabitha Harrison, David Conti, Christopher Dampier, Mathew Devall, Fredrick Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Ferran Moratalla-Navarro, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun Seog Kweon, Min Ho Shin, Aesun Shin, Yoon Ok Ahn, Dong Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu Tang Gao, Wei Hua Jia, John Hopper, Mark Jenkins, Aung Ko Win, Rish Pai, Jane Figueiredo, Robert Haile, Steven Gallinger, Michael Woods, Polly Newcomb, David Duggan, Jeremy Cheadle, Richard Kaplan, Timothy Maughan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Lukka Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri Aaltonen, Harri Rissanen, Eero Pukkala, Johan Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Brent Zanke, Satu Männistö, Demetrius Albanes, Stephanie Weinstein, Edward Ruiz-Narvaez, Julie Palmer, Daniel Buchanan, Elizabeth Platz, Kala Visvanathan, Cornelia Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha Slattery, John Potter, Konstantinos Tsilidis, Matthias Schulze, Marc Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, Mariana Stern, Bens Pardamean, Timothy Bishop, Graham Giles, Melissa Southey, Gregory Idos, Kevin McDonnell, Zomoroda Abu-Ful, Joel Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu Ru Su, Robert Steinfelder, Temitope Keku, Bethany van Guelpen, Thomas Hudson, Heather Hampel, Rachel Pearlman, Sonja Berndt, Richard Hayes, Marie Elena Martinez, Sushma Thomas, Douglas Corley, Paul Pharoah, Susanna Larsson, Yun Yen, Heinz Josef Lenz, Emily White, Li Li, Kimberly Doheny, Elizabeth Pugh, Tameka Shelford, Andrew Chan, Marcia Cruz-Correa, Annika Lindblom, David Hunter, Amit Joshi, Clemens Schafmayer, Peter Scacheri, Anshul Kundaje, Deborah Nickerson, Robert Schoen, Jochen Hampe, Zsofia Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Nickolas Papadopoulos, Chistopher Edlund, William Gauderman, Duncan Thomas, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen Chanock, Franzel van Duijnhoven, Edith Feskens, Lori Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Alessio Naccarati, Barbara Pardini, Liesel FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie Bien, Charles Kooperberg, Christopher Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Catherine Tangen, Elaine Mardis, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Christopher Haiman, Loic Le Marchand, Anna Wu, Chenxu Qu, Caroline McNeil, Gerhard Coetzee, Caroline Hayward, Ian Deary, Sarah Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Victor Moreno, Graham Casey, Stephen Gruber, Ian Tomlinson, Wei Zheng, Malcolm Dunlop, Richard Houlston, Ulrike Peters

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

71 Citations (Scopus)

Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Original language	English
Pages (from-to)	89-99
Number of pages	11
Journal	Nature Genetics
Volume	55
Issue number	1
DOIs	https://doi.org/10.1038/s41588-022-01222-9
Publication status	Published - Jan 2023

ASJC Scopus subject areas

Genetics

UN SDGs

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

Access to Document

10.1038/s41588-022-01222-9

Cite this

Fernandez-Rozadilla, C., Timofeeva, M., Chen, Z., Law, P., Thomas, M., Schmit, S., Díez-Obrero, V., Hsu, L., Fernandez-Tajes, J., Palles, C., Sherwood, K., Briggs, S., Svinti, V., Donnelly, K., Farrington, S., Blackmur, J., Vaughan-Shaw, P., Shu, X. O., Long, J., ... Peters, U. (2023). Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries. Nature Genetics, 55(1), 89-99. https://doi.org/10.1038/s41588-022-01222-9

Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Schmit, S, Díez-Obrero, V, Hsu, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Briggs, S, Svinti, V, Donnelly, K, Farrington, S, Blackmur, J, Vaughan-Shaw, P, Shu, XO, Long, J, Cai, Q, Guo, X, Lu, Y, Broderick, P, Studd, J, Huyghe, J, Harrison, T, Conti, D, Dampier, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obón-Santacana, M, Martín-Sánchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, SS, Shin, MH, Shin, A, Ahn, YO, Kim, DH, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, YT, Jia, WH, Hopper, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Duggan, D, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Böhm, J, Mecklin, LP, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hänninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Männistö, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Potter, J, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellví-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, McDonnell, K, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, YR, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, HJ, White, E, Li, L, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Hunter, D, Joshi, A, Schafmayer, C, Scacheri, P, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Shibata, D, Toland, A, Markowitz, S, Kim, A, Chanock, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Bien, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bézieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Haiman, C, Le Marchand, L, Wu, A, Qu, C, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Harris, S, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Gruber, S, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R & Peters, U 2023, 'Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries', Nature Genetics, vol. 55, no. 1, pp. 89-99. https://doi.org/10.1038/s41588-022-01222-9

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title = "Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries",

abstract = "Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.",

author = "Ceres Fernandez-Rozadilla and Maria Timofeeva and Zhishan Chen and Philip Law and Minta Thomas and Stephanie Schmit and Virginia D{\'i}ez-Obrero and Li Hsu and Juan Fernandez-Tajes and Claire Palles and Kitty Sherwood and Sarah Briggs and Victoria Svinti and Kevin Donnelly and Susan Farrington and James Blackmur and Peter Vaughan-Shaw and Shu, {Xiao ou} and Jirong Long and Qiuyin Cai and Xingyi Guo and Yingchang Lu and Peter Broderick and James Studd and Jeroen Huyghe and Tabitha Harrison and David Conti and Christopher Dampier and Mathew Devall and Fredrick Schumacher and Marilena Melas and Gad Rennert and Mireia Ob{\'o}n-Santacana and Vicente Mart{\'i}n-S{\'a}nchez and Ferran Moratalla-Navarro and Oh, {Jae Hwan} and Jeongseon Kim and Jee, {Sun Ha} and Jung, {Keum Ji} and Kweon, {Sun Seog} and Shin, {Min Ho} and Aesun Shin and Ahn, {Yoon Ok} and Kim, {Dong Hyun} and Isao Oze and Wanqing Wen and Keitaro Matsuo and Koichi Matsuda and Chizu Tanikawa and Zefang Ren and Gao, {Yu Tang} and Jia, {Wei Hua} and John Hopper and Mark Jenkins and Win, {Aung Ko} and Rish Pai and Jane Figueiredo and Robert Haile and Steven Gallinger and Michael Woods and Polly Newcomb and David Duggan and Jeremy Cheadle and Richard Kaplan and Timothy Maughan and Rachel Kerr and David Kerr and Iva Kirac and Jan B{\"o}hm and Mecklin, {Lukka Pekka} and Pekka Jousilahti and Paul Knekt and Lauri Aaltonen and Harri Rissanen and Eero Pukkala and Johan Eriksson and Tatiana Cajuso and Ulrika H{\"a}nninen and Johanna Kondelin and Kimmo Palin and Tomas Tanskanen and Laura Renkonen-Sinisalo and Brent Zanke and Satu M{\"a}nnist{\"o} and Demetrius Albanes and Stephanie Weinstein and Edward Ruiz-Narvaez and Julie Palmer and Daniel Buchanan and Elizabeth Platz and Kala Visvanathan and Cornelia Ulrich and Erin Siegel and Stefanie Brezina and Andrea Gsur and Peter Campbell and Jenny Chang-Claude and Michael Hoffmeister and Hermann Brenner and Martha Slattery and John Potter and Konstantinos Tsilidis and Matthias Schulze and Marc Gunter and Neil Murphy and Antoni Castells and Sergi Castellv{\'i}-Bel and Leticia Moreira and Volker Arndt and Anna Shcherbina and Mariana Stern and Bens Pardamean and Timothy Bishop and Graham Giles and Melissa Southey and Gregory Idos and Kevin McDonnell and Zomoroda Abu-Ful and Joel Greenson and Katerina Shulman and Flavio Lejbkowicz and Kenneth Offit and Su, {Yu Ru} and Robert Steinfelder and Temitope Keku and {van Guelpen}, Bethany and Thomas Hudson and Heather Hampel and Rachel Pearlman and Sonja Berndt and Richard Hayes and Martinez, {Marie Elena} and Sushma Thomas and Douglas Corley and Paul Pharoah and Susanna Larsson and Yun Yen and Lenz, {Heinz Josef} and Emily White and Li Li and Kimberly Doheny and Elizabeth Pugh and Tameka Shelford and Andrew Chan and Marcia Cruz-Correa and Annika Lindblom and David Hunter and Amit Joshi and Clemens Schafmayer and Peter Scacheri and Anshul Kundaje and Deborah Nickerson and Robert Schoen and Jochen Hampe and Zsofia Stadler and Pavel Vodicka and Ludmila Vodickova and Veronika Vymetalkova and Nickolas Papadopoulos and Chistopher Edlund and William Gauderman and Duncan Thomas and David Shibata and Amanda Toland and Sanford Markowitz and Andre Kim and Stephen Chanock and {van Duijnhoven}, Franzel and Edith Feskens and Lori Sakoda and Manuela Gago-Dominguez and Alicja Wolk and Alessio Naccarati and Barbara Pardini and Liesel FitzGerald and Lee, {Soo Chin} and Shuji Ogino and Stephanie Bien and Charles Kooperberg and Christopher Li and Yi Lin and Ross Prentice and Conghui Qu and St{\'e}phane B{\'e}zieau and Catherine Tangen and Elaine Mardis and Taiki Yamaji and Norie Sawada and Motoki Iwasaki and Christopher Haiman and {Le Marchand}, Loic and Anna Wu and Chenxu Qu and Caroline McNeil and Gerhard Coetzee and Caroline Hayward and Ian Deary and Sarah Harris and Evropi Theodoratou and Stuart Reid and Marion Walker and Ooi, {Li Yin} and Victor Moreno and Graham Casey and Stephen Gruber and Ian Tomlinson and Wei Zheng and Malcolm Dunlop and Richard Houlston and Ulrike Peters",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = jan,

doi = "10.1038/s41588-022-01222-9",

language = "English",

volume = "55",

pages = "89--99",

journal = "Nature Genetics",

issn = "1061-4036",

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TY - JOUR

T1 - Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

AU - Fernandez-Rozadilla, Ceres

AU - Timofeeva, Maria

AU - Chen, Zhishan

AU - Law, Philip

AU - Thomas, Minta

AU - Schmit, Stephanie

AU - Díez-Obrero, Virginia

AU - Hsu, Li

AU - Fernandez-Tajes, Juan

AU - Palles, Claire

AU - Sherwood, Kitty

AU - Briggs, Sarah

AU - Svinti, Victoria

AU - Donnelly, Kevin

AU - Farrington, Susan

AU - Blackmur, James

AU - Vaughan-Shaw, Peter

AU - Shu, Xiao ou

AU - Long, Jirong

AU - Cai, Qiuyin

AU - Guo, Xingyi

AU - Lu, Yingchang

AU - Broderick, Peter

AU - Studd, James

AU - Huyghe, Jeroen

AU - Harrison, Tabitha

AU - Conti, David

AU - Dampier, Christopher

AU - Devall, Mathew

AU - Schumacher, Fredrick

AU - Melas, Marilena

AU - Rennert, Gad

AU - Obón-Santacana, Mireia

AU - Martín-Sánchez, Vicente

AU - Moratalla-Navarro, Ferran

AU - Oh, Jae Hwan

AU - Kim, Jeongseon

AU - Jee, Sun Ha

AU - Jung, Keum Ji

AU - Kweon, Sun Seog

AU - Shin, Min Ho

AU - Shin, Aesun

AU - Ahn, Yoon Ok

AU - Kim, Dong Hyun

AU - Oze, Isao

AU - Wen, Wanqing

AU - Matsuo, Keitaro

AU - Matsuda, Koichi

AU - Tanikawa, Chizu

AU - Ren, Zefang

AU - Gao, Yu Tang

AU - Jia, Wei Hua

AU - Hopper, John

AU - Jenkins, Mark

AU - Win, Aung Ko

AU - Pai, Rish

AU - Figueiredo, Jane

AU - Haile, Robert

AU - Gallinger, Steven

AU - Woods, Michael

AU - Newcomb, Polly

AU - Duggan, David

AU - Cheadle, Jeremy

AU - Kaplan, Richard

AU - Maughan, Timothy

AU - Kerr, Rachel

AU - Kerr, David

AU - Kirac, Iva

AU - Böhm, Jan

AU - Mecklin, Lukka Pekka

AU - Jousilahti, Pekka

AU - Knekt, Paul

AU - Aaltonen, Lauri

AU - Rissanen, Harri

AU - Pukkala, Eero

AU - Eriksson, Johan

AU - Cajuso, Tatiana

AU - Hänninen, Ulrika

AU - Kondelin, Johanna

AU - Palin, Kimmo

AU - Tanskanen, Tomas

AU - Renkonen-Sinisalo, Laura

AU - Zanke, Brent

AU - Männistö, Satu

AU - Albanes, Demetrius

AU - Weinstein, Stephanie

AU - Ruiz-Narvaez, Edward

AU - Palmer, Julie

AU - Buchanan, Daniel

AU - Platz, Elizabeth

AU - Visvanathan, Kala

AU - Ulrich, Cornelia

AU - Siegel, Erin

AU - Brezina, Stefanie

AU - Gsur, Andrea

AU - Campbell, Peter

AU - Chang-Claude, Jenny

AU - Hoffmeister, Michael

AU - Brenner, Hermann

AU - Slattery, Martha

AU - Potter, John

AU - Tsilidis, Konstantinos

AU - Schulze, Matthias

AU - Gunter, Marc

AU - Murphy, Neil

AU - Castells, Antoni

AU - Castellví-Bel, Sergi

AU - Moreira, Leticia

AU - Arndt, Volker

AU - Shcherbina, Anna

AU - Stern, Mariana

AU - Pardamean, Bens

AU - Bishop, Timothy

AU - Giles, Graham

AU - Southey, Melissa

AU - Idos, Gregory

AU - McDonnell, Kevin

AU - Abu-Ful, Zomoroda

AU - Greenson, Joel

AU - Shulman, Katerina

AU - Lejbkowicz, Flavio

AU - Offit, Kenneth

AU - Su, Yu Ru

AU - Steinfelder, Robert

AU - Keku, Temitope

AU - van Guelpen, Bethany

AU - Hudson, Thomas

AU - Hampel, Heather

AU - Pearlman, Rachel

AU - Berndt, Sonja

AU - Hayes, Richard

AU - Martinez, Marie Elena

AU - Thomas, Sushma

AU - Corley, Douglas

AU - Pharoah, Paul

AU - Larsson, Susanna

AU - Yen, Yun

AU - Lenz, Heinz Josef

AU - White, Emily

AU - Li, Li

AU - Doheny, Kimberly

AU - Pugh, Elizabeth

AU - Shelford, Tameka

AU - Chan, Andrew

AU - Cruz-Correa, Marcia

AU - Lindblom, Annika

AU - Hunter, David

AU - Joshi, Amit

AU - Schafmayer, Clemens

AU - Scacheri, Peter

AU - Kundaje, Anshul

AU - Nickerson, Deborah

AU - Schoen, Robert

AU - Hampe, Jochen

AU - Stadler, Zsofia

AU - Vodicka, Pavel

AU - Vodickova, Ludmila

AU - Vymetalkova, Veronika

AU - Papadopoulos, Nickolas

AU - Edlund, Chistopher

AU - Gauderman, William

AU - Thomas, Duncan

AU - Shibata, David

AU - Toland, Amanda

AU - Markowitz, Sanford

AU - Kim, Andre

AU - Chanock, Stephen

AU - van Duijnhoven, Franzel

AU - Feskens, Edith

AU - Sakoda, Lori

AU - Gago-Dominguez, Manuela

AU - Wolk, Alicja

AU - Naccarati, Alessio

AU - Pardini, Barbara

AU - FitzGerald, Liesel

AU - Lee, Soo Chin

AU - Ogino, Shuji

AU - Bien, Stephanie

AU - Kooperberg, Charles

AU - Li, Christopher

AU - Lin, Yi

AU - Prentice, Ross

AU - Qu, Conghui

AU - Bézieau, Stéphane

AU - Tangen, Catherine

AU - Mardis, Elaine

AU - Yamaji, Taiki

AU - Sawada, Norie

AU - Iwasaki, Motoki

AU - Haiman, Christopher

AU - Le Marchand, Loic

AU - Wu, Anna

AU - Qu, Chenxu

AU - McNeil, Caroline

AU - Coetzee, Gerhard

AU - Hayward, Caroline

AU - Deary, Ian

AU - Harris, Sarah

AU - Theodoratou, Evropi

AU - Reid, Stuart

AU - Walker, Marion

AU - Ooi, Li Yin

AU - Moreno, Victor

AU - Casey, Graham

AU - Gruber, Stephen

AU - Tomlinson, Ian

AU - Zheng, Wei

AU - Dunlop, Malcolm

AU - Houlston, Richard

AU - Peters, Ulrike

PY - 2023/1

Y1 - 2023/1

N2 - Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

AB - Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

UR - http://www.scopus.com/inward/record.url?scp=85144441436&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85144441436&partnerID=8YFLogxK

U2 - 10.1038/s41588-022-01222-9

DO - 10.1038/s41588-022-01222-9

M3 - Article

C2 - 36539618

AN - SCOPUS:85144441436

SN - 1061-4036

VL - 55

SP - 89

EP - 99

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

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UN SDGs

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