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 | 03 Dec 2018 |
| DOIs | |
| Publication status | Published - 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
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Discovery of common and rare genetic risk variants for colorectal cancer. / Huyghe, Jeroen R; Bien, Stephanie A; Harrison, Tabitha A; Kang, Hyun Min; Chen, Sai; Schmit, Stephanie L; Conti, David V; Qu, Conghui; Jeon, Jihyoun; Edlund, Christopher K; Greenside, Peyton; Wainberg, Michael; Schumacher, Fredrick R; Smith, Joshua D; Levine, David M; Nelson, Sarah C; Sinnott-Armstrong, Nasa A; Albanes, Demetrius; Alonso, M Henar; Anderson, Kristin; Arnau-Collell, Coral; Arndt, Volker; Bamia, Christina; Banbury, Barbara L; Baron, John A; Berndt, Sonja I; Bézieau, Stéphane; Bishop, D Timothy; Boehm, Juergen; Boeing, Heiner; Brenner, Hermann; Brezina, Stefanie; Buch, Stephan; Buchanan, Daniel D; Burnett-Hartman, Andrea; Butterbach, Katja; Caan, Bette J; Campbell, Peter T; Carlson, Christopher S; Castellví-Bel, Sergi; Chan, Andrew T; Chang-Claude, Jenny; Chanock, Stephen J; Chirlaque, Maria-Dolores; Cho, Sang Hee; Connolly, Charles M; Cross, Amanda J; Cuk, Katarina; Curtis, Keith R; de la Chapelle, Albert; Doheny, Kimberly F; Duggan, David; Easton, Douglas F; Elias, Sjoerd G; Elliott, Faye; English, Dallas R; Feskens, Edith J M; Figueiredo, Jane C; Fischer, Rocky; FitzGerald, Liesel M; Forman, David; Gala, Manish; Gallinger, Steven; Gauderman, W James; Giles, Graham G; Gillanders, Elizabeth; Gong, Jian; Goodman, Phyllis J; Grady, William M; Grove, John S; Gsur, Andrea; Gunter, Marc J; Haile, Robert W; Hampe, Jochen; Hampel, Heather; Harlid, Sophia; Hayes, Richard B; Hofer, Philipp; Hoffmeister, Michael; Hopper, John L; Hsu, Wan-Ling; Huang, Wen-Yi; Hudson, Thomas J; Hunter, David J; Ibañez-Sanz, Gemma; Idos, Gregory E; Ingersoll, Roxann; Jackson, Rebecca D; Jacobs, Eric J; Jenkins, Mark A; Joshi, Amit D; Joshu, Corinne E; Keku, Temitope O; Key, Timothy J; Kim, Hyeong Rok; Kobayashi, Emiko; Kolonel, Laurence N; Kooperberg, Charles; Kühn, Tilman; Küry, Sébastien; Kweon, Sun-Seog; Larsson, Susanna C; Laurie, Cecelia A; Le Marchand, Loic; Leal, Suzanne M; Lee, Soo Chin; Lejbkowicz, Flavio; Lemire, Mathieu; Li, Christopher I; Li, Li; Lieb, Wolfgang; Lin, Yi; Lindblom, Annika; Lindor, Noralane M; Ling, Hua; Louie, Tin L; Männistö, Satu; Markowitz, Sanford D; Martín, Vicente; Masala, Giovanna; McNeil, Caroline E; Melas, Marilena; Milne, Roger L; Moreno, Lorena; Murphy, Neil; Myte, Robin; Naccarati, Alessio; Newcomb, Polly A; Offit, Kenneth; Ogino, Shuji; Onland-Moret, N Charlotte; Pardini, Barbara; Parfrey, Patrick S; Pearlman, Rachel; Perduca, Vittorio; Pharoah, Paul D P; Pinchev, Mila; Platz, Elizabeth A; Prentice, Ross L; Pugh, Elizabeth; Raskin, Leon; Rennert, Gad; Rennert, Hedy S; Riboli, Elio; Rodríguez-Barranco, Miguel; Romm, Jane; Sakoda, Lori C; Schafmayer, Clemens; Schoen, Robert E; Seminara, Daniela; Shah, Mitul; Shelford, Tameka; Shin, Min-Ho; Shulman, Katerina; Sieri, Sabina; Slattery, Martha L; Southey, Melissa C; Stadler, Zsofia K; Stegmaier, Christa; Su, Yu-Ru; Tangen, Catherine M; Thibodeau, Stephen N; Thomas, Duncan C; Thomas, Sushma S; Toland, Amanda E; Trichopoulou, Antonia; Ulrich, Cornelia M; Van Den Berg, David J; van Duijnhoven, Franzel J B; Van Guelpen, Bethany; van Kranen, Henk; Vijai, Joseph; Visvanathan, Kala; Vodicka, Pavel; Vodickova, Ludmila; Vymetalkova, Veronika; Weigl, Korbinian; Weinstein, Stephanie J; White, Emily; Win, Aung Ko; Wolf, C Roland; Wolk, Alicja; Woods, Michael O; Wu, Anna H; Zaidi, Syed H; Zanke, Brent W; Zhang, Qing; Zheng, Wei; Scacheri, Peter C; Potter, John D; Bassik, Michael C; Kundaje, Anshul; Casey, Graham; Moreno, Victor; Abecasis, Goncalo R; Nickerson, Deborah A; Gruber, Stephen B; Hsu, Li; Peters, Ulrike.
In: Nature Genetics, Vol. 51, No. 1, 01.2019, p. 76-87.Research output: Contribution to journal › Article › peer-review
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
Y1 - 2019/1
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
U2 - 10.1038/s41588-018-0286-6
DO - 10.1038/s41588-018-0286-6
M3 - Article
C2 - 30510241
VL - 51
SP - 76
EP - 87
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 1
ER -