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 |
|---|---|
| Journal | Journal of the National Cancer Institute |
| DOIs | |
| Publication status | E-pub ahead of print - Jun 16 2018 |
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer. / Schmit, Stephanie L; Edlund, Christopher K; Schumacher, Fredrick R; Gong, Jian; Harrison, Tabitha A; Huyghe, Jeroen R; Qu, Chenxu; Melas, Marilena; Van Den Berg, David J; Wang, Hansong; Tring, Stephanie; Plummer, Sarah J; Albanes, Demetrius; Alonso, M Henar; Amos, Christopher I; Anton, Kristen; Aragaki, Aaron K; Arndt, Volker; Barry, Elizabeth L; Berndt, Sonja I; Bezieau, Stéphane; Bien, Stephanie; Bloomer, Amanda; Boehm, Juergen; Boutron-Ruault, Marie-Christine; Brenner, Hermann; Brezina, Stefanie; Buchanan, Daniel D; Butterbach, Katja; Caan, Bette J; Campbell, Peter T; Carlson, Christopher S; Castelao, Jose E; Chan, Andrew T; Chang-Claude, Jenny; Chanock, Stephen J; Cheng, Iona; Cheng, Ya-Wen; Chin, Lee Soo; Church, James M; Church, Timothy; Coetzee, Gerhard A; Cotterchio, Michelle; Cruz Correa, Marcia; Curtis, Keith R; Duggan, David; Easton, Douglas F; English, Dallas; Feskens, Edith J M; Fischer, Rocky; FitzGerald, Liesel M; Fortini, Barbara K; Fritsche, Lars G; Fuchs, Charles S; Gago-Dominguez, Manuela; Gala, Manish; Gallinger, Steven J; Gauderman, W James; Giles, Graham G; Giovannucci, Edward L; Gogarten, Stephanie M; Gonzalez-Villalpando, Clicerio; Gonzalez-Villalpando, Elena M; Grady, William M; Greenson, Joel K; Gsur, Andrea; Gunter, Marc; Haiman, Christopher A; Hampe, Jochen; Harlid, Sophia; Harju, John F; Hayes, Richard B; Hofer, Philipp; Hoffmeister, Michael; Hopper, John L; Huang, Shu-Chen; Huerta, Jose Maria; Hudson, Thomas J; Hunter, David J; Idos, Gregory E; Iwasaki, Motoki; Jackson, Rebecca D; Jacobs, Eric J; Jee, Sun Ha; Jenkins, Mark A; Jia, Wei-Hua; Jiao, Shuo; Joshi, Amit D; Kolonel, Laurence N; Kono, Suminori; Kooperberg, Charles; Krogh, Vittorio; Kuehn, Tilman; Küry, Sébastien; LaCroix, Andrea; Laurie, Cecelia A; Lejbkowicz, Flavio; Lemire, Mathieu; Lenz, Heinz-Josef; Levine, David; Li, Christopher I; Li, Li; Lieb, Wolfgang; Lin, Yi; Lindor, Noralane M; Liu, Yun-Ru; Loupakis, Fotios; Lu, Yingchang; Luh, Frank; Ma, Jing; Mancao, Christoph; Manion, Frank J; Markowitz, Sanford D; Martin, Vicente; Matsuda, Koichi; Matsuo, Keitaro; McDonnell, Kevin J; McNeil, Caroline E; Milne, Roger; Molina, Antonio J; Mukherjee, Bhramar; Murphy, Neil; Newcomb, Polly A; Offit, Kenneth; Omichessan, Hanane; Palli, Domenico; Cotoré, Jesus P Paredes; Pérez-Mayoral, Julyann; Pharoah, Paul D; Potter, John D; Qu, Conghui; Raskin, Leon; Rennert, Gad; Rennert, Hedy S; Riggs, Bridget M; Schafmayer, Clemens; Schoen, Robert E; Sellers, Thomas A; Seminara, Daniela; Severi, Gianluca; Shi, Wei; Shibata, David; Shu, Xiao-Ou; Siegel, Erin M; Slattery, Martha L; Southey, Melissa; Stadler, Zsofia K; Stern, Mariana C; Stintzing, Sebastian; Taverna, Darin; Thibodeau, Stephen N; Thomas, Duncan C; Trichopoulou, Antonia; Tsugane, Shoichiro; Ulrich, Cornelia M; van Duijnhoven, Franzel J B; van Guelpan, Bethany; Vijai, Joseph; Virtamo, Jarmo; Weinstein, Stephanie J; White, Emily; Win, Aung Ko; Wolk, Alicja; Woods, Michael; Wu, Anna H; Wu, Kana; Xiang, Yong-Bing; Yen, Yun; Zanke, Brent W; Zeng, Yi-Xin; Zhang, Ben; Zubair, Niha; Kweon, Sun-Seog; Figueiredo, Jane C; Zheng, Wei; Marchand, Loic Le; Lindblom, Annika; Moreno, Victor; Peters, Ulrike; Casey, Graham; Hsu, Li; Conti, David V; Gruber, Stephen B.
In: Journal of the National Cancer Institute, 16.06.2018.Research output: Contribution to journal › Article › peer-review
}
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 - Cruz Correa, Marcia
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 - Cotoré, Jesus P Paredes
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 - Marchand, Loic Le
AU - Lindblom, Annika
AU - Moreno, Victor
AU - Peters, Ulrike
AU - Casey, Graham
AU - Hsu, Li
AU - Conti, David V
AU - Gruber, Stephen B
PY - 2018/6/16
Y1 - 2018/6/16
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.
U2 - 10.1093/jnci/djy099
DO - 10.1093/jnci/djy099
M3 - Article
C2 - 29917119
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
ER -