Résumé
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.
langue originale | Anglais |
---|---|
Pages (de - à) | 146-157 |
Nombre de pages | 12 |
journal | Journal of the National Cancer Institute |
Volume | 111 |
Numéro de publication | 2 |
Les DOIs | |
état | Publié - 1 févr. 2019 |
Modification externe | Oui |
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Dans: Journal of the National Cancer Institute, Vol 111, Numéro 2, 01.02.2019, p. 146-157.
Résultats de recherche: Contribution à un journal › Article › Revue par des pairs
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 - Correa, Marcia Cruz
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 - Paredes Cotoré, Jesus P.
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 - Le Marchand, Loic
AU - Lindblom, Annika
AU - Moreno, Victor
AU - Peters, Ulrike
AU - Casey, Graham
AU - Hsu, Li
AU - Conti, David V.
AU - Gruber, Stephen B.
N1 - Publisher Copyright: © The Author(s) 2018. Published by Oxford University Press. All rights reserved.
PY - 2019/2/1
Y1 - 2019/2/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85060758530&partnerID=8YFLogxK
U2 - 10.1093/jnci/djy099
DO - 10.1093/jnci/djy099
M3 - Article
C2 - 29917119
AN - SCOPUS:85060758530
SN - 0027-8874
VL - 111
SP - 146
EP - 157
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 2
ER -