Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Stephanie L. Schmit, Christopher K. Edlund, Fredrick R. Schumacher, Jian Gong, Tabitha A. Harrison, Jeroen R. Huyghe, Chenxu Qu, Marilena Melas, David J. Van Den Berg, Hansong Wang, Stephanie Tring, Sarah J. Plummer, Demetrius Albanes, M. Henar Alonso, Christopher I. Amos, Kristen Anton, Aaron K. Aragaki, Volker Arndt, Elizabeth L. Barry, Sonja I. Berndt & 30 others Stéphane Bezieau, Stephanie Bien, Amanda Bloomer, Juergen Boehm, Marie Christine Boutron-Ruault, Hermann Brenner, Stefanie Brezina, Daniel D. Buchanan, Katja Butterbach, Bette J. Caan, Peter T. Campbell, Christopher S. Carlson, Jose E. Castelao, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Iona Cheng, Ya Wen Cheng, Lee Soo Chin, James M. Church, Timothy Church, Gerhard A. Coetzee, Michelle Cotterchio, Marcia Cruz Correa, Keith R. Curtis, David Duggan, Yi Lin, Yun Ru Liu, Yun Yen, Li Hsu

研究成果: 雜誌貢獻文章

12 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)146-157
頁數12
期刊Journal of the National Cancer Institute
111
發行號2
DOIs
出版狀態已發佈 - 二月 1 2019

指紋

Genetic Loci
Genetic Predisposition to Disease
Colorectal Neoplasms
Genome-Wide Association Study
Confidence Intervals
Asian Americans
Hispanic Americans
Gene Frequency
African Americans
Meta-Analysis
Logistic Models
Alleles
Odds Ratio
Genome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

引用此文

Schmit, S. L., Edlund, C. K., Schumacher, F. R., Gong, J., Harrison, T. A., Huyghe, J. R., ... Hsu, L. (2019). Novel Common Genetic Susceptibility Loci for Colorectal Cancer. Journal of the National Cancer Institute, 111(2), 146-157. https://doi.org/10.1093/jnci/djy099

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; Lin, Yi; Liu, Yun Ru; Yen, Yun; Hsu, Li.

於: Journal of the National Cancer Institute, 卷 111, 編號 2, 01.02.2019, p. 146-157.

研究成果: 雜誌貢獻文章

Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van Den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, MC, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, YW, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Cruz Correa, M, Curtis, KR, Duggan, D, Lin, Y, Liu, YR, Yen, Y & Hsu, L 2019, 'Novel Common Genetic Susceptibility Loci for Colorectal Cancer', Journal of the National Cancer Institute, 卷 111, 編號 2, 頁 146-157. https://doi.org/10.1093/jnci/djy099
Schmit SL, Edlund CK, Schumacher FR, Gong J, Harrison TA, Huyghe JR 等. Novel Common Genetic Susceptibility Loci for Colorectal Cancer. Journal of the National Cancer Institute. 2019 2月 1;111(2):146-157. https://doi.org/10.1093/jnci/djy099
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 ; Lin, Yi ; Liu, Yun Ru ; Yen, Yun ; Hsu, Li. / Novel Common Genetic Susceptibility Loci for Colorectal Cancer. 於: Journal of the National Cancer Institute. 2019 ; 卷 111, 編號 2. 頁 146-157.
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title = "Novel Common Genetic Susceptibility Loci for Colorectal Cancer",
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.",
author = "Schmit, {Stephanie L.} and Edlund, {Christopher K.} and Schumacher, {Fredrick R.} and Jian Gong and Harrison, {Tabitha A.} and Huyghe, {Jeroen R.} and Chenxu Qu and Marilena Melas and {Van Den Berg}, {David J.} and Hansong Wang and Stephanie Tring and Plummer, {Sarah J.} and Demetrius Albanes and Alonso, {M. Henar} and Amos, {Christopher I.} and Kristen Anton and Aragaki, {Aaron K.} and Volker Arndt and Barry, {Elizabeth L.} and Berndt, {Sonja I.} and St{\'e}phane Bezieau and Stephanie Bien and Amanda Bloomer and Juergen Boehm and Boutron-Ruault, {Marie Christine} and Hermann Brenner and Stefanie Brezina and Buchanan, {Daniel D.} and Katja Butterbach and Caan, {Bette J.} and Campbell, {Peter T.} and Carlson, {Christopher S.} and Castelao, {Jose E.} and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Iona Cheng and Cheng, {Ya Wen} and Chin, {Lee Soo} and Church, {James M.} and Timothy Church and Coetzee, {Gerhard A.} and Michelle Cotterchio and {Cruz Correa}, Marcia and Curtis, {Keith R.} and David Duggan and Yi Lin and Liu, {Yun Ru} and Yun Yen and Li Hsu",
year = "2019",
month = "2",
day = "1",
doi = "10.1093/jnci/djy099",
language = "English",
volume = "111",
pages = "146--157",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
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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 - Lin, Yi

AU - Liu, Yun Ru

AU - Yen, Yun

AU - Hsu, Li

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.

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