Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

Chenjie Zeng, Koichi Matsuda, Wei Hua Jia, Jiang Chang, Sun Seog Kweon, Yong Bing Xiang, Aesun Shin, Sun Ha Jee, Dong Hyun Kim, Ben Zhang, Qiuyin Cai, Xingyi Guo, Jirong Long, Nan Wang, Regina Courtney, Zhi Zhong Pan, Chen Wu, Atsushi Takahashi, Min Ho Shin, Keitaro MatsuoFumihiko Matsuda, Yu Tang Gao, Jae Hwan Oh, Soriul Kim, Keum Ji Jung, Yoon Ok Ahn, Zefang Ren, Hong Lan Li, Jie Wu, Jiajun Shi, Wanqing Wen, Gong Yang, Bingshan Li, Bu Tian Ji, Stephen B. Gruber, Fredrick R. Schumacher, Stephanie L. Stenzel, Graham Casey, John L. Hopper, Mark A. Jenkins, Hyeong Rok Kim, Jin Young Jeong, Ji Won Park, Kazuo Tajima, Sang Hee Cho, Michiaki Kubo, Xiao Ou Shu, Dongxin Lin, Yi Xin Zeng, Wei Zheng, Hermann Brenner, Robert E. Schoen, Sébastien Küry, John A. Baron, Sonja I. Berndt, Stéphane Bezieau, Bette J. Caan, Christopher S. Carlson, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, David V. Conti, Keith Curtis, David Duggan, Charles S. Fuchs, Steven Gallinger, Edward L. Giovannucci, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael Hoffmeister, Li Hsu, Thomas J. Hudson, David J. Hunter, Carolyn M. Hutter, Rebecca D. Jackson, Shuo Jiao, Loic Le Marchand, Mathieu Lemire, Noralane Morey Lindor, Jing Ma, Polly A. Newcomb, Ulrike Peters, John D. Potter, Conghui Qu, Daniela Seminara, Martha L. Slattery, Stephen N Thibodeau, Emily White, Brent W. Zanke, Kendra Blalock, Peter T. Campbell, Christopher K. Edlund, Jane Figueiredo, W. James Gauderman, Jian Gong, Roger C. Green, John F. Harju, Eric J. Jacobs, Li Li, Yi Lin, Frank J. Manion, Victor Moreno, Bhramar Mukherjee, Leon Raskin, Gianluca Severi, Duncan C. Thomas

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background & Aims Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. Methods This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. Results We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10-8 to 1.24 × 10-12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P <.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. Conclusions We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

Original languageEnglish (US)
Pages (from-to)1633-1645
Number of pages13
JournalGastroenterology
Volume150
Issue number7
DOIs
StatePublished - Jun 1 2016

Fingerprint

Colorectal Neoplasms
Genes
Prokaryotic Initiation Factor-3
Eukaryotic Initiation Factor-3
Eukaryotic Initiation Factors
Ryanodine Receptor Calcium Release Channel
Autophagy
Transcription Factors
Genome-Wide Association Study
Proteasome Endopeptidase Complex
Lysosomes
Ribosomes
Epigenomics
Proteolysis
Alleles
Steroids
Databases
Hormones
Gene Expression
Peptides

Keywords

  • Colon Cancer
  • Epidemiology
  • eQTL
  • Single Nucleotide Polymorphisms

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Zeng, C., Matsuda, K., Jia, W. H., Chang, J., Kweon, S. S., Xiang, Y. B., ... Thomas, D. C. (2016). Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. Gastroenterology, 150(7), 1633-1645. https://doi.org/10.1053/j.gastro.2016.02.076

Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. / Zeng, Chenjie; Matsuda, Koichi; Jia, Wei Hua; Chang, Jiang; Kweon, Sun Seog; Xiang, Yong Bing; Shin, Aesun; Jee, Sun Ha; Kim, Dong Hyun; Zhang, Ben; Cai, Qiuyin; Guo, Xingyi; Long, Jirong; Wang, Nan; Courtney, Regina; Pan, Zhi Zhong; Wu, Chen; Takahashi, Atsushi; Shin, Min Ho; Matsuo, Keitaro; Matsuda, Fumihiko; Gao, Yu Tang; Oh, Jae Hwan; Kim, Soriul; Jung, Keum Ji; Ahn, Yoon Ok; Ren, Zefang; Li, Hong Lan; Wu, Jie; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Li, Bingshan; Ji, Bu Tian; Gruber, Stephen B.; Schumacher, Fredrick R.; Stenzel, Stephanie L.; Casey, Graham; Hopper, John L.; Jenkins, Mark A.; Kim, Hyeong Rok; Jeong, Jin Young; Park, Ji Won; Tajima, Kazuo; Cho, Sang Hee; Kubo, Michiaki; Shu, Xiao Ou; Lin, Dongxin; Zeng, Yi Xin; Zheng, Wei; Brenner, Hermann; Schoen, Robert E.; Küry, Sébastien; Baron, John A.; Berndt, Sonja I.; Bezieau, Stéphane; Caan, Bette J.; Carlson, Christopher S.; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Conti, David V.; Curtis, Keith; Duggan, David; Fuchs, Charles S.; Gallinger, Steven; Giovannucci, Edward L.; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hsu, Li; Hudson, Thomas J.; Hunter, David J.; Hutter, Carolyn M.; Jackson, Rebecca D.; Jiao, Shuo; Le Marchand, Loic; Lemire, Mathieu; Lindor, Noralane Morey; Ma, Jing; Newcomb, Polly A.; Peters, Ulrike; Potter, John D.; Qu, Conghui; Seminara, Daniela; Slattery, Martha L.; Thibodeau, Stephen N; White, Emily; Zanke, Brent W.; Blalock, Kendra; Campbell, Peter T.; Edlund, Christopher K.; Figueiredo, Jane; Gauderman, W. James; Gong, Jian; Green, Roger C.; Harju, John F.; Jacobs, Eric J.; Li, Li; Lin, Yi; Manion, Frank J.; Moreno, Victor; Mukherjee, Bhramar; Raskin, Leon; Severi, Gianluca; Thomas, Duncan C.

In: Gastroenterology, Vol. 150, No. 7, 01.06.2016, p. 1633-1645.

Research output: Contribution to journalArticle

Zeng, C, Matsuda, K, Jia, WH, Chang, J, Kweon, SS, Xiang, YB, Shin, A, Jee, SH, Kim, DH, Zhang, B, Cai, Q, Guo, X, Long, J, Wang, N, Courtney, R, Pan, ZZ, Wu, C, Takahashi, A, Shin, MH, Matsuo, K, Matsuda, F, Gao, YT, Oh, JH, Kim, S, Jung, KJ, Ahn, YO, Ren, Z, Li, HL, Wu, J, Shi, J, Wen, W, Yang, G, Li, B, Ji, BT, Gruber, SB, Schumacher, FR, Stenzel, SL, Casey, G, Hopper, JL, Jenkins, MA, Kim, HR, Jeong, JY, Park, JW, Tajima, K, Cho, SH, Kubo, M, Shu, XO, Lin, D, Zeng, YX, Zheng, W, Brenner, H, Schoen, RE, Küry, S, Baron, JA, Berndt, SI, Bezieau, S, Caan, BJ, Carlson, CS, Chan, AT, Chang-Claude, J, Chanock, SJ, Conti, DV, Curtis, K, Duggan, D, Fuchs, CS, Gallinger, S, Giovannucci, EL, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hsu, L, Hudson, TJ, Hunter, DJ, Hutter, CM, Jackson, RD, Jiao, S, Le Marchand, L, Lemire, M, Lindor, NM, Ma, J, Newcomb, PA, Peters, U, Potter, JD, Qu, C, Seminara, D, Slattery, ML, Thibodeau, SN, White, E, Zanke, BW, Blalock, K, Campbell, PT, Edlund, CK, Figueiredo, J, Gauderman, WJ, Gong, J, Green, RC, Harju, JF, Jacobs, EJ, Li, L, Lin, Y, Manion, FJ, Moreno, V, Mukherjee, B, Raskin, L, Severi, G & Thomas, DC 2016, 'Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk', Gastroenterology, vol. 150, no. 7, pp. 1633-1645. https://doi.org/10.1053/j.gastro.2016.02.076
Zeng C, Matsuda K, Jia WH, Chang J, Kweon SS, Xiang YB et al. Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. Gastroenterology. 2016 Jun 1;150(7):1633-1645. https://doi.org/10.1053/j.gastro.2016.02.076
Zeng, Chenjie ; Matsuda, Koichi ; Jia, Wei Hua ; Chang, Jiang ; Kweon, Sun Seog ; Xiang, Yong Bing ; Shin, Aesun ; Jee, Sun Ha ; Kim, Dong Hyun ; Zhang, Ben ; Cai, Qiuyin ; Guo, Xingyi ; Long, Jirong ; Wang, Nan ; Courtney, Regina ; Pan, Zhi Zhong ; Wu, Chen ; Takahashi, Atsushi ; Shin, Min Ho ; Matsuo, Keitaro ; Matsuda, Fumihiko ; Gao, Yu Tang ; Oh, Jae Hwan ; Kim, Soriul ; Jung, Keum Ji ; Ahn, Yoon Ok ; Ren, Zefang ; Li, Hong Lan ; Wu, Jie ; Shi, Jiajun ; Wen, Wanqing ; Yang, Gong ; Li, Bingshan ; Ji, Bu Tian ; Gruber, Stephen B. ; Schumacher, Fredrick R. ; Stenzel, Stephanie L. ; Casey, Graham ; Hopper, John L. ; Jenkins, Mark A. ; Kim, Hyeong Rok ; Jeong, Jin Young ; Park, Ji Won ; Tajima, Kazuo ; Cho, Sang Hee ; Kubo, Michiaki ; Shu, Xiao Ou ; Lin, Dongxin ; Zeng, Yi Xin ; Zheng, Wei ; Brenner, Hermann ; Schoen, Robert E. ; Küry, Sébastien ; Baron, John A. ; Berndt, Sonja I. ; Bezieau, Stéphane ; Caan, Bette J. ; Carlson, Christopher S. ; Chan, Andrew T. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Conti, David V. ; Curtis, Keith ; Duggan, David ; Fuchs, Charles S. ; Gallinger, Steven ; Giovannucci, Edward L. ; Haile, Robert W. ; Harrison, Tabitha A. ; Hayes, Richard B. ; Hoffmeister, Michael ; Hsu, Li ; Hudson, Thomas J. ; Hunter, David J. ; Hutter, Carolyn M. ; Jackson, Rebecca D. ; Jiao, Shuo ; Le Marchand, Loic ; Lemire, Mathieu ; Lindor, Noralane Morey ; Ma, Jing ; Newcomb, Polly A. ; Peters, Ulrike ; Potter, John D. ; Qu, Conghui ; Seminara, Daniela ; Slattery, Martha L. ; Thibodeau, Stephen N ; White, Emily ; Zanke, Brent W. ; Blalock, Kendra ; Campbell, Peter T. ; Edlund, Christopher K. ; Figueiredo, Jane ; Gauderman, W. James ; Gong, Jian ; Green, Roger C. ; Harju, John F. ; Jacobs, Eric J. ; Li, Li ; Lin, Yi ; Manion, Frank J. ; Moreno, Victor ; Mukherjee, Bhramar ; Raskin, Leon ; Severi, Gianluca ; Thomas, Duncan C. / Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. In: Gastroenterology. 2016 ; Vol. 150, No. 7. pp. 1633-1645.
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abstract = "Background & Aims Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. Methods This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. Results We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10-8 to 1.24 × 10-12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10{\%}-18{\%} increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P <.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. Conclusions We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.",
keywords = "Colon Cancer, Epidemiology, eQTL, Single Nucleotide Polymorphisms",
author = "Chenjie Zeng and Koichi Matsuda and Jia, {Wei Hua} and Jiang Chang and Kweon, {Sun Seog} and Xiang, {Yong Bing} and Aesun Shin and Jee, {Sun Ha} and Kim, {Dong Hyun} and Ben Zhang and Qiuyin Cai and Xingyi Guo and Jirong Long and Nan Wang and Regina Courtney and Pan, {Zhi Zhong} and Chen Wu and Atsushi Takahashi and Shin, {Min Ho} and Keitaro Matsuo and Fumihiko Matsuda and Gao, {Yu Tang} and Oh, {Jae Hwan} and Soriul Kim and Jung, {Keum Ji} and Ahn, {Yoon Ok} and Zefang Ren and Li, {Hong Lan} and Jie Wu and Jiajun Shi and Wanqing Wen and Gong Yang and Bingshan Li and Ji, {Bu Tian} and Gruber, {Stephen B.} and Schumacher, {Fredrick R.} and Stenzel, {Stephanie L.} and Graham Casey and Hopper, {John L.} and Jenkins, {Mark A.} and Kim, {Hyeong Rok} and Jeong, {Jin Young} and Park, {Ji Won} and Kazuo Tajima and Cho, {Sang Hee} and Michiaki Kubo and Shu, {Xiao Ou} and Dongxin Lin and Zeng, {Yi Xin} and Wei Zheng and Hermann Brenner and Schoen, {Robert E.} and S{\'e}bastien K{\"u}ry and Baron, {John A.} and Berndt, {Sonja I.} and St{\'e}phane Bezieau and Caan, {Bette J.} and Carlson, {Christopher S.} and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Conti, {David V.} and Keith Curtis and David Duggan and Fuchs, {Charles S.} and Steven Gallinger and Giovannucci, {Edward L.} and Haile, {Robert W.} and Harrison, {Tabitha A.} and Hayes, {Richard B.} and Michael Hoffmeister and Li Hsu and Hudson, {Thomas J.} and Hunter, {David J.} and Hutter, {Carolyn M.} and Jackson, {Rebecca D.} and Shuo Jiao and {Le Marchand}, Loic and Mathieu Lemire and Lindor, {Noralane Morey} and Jing Ma and Newcomb, {Polly A.} and Ulrike Peters and Potter, {John D.} and Conghui Qu and Daniela Seminara and Slattery, {Martha L.} and Thibodeau, {Stephen N} and Emily White and Zanke, {Brent W.} and Kendra Blalock and Campbell, {Peter T.} and Edlund, {Christopher K.} and Jane Figueiredo and Gauderman, {W. James} and Jian Gong and Green, {Roger C.} and Harju, {John F.} and Jacobs, {Eric J.} and Li Li and Yi Lin and Manion, {Frank J.} and Victor Moreno and Bhramar Mukherjee and Leon Raskin and Gianluca Severi and Thomas, {Duncan C.}",
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TY - JOUR

T1 - Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

AU - Zeng, Chenjie

AU - Matsuda, Koichi

AU - Jia, Wei Hua

AU - Chang, Jiang

AU - Kweon, Sun Seog

AU - Xiang, Yong Bing

AU - Shin, Aesun

AU - Jee, Sun Ha

AU - Kim, Dong Hyun

AU - Zhang, Ben

AU - Cai, Qiuyin

AU - Guo, Xingyi

AU - Long, Jirong

AU - Wang, Nan

AU - Courtney, Regina

AU - Pan, Zhi Zhong

AU - Wu, Chen

AU - Takahashi, Atsushi

AU - Shin, Min Ho

AU - Matsuo, Keitaro

AU - Matsuda, Fumihiko

AU - Gao, Yu Tang

AU - Oh, Jae Hwan

AU - Kim, Soriul

AU - Jung, Keum Ji

AU - Ahn, Yoon Ok

AU - Ren, Zefang

AU - Li, Hong Lan

AU - Wu, Jie

AU - Shi, Jiajun

AU - Wen, Wanqing

AU - Yang, Gong

AU - Li, Bingshan

AU - Ji, Bu Tian

AU - Gruber, Stephen B.

AU - Schumacher, Fredrick R.

AU - Stenzel, Stephanie L.

AU - Casey, Graham

AU - Hopper, John L.

AU - Jenkins, Mark A.

AU - Kim, Hyeong Rok

AU - Jeong, Jin Young

AU - Park, Ji Won

AU - Tajima, Kazuo

AU - Cho, Sang Hee

AU - Kubo, Michiaki

AU - Shu, Xiao Ou

AU - Lin, Dongxin

AU - Zeng, Yi Xin

AU - Zheng, Wei

AU - Brenner, Hermann

AU - Schoen, Robert E.

AU - Küry, Sébastien

AU - Baron, John A.

AU - Berndt, Sonja I.

AU - Bezieau, Stéphane

AU - Caan, Bette J.

AU - Carlson, Christopher S.

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Conti, David V.

AU - Curtis, Keith

AU - Duggan, David

AU - Fuchs, Charles S.

AU - Gallinger, Steven

AU - Giovannucci, Edward L.

AU - Haile, Robert W.

AU - Harrison, Tabitha A.

AU - Hayes, Richard B.

AU - Hoffmeister, Michael

AU - Hsu, Li

AU - Hudson, Thomas J.

AU - Hunter, David J.

AU - Hutter, Carolyn M.

AU - Jackson, Rebecca D.

AU - Jiao, Shuo

AU - Le Marchand, Loic

AU - Lemire, Mathieu

AU - Lindor, Noralane Morey

AU - Ma, Jing

AU - Newcomb, Polly A.

AU - Peters, Ulrike

AU - Potter, John D.

AU - Qu, Conghui

AU - Seminara, Daniela

AU - Slattery, Martha L.

AU - Thibodeau, Stephen N

AU - White, Emily

AU - Zanke, Brent W.

AU - Blalock, Kendra

AU - Campbell, Peter T.

AU - Edlund, Christopher K.

AU - Figueiredo, Jane

AU - Gauderman, W. James

AU - Gong, Jian

AU - Green, Roger C.

AU - Harju, John F.

AU - Jacobs, Eric J.

AU - Li, Li

AU - Lin, Yi

AU - Manion, Frank J.

AU - Moreno, Victor

AU - Mukherjee, Bhramar

AU - Raskin, Leon

AU - Severi, Gianluca

AU - Thomas, Duncan C.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Background & Aims Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. Methods This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. Results We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10-8 to 1.24 × 10-12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P <.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. Conclusions We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

AB - Background & Aims Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. Methods This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. Results We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10-8 to 1.24 × 10-12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P <.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. Conclusions We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

KW - Colon Cancer

KW - Epidemiology

KW - eQTL

KW - Single Nucleotide Polymorphisms

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U2 - 10.1053/j.gastro.2016.02.076

DO - 10.1053/j.gastro.2016.02.076

M3 - Article

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