A novel colorectal cancer risk locus at 4q32.2 identified from an international genomewide association study

Stephanie L. Schmit; Fredrick R. Schumacher; Christopher K. Edlund; David V. Conti; Leon Raskin; Flavio Lejbkowicz; Mila Pinchev; Hedy S. Rennert; Mark A. Jenkins; John L. Hopper; Daniel D. Buchanan; Noralane M. Lindor; Loic Le Marchand; Steven Gallinger; Robert W. Haile; Polly A. Newcomb; Shu Chen Huang; Gad Rennert; Graham Casey; Stephen B. Gruber

doi:10.1093/carcin/bgu148

A novel colorectal cancer risk locus at 4q32.2 identified from an international genomewide association study

Stephanie L. Schmit, Fredrick R. Schumacher, Christopher K. Edlund, David V. Conti, Leon Raskin, Flavio Lejbkowicz, Mila Pinchev, Hedy S. Rennert, Mark A. Jenkins, John L. Hopper, Daniel D. Buchanan, Noralane M. Lindor, Loic Le Marchand, Steven Gallinger, Robert W. Haile, Polly A. Newcomb, Shu Chen Huang, Gad Rennert, Graham Casey, Stephen B. Gruber

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Abstract

Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genomewide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10^-9; nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.

Original language	English (US)
Pages (from-to)	2512-2519
Number of pages	8
Journal	Carcinogenesis
Volume	35
Issue number	11
DOIs	https://doi.org/10.1093/carcin/bgu148
State	Published - Nov 1 2014

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Cancer Research

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Schmit, S. L., Schumacher, F. R., Edlund, C. K., Conti, D. V., Raskin, L., Lejbkowicz, F., Pinchev, M., Rennert, H. S., Jenkins, M. A., Hopper, J. L., Buchanan, D. D., Lindor, N. M., Le Marchand, L., Gallinger, S., Haile, R. W., Newcomb, P. A., Huang, S. C., Rennert, G., Casey, G., & Gruber, S. B. (2014). A novel colorectal cancer risk locus at 4q32.2 identified from an international genomewide association study. Carcinogenesis, 35(11), 2512-2519. https://doi.org/10.1093/carcin/bgu148

Schmit, SL, Schumacher, FR, Edlund, CK, Conti, DV, Raskin, L, Lejbkowicz, F, Pinchev, M, Rennert, HS, Jenkins, MA, Hopper, JL, Buchanan, DD, Lindor, NM, Le Marchand, L, Gallinger, S, Haile, RW, Newcomb, PA, Huang, SC, Rennert, G, Casey, G & Gruber, SB 2014, 'A novel colorectal cancer risk locus at 4q32.2 identified from an international genomewide association study', Carcinogenesis, vol. 35, no. 11, pp. 2512-2519. https://doi.org/10.1093/carcin/bgu148

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title = "A novel colorectal cancer risk locus at 4q32.2 identified from an international genomewide association study",

abstract = "Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genomewide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10-9; nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.",

author = "Schmit, {Stephanie L.} and Schumacher, {Fredrick R.} and Edlund, {Christopher K.} and Conti, {David V.} and Leon Raskin and Flavio Lejbkowicz and Mila Pinchev and Rennert, {Hedy S.} and Jenkins, {Mark A.} and Hopper, {John L.} and Buchanan, {Daniel D.} and Lindor, {Noralane M.} and {Le Marchand}, Loic and Steven Gallinger and Haile, {Robert W.} and Newcomb, {Polly A.} and Huang, {Shu Chen} and Gad Rennert and Graham Casey and Gruber, {Stephen B.}",

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AU - Conti, David V.

AU - Raskin, Leon

AU - Lejbkowicz, Flavio

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AU - Jenkins, Mark A.

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AU - Gallinger, Steven

AU - Haile, Robert W.

AU - Newcomb, Polly A.

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AU - Rennert, Gad

AU - Casey, Graham

AU - Gruber, Stephen B.

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N2 - Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genomewide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10-9; nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.

AB - Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genomewide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10-9; nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.

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A novel colorectal cancer risk locus at 4q32.2 identified from an international genomewide association study

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