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. 2015 Nov;134(11-12):1249-1262.
doi: 10.1007/s00439-015-1598-6. Epub 2015 Sep 24.

A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

Mathieu Lemire #  1 , Conghui Qu #  2 , Lenora W M Loo  3 , Syed H E Zaidi  1 , Hansong Wang  3 , Sonja I Berndt  4 , Stéphane Bézieau  5   6 , Hermann Brenner  7   8   9 , Peter T Campbell  10 , Andrew T Chan  11   12 , Jenny Chang-Claude  13 , Mengmeng Du  2 , Christopher K Edlund  14 , Steven Gallinger  15   16 , Robert W Haile  17 , Tabitha A Harrison  2 , Michael Hoffmeister  7 , John L Hopper  18 , Lifang Hou  19 , Li Hsu  2   20 , Eric J Jacobs  10 , Mark A Jenkins  18 , Jihyoun Jeon  2 , Sébastien Küry  5 , Li Li  21 , Noralane M Lindor  22 , Polly A Newcomb  2   23 , John D Potter  2   23   24 , Gad Rennert  25   26   27 , Anja Rudolph  13 , Robert E Schoen  28 , Fredrick R Schumacher  14 , Daniela Seminara  29 , Gianluca Severi  18   30   31 , Martha L Slattery  32 , Emily White  2   23 , Michael O Woods  33 , Michelle Cotterchio  34 , Loic Le Marchand  3 , Graham Casey  14 , Steven B Gruber  14   35 , Ulrike Peters  2   36 , Thomas J Hudson  1   37   38
Affiliations

A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

Mathieu Lemire et al. Hum Genet. 2015 Nov.

Abstract

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95% confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13%]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95% CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10(-8)).

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Figures

Figure 1
Figure 1. Count of risk alleles
Boxplot representation for the total count of risk alleles in cases and controls, stratified based on family history (FH).
Figure 2
Figure 2. Association results
(a) Manhattan plot of results in GECCO/CCFR. Controls with family history and/or polyps are excluded from the analysis. Each dot represents a SNP plotted on the x-axis relative to its position in the genome, whose level of significance is represented on the y-axis. Green dots represent SNPs in LD with SNPs identified in published GWAS for CRC. Replication in CORECT was attempted for SNPs with p<10−5 (blue horizontal line). The red horizontal line indicates p=5×10−8; (b) quantile-quantile plot of p-values in (a), on the negative log scale. λ is the inflation factor (the ratio of observed to expected median); (c) quantile-quantile plot of p-values when no controls are excluded from the analysis.
Figure 3
Figure 3. UCSC browser representation of the 14q23.1 locus
Window is centered at rs17094983 +/− 2Mbp. Top track indicates position of SNPs in LD with rs17094983 (r2>0.05) along with r2 values.
Figure 4
Figure 4. Expression of RTN1 in TCGA
(a) Boxplot representation of the expression of RTN1 in normal colon tissues and tumors. Significance calculated from Wilcoxon test. (b–d) Boxplot representations of the expression of RTN1 in tumors as a function of (b) rs17094971; (c) rs1432096; (d) rs710005. Significance calculated from Kruskal-Wallis tests.
Figure 5
Figure 5. Expression of RTN1 in CCFR
(a) Boxplot representation of the expression of RTN1 in normal colon tissues and tumors. Significance calculated from Wilcoxon test. (b–d) Boxplot representations of the expression of RTN1 in normal tissues as a function of (b) rs17094971; (c) rs1432096; (d) rs710005. Significance calculated from Kruskal-Wallis tests.
See this image and copyright information in PMC

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