Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

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Abstract

Genome-wide association (GWA) studies have thus far identified 10 loci at which common variants influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci, we conducted a meta-analysis of three GWA studies from the UK totalling 3,334 cases and 4,628 controls, followed by multiple validation analyses, involving a total of 18,095 CRC cases and 20,197 controls. We identified new associations at 4 CRC risk loci: 1q41 (rs6691170, OR=1.06, P=9.55x10 ^-10; rs6687758, OR=1.09, P=2.27x10 ^-9); 3q26.2 (rs10936599, OR=0.93, P=3.39x10 ^-8); 12q13.13 (rs11169552, OR=0.92, P=1.89x10 ^-10; rs7136702, OR=1.06, P=4.02=x10 ^-8); and 20q13.33 (rs4925386, OR=0.93, P=1.89x10 ^-10). As well as identifying multiple new CRC risk loci this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.

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Most cited references 11

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A genome-wide association study of global gene expression.

Anna L. Dixon, Liming Liang, Miriam Moffatt … (2007)

We have created a global map of the effects of polymorphism on gene expression in 400 children from families recruited through a proband with asthma. We genotyped 408,273 SNPs and identified expression quantitative trait loci from measurements of 54,675 transcripts representing 20,599 genes in Epstein-Barr virus-transformed lymphoblastoid cell lines. We found that 15,084 transcripts (28%) representing 6,660 genes had narrow-sense heritabilities (H2) > 0.3. We executed genome-wide association scans for these traits and found peak lod scores between 3.68 and 59.1. The most highly heritable traits were markedly enriched in Gene Ontology descriptors for response to unfolded protein (chaperonins and heat shock proteins), regulation of progression through the cell cycle, RNA processing, DNA repair, immune responses and apoptosis. SNPs that regulate expression of these genes are candidates in the study of degenerative diseases, malignancy, infection and inflammation. We have created a downloadable database to facilitate use of our findings in the mapping of complex disease loci.

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A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.

Kenneth R. Muir, Lynn Martin, Gabrielle Sellick … (2007)

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.

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Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24.

Brent Zanke, Celia MT Greenwood, Jagadish Rangrej … (2007)

Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 12 October 2016

Publication date (Electronic): 24 October 2010

Publication date (Print): November 2010

Publication date PMC-release: 07 November 2016

Volume: 42

Issue: 11

Pages: 973-977

Affiliations

[1 ]Section of Cancer Genetics, Institute of Cancer Research, Sutton, SM2 5NG, United Kingdom

[2 ]Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom

[3 ]Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Edinburgh EH4 2XU, United Kingdom

[4 ]Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN. United Kingdom

[5 ]Department of Clinical Pharmacology, Oxford University, Radcliffe Infirmary, Old Road Campus Research Building, Headington, Oxford, OX3 7DQ, United Kingdom

[6 ]Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

[7 ]Colorectal Cancer Unit, Cancer Research UK, St Mark's Hospital, Harrow HA1 3UJ, UK

[8 ]Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK

[9 ]Medical Genetics, St Mary's Hospital, Manchester M13 0JH, UK

[10 ]Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Institute of Biomedical Research, and West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Edgbaston, Birmingham B15 2TT, UK

[11 ]Department of Oncology and Palliative Care, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK

[12 ]Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva CH-1211, Switzerland

[13 ]Cancer Research UK Laboratories, Strangeways Research Laboratory Department of Oncology, University of Cambridge, Cambridge CB1 8RN, United Kingdom

[14 ]SIDRA Medical & Research Center, Qatar Foundation, PO Box 26999, Doha, Qatar

[15 ]Public Health Sciences, University of Edinburgh, EH8 9AG, United Kingdom

Author notes

[* ]Corresponding authors: Richard Houlston, Institute of Cancer Research, 15, Cotswold Rd, Sutton, Surrey SM2 5NG, UK. Tel: +44-(0)-208-722-4175. Fax: +44-(0)-208-722-4359. richard.houlston@ 123456icr.ac.uk

Malcolm Dunlop, Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK. Tel: +44 (0)-131-467-8454. Fax: +44 (0)-131-467-8450. malcolm.dunlop@ 123456hgu.mrc.ac.uk

Ian Tomlinson, Molecular and Population Genetics, Nuffield Dept. of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN. Tel: +44 (0)-1865-287832. Fax: +44 (0)-1865-287501. iant@ 123456well.ox.ac.uk

[16]

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Manuscript ID: EMS31870

DOI: 10.1038/ng.670

PMC ID: 5098601

PubMed ID: 20972440

SO-VID: ef251c9a-b343-4662-9fa2-e12b1e47a40f

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Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

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Most cited references 11

A genome-wide association study of global gene expression.

A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.

Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24.

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