Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

Tenesa, Albert; Farrington, Susan M.; Prendergast, James; Porteous, Mary; Walker, Marion; Haq, Naila; Barnetson, Rebecca A.; Τheodoratou, Evropi; Cetnarskyj, Roseanne; Cartwright, Nicola; Semple, Colin A.; Clark, A. J.; Reid, Fiona; Smith, Lorna; Kavoussanakis, Kostas; Koessler, Thibaud; Pharoah, Paul D.P.; Buch, Stephan; Schafmayer, Clemens; Tepel, Jürgen; Schreiber, Stefan; Völzke, Henry; Schmidt, Carsten Oliver; Chang‐Claude, Jenny; Hoffmeister, Michael; Brenner, Hermann; Wilkening, Stefan; Canzian, Federico; Capellà, Gabriel; Moreno, Vı́ctor; Deary, Ian J.; Starr, John M.; Tomlinson, Ian; Kemp, Zoe; Howarth, Kimberley; Carvajal‐Carmona, Luis G.; Webb, Emily L.; Broderick, Peter; Vijayakrishnan, Jayaram; Houlston, Richard S.; Rennert, Gad; Ballinger, Dennis G.; Rozek, Laura S.; Gruber, Stephen B.; Matsuda, Koichi; Kidokoro, Tetsuo; Nakamura, Yusuke; Zanke, Brent W.; Greenwood, Celia M.T.; Rangrej, Jagadish; Kustra, Rafal; Montpetit, Alexandre; Hudson, Thomas J.; Gallinger, Steven; Campbell, Harry; Dunlop, Malcolm G.

doi:10.1038/ng.133

Cited by 538 publications

(463 citation statements)

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“…This assertion has recently been vindicated by genome-wide association (GWA) studies, which have provided robust evidence for several common low-risk variants influencing CRC risk (Tomlinson et al, 2005Broderick et al, 2007;Zanke et al, 2007;Houlston et al, 2008;Jaeger et al, 2008;Tenesa et al, 2008). Although the risk of CRC associated with each of these common variants is individually modest, they make a significant contribution to the overall disease burden by virtue of their high frequencies in the population.…”

Section: Introductionmentioning

confidence: 99%

“…Three GWA studies of CRC have so far been reported and 10 independent loci shown conclusively to be associated with CRC risk: 8q24.21, 11q23, 18q21.1 (SMAD7), 8q23.1 (EIF3H), 15q (GREM1), 19q13.1 (RHPN2), 20q12.3, 14q22.2 (BMP4), 16q22.1 (CDH1) and 10p14 (Tomlinson et al, 2005Broderick et al, 2007;Zanke et al, 2007;Houlston et al, 2008;Jaeger et al, 2008;Tenesa et al, 2008). Risks associated with each of the common variants at each of these loci are modest (ORs 1.1 -1.3; Table 2) and there is little evidence of interactive effects.…”

Section: Characteristics Of Low-penetrance Variantsmentioning

confidence: 99%

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COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Tomlinson¹,

Dunlop²,

Campbell³

et al. 2009

Br J Cancer

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It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

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Section: Introductionmentioning

confidence: 99%

Section: Characteristics Of Low-penetrance Variantsmentioning

confidence: 99%

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Tomlinson¹,

Dunlop²,

Campbell³

et al. 2009

Br J Cancer

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“…Genotyping was conducted using Illumina HumanHap300 and Illumina Human-Hap240S arrays according to established protocols. 7 …”

Section: British Cases and Controlsmentioning

confidence: 99%

Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene

Elstner

Morris

Heim

et al. 2009

Annals of Neurology

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Objective-The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined.Methods-We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts.Results-We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10 −7 ), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10 −6 ), SRGAP3 (axon guidance, p = 5.65 × 10 −6 ), and TRAPPC4 (vesicle transport, p = 5.81 × 10 −6 ). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10 −7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44).Interpretation-We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.Parkinson's disease (PD) is a neurodegenerative disorder, characterized by age-related dysfunction and loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (SNc). Hereditary forms of PD have provided evidence for linkage to 13 loci and nine causative genes, and their functional study has greatly helped to elucidate molecular disease mechanisms. 1 For idiopathic PD, both genetic and environmental factors are believed to modulate disease risk, but the impact of genetic variants remains unclear. 2 Genome-wide association (GWA) studies offer an unbiased approach for detecting effects in common variants, but large studies with sufficient power are still lacking. Restriction to candidate genes increases the a priori odds for phenotypic involvement and thus the chance of detecting significant associations. Here, we applied a functional genomic approach for the discovery of candidate genes and key regulatory pathways. We focused directly on the In order to isolate high-quality RNA from frozen human brain tissues, tissue pH and RNA integrity numbers (RIN) were measured in homogenates of frontal cortex and mid-brain sections from 41 suitable cases and 39 controls. This provided eight cases and nine agematched controls of good RNA quality for laser microdissection (LMD). Postmortem data for matched cases/controls were as follows: age at death 78.6 ± 6.5/76.8 ± 9.8 years; postmorte...

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“…Direct evidence for common variants for colorectal cancer is highlighted by recent genome-wide association studies (GWAS). These GWAS on colorectal cancer have identified 10 independent loci that confer risk of colorectal cancer, including those on chromosomes 8q24.21, 11q23, 18q21.1, 8q23.1 15q, 19q13.1, 20q12.3, 14q22.2, 16q22.1, and 10p14 (4)(5)(6)(7)(8)(9)(10). However, risk associated with these common variants is modest and only a small proportion of colorectal cancer risk can be explained by currently identified loci.…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

Liu

Lü

Liu

et al. 2012

Molecular Cancer Research

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To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean ¼ 6.5 AE 8.6) and tumor volume ranged from 0 to 706.5 mm 3 (mean ¼ 87.4 AE 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P ¼ 6.31 Â 10 -6 ). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies. Mol Cancer Res; 10(1); 66-74. Ó2011 AACR.

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Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

Cited by 538 publications

References 15 publications

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

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