Meta-analysis of genome-wide association data identifies four new susceptibility … (original) (raw)
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Nature Genetics, 2010
Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10 −10 and rs6687758, OR = 1.09, P = 2.27 × 10 −9 ), 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10 −8 ), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10 −10 and rs7136702, OR = 1.06, P = 4.02 × 10 −8 ) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10 −10 ). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.
Gut, 2019
Objective To provide an understanding of the role of common genetic variations in colorectal cancer (crc) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for crc (crcgene2). Design We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Metaanalyses were performed for 308 single nucleotide polymorphisms (snPs) in 158 different genes with at least three independent studies available for analysis. scottish, canadian and spanish data from genome-wide association studies (gWass) were incorporated for the meta-analyses of 132 snPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). genetic associations classified as 'positive' and 'lesscredible positive' were further validated in three large gWas consortia conducted in populations of european origin. Results We initially identified 18 independent variants at 16 loci that were classified as 'positive' polymorphisms for their highly credible associations with crc risk and 59 variants at 49 loci that were classified as 'less-credible positive' snPs; 72.2% of the 'positive' snPs were successfully replicated in three large gWass and the ones that were not replicated were downgraded to 'less-credible' positive (reducing the 'positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with crc risk. Conclusion The crcgene2 database provides an updated list of genetic variants related to crc risk by using harmonised methods to assess their credibility. InTRODuCTIOn Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and the leading cause of cancer deaths in the world, with 1.65 million new cases and about 835 000 deaths in 2015. 1 The global burden of CRC is expected to increase by 60%, with more than 2.2 million new cases and almost 1.1 million deaths occurring annually by 2030. 2 The distribution of CRC global burden varies widely, with more than two-thirds Summary box What is already known on this subject? ► Colorectal cancer (CRC) is a global public health challenge. A large number of genetic association studies have been conducted to assess the potential correlation between common genetic variations and CRC risk. What are the new findings? ► Using an established framework for grading credibility of genetic associations, we classified 14 independent variants at 12 loci (MUTYH, SMAD7, TERT, CDH1, RHPN2, BMP2, TGFB1 and common variants tagging loci at 8q24, 8q23.3, 10p14, 11q23.1, 20p12.3) as highly credibly associated with CRC risk. A total of 63 variants at 52 loci were classified as 'less-credible positive' SNPs; variants of nine of these genes could be mostly highly prioritised for further investigation. For 231 variants previously reported to be associated with CRC, our metaanalyses found no evidence to support such associations. How might it impact on clinical practice in the foreseeable future? ► This database will be helpful for future research by promoting the investigation of these variants and corresponding genetic loci in populations other than of European origin, serving as a genetic basis for predicting risk estimates for population groups and providing candidate genes for further functional studies or geneenvironment interaction studies.
International Journal of Cancer, 2017
Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer, but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 colorectal cancer cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism rs992157 (2q35) and colorectal cancer was independently replicated (p=2.08x10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p=1.50x10-9 ; OR, 1.12;
Association analyses identify 31 new risk loci for colorectal cancer susceptibility
Nature Communications
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
Genome-wide association study of colorectal cancer identifies six new susceptibility loci
Nature communications, 2015
Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of…
Novel Common Genetic Susceptibility Loci for Colorectal Cancer
Journal of the National Cancer Institute, 2018
Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability...
Association studies on 11 published colorectal cancer risk loci
British journal of cancer, 2010
Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. The aim of this study was to test 11 loci, reported to be associated with an increased or decreased risk of colorectal cancer: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253), in a Swedish-based cohort. The cohort was composed of 1786 cases and 1749 controls that were genotyped and analysed statistically. Genotype-phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumour location, was performed. Of eleven loci, 5 showed statistically significant odds ratios similar to previously published findings: 8q23.3, 8q24.21, 10p14, 15q13.3 and 18q21.1. The remaining loci 11q...