Dataset Information

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.

ABSTRACT:

Background

Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.

Methods

We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians.

Results

An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10^-8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10^-3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10^-8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10^-8; rs62558833, P = 7.5 × 10^-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS.

Conclusions

In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously.

Impact

Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

SUBMITTER: Lu Y

PROVIDER: S-EPMC7571256 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.

Lu Yingchang Y Kweon Sun-Seog SS Cai Qiuyin Q Tanikawa Chizu C Shu Xiao-Ou XO Jia Wei-Hua WH Xiang Yong-Bing YB Huyghe Jeroen R JR Harrison Tabitha A TA Kim Jeongseon J Shin Aesun A Kim Dong-Hyun DH Matsuo Keitaro K Jee Sun Ha SH Guo Xingyi X Wen Wanqing W Shi Jiajun J Li Bingshan B Wang Nan N Shin Min-Ho MH Li Hong-Lan HL Ren Zefang Z Oh Jae Hwan JH Oze Isao I Ahn Yoon-Ok YO Jung Keum Ji KJ Gao Jing J Gao Yu-Tang YT Pan Zhi-Zhong ZZ Kamatani Yoichiro Y Chan Andrew T AT Gsur Andrea A Hampe Jochen J Le Marchand Loic L Li Li L Lindblom Annika A Moreno Victor V Newcomb Polly A PA Offit Kenneth K Pharoah Paul D P PDP van Duijnhoven Franzel J B FJB Van Guelpen Bethany B Vodicka Pavel P Weinstein Stephanie J SJ Wolk Alicja A Wu Anna H AH Hsu Li L Zeng Yi-Xin YX Long Jirong J Peters Ulrike U Matsuda Koichi K Zheng Wei W

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20191211 2

<h4>Background</h4>Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.<h4>Methods</h4>We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. ...[more]

PMID: 31826910

Similar Datasets

Project description:Background & aimsGenome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.MethodsWe analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.ResultsA meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.ConclusionsWe showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Dataset Information

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.

Background

Methods

Results

Conclusions

Impact

Publications

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.

Similar Datasets

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