A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

被引：101

作者：

Al-Tassan, Nada A. ^{[1
]}

Whiffin, Nicola ^{[2
]}

Hosking, Fay J. ^{[2
]}

Palles, Claire ^{[3
,4
]}

Farrington, Susan M. ^{[5
,6
]}

Dobbins, Sara E. ^{[2
]}

Harris, Rebecca ^{[7
]}

Gorman, Maggie ^{[3
,4
]}

Tenesa, Albert ^{[5
,6
,8
]}

Meyer, Brian F. ^{[1
]}

Wakil, Salma M. ^{[1
]}

Kinnersley, Ben ^{[2
]}

Campbell, Harry ^{[9
]}

Martin, Lynn ^{[3
,4
]}

Smith, Christopher G. ^{[7
]}

Idziaszczyk, Shelley ^{[7
]}

Barclay, Ella ^{[3
,4
]}

Maughan, Timothy S. ^{[10
]}

Kaplan, Richard ^{[11
]}

Kerr, Rachel ^{[12
]}

Kerr, David ^{[13
]}

Buchannan, Daniel D. ^{[14
,15
]}

Win, Aung Ko ^{[15
]}

Hopper, John ^{[15
]}

Jenkins, Mark ^{[15
]}

Lindor, Noralane M. ^{[16
]}

Newcomb, Polly A. ^{[17
]}

Gallinger, Steve ^{[18
]}

Conti, David ^{[19
]}

Schumacher, Fred ^{[19
]}

Casey, Graham ^{[19
]}

Dunlop, Malcolm G. ^{[5
,6
]}

Tomlinson, Ian P. ^{[3
,4
]}

Cheadle, Jeremy P. ^{[7
]}

Houlston, Richard S. ^{[2
]}

机构：

[1] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia

[2] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England

[3] Wellcome Trust Ctr Human Genet, Oxford, England

[4] NIHR Comprehens Biomed Res Ctr, Oxford, England

[5] Univ Edinburgh, Inst Genet & Mol Med, Colon Canc Genet Grp, Edinburgh EH4 2XU, Midlothian, Scotland

[6] Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[7] Sch Med, Cardiff Univ, Inst Canc & Genet, Cardiff CF14 4XN, S Glam, Wales

[8] Roslin Inst, Univ Edinburgh, Roslin EH25 9RG, Midlothian, Scotland

[9] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland

[10] Univ Oxford, CRUK MRC Oxford Inst Radiat Oncol, Oxford OX3 7DQ, England

[11] MRC, Clin Trials Unit, London WC2B 6NH, England

[12] Univ Oxford, Churchill Hosp, Oxford Canc Ctr, Dept Oncol, Oxford OX3 7LE, England

[13] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England

[14] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Oncogen Grp, Melbourne, Vic 3010, Australia

[15] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia

[16] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA

[17] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA

[18] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[19] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COMMON VARIATION; MICROSATELLITE INSTABILITY; COLON-CANCER; LARGE-SCALE; CHEMOTHERAPY; CDC42; DISCOVERY; CETUXIMAB;

D O I：

10.1038/srep10442

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 x 10(-8), odds ratio [OR] = 1.21) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 x 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and similar to 500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 x 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.

引用

页数：10

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