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Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.


Type

Article

Change log

Authors

Michailidou, Kyriaki 
Beesley, Jonathan 
Lindstrom, Sara 
Canisius, Sander 

Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

Description

Keywords

Breast Neoplasms, Case-Control Studies, Cohort Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Microarray Analysis, Polymorphism, Single Nucleotide

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

47

Publisher

Springer Science and Business Media LLC
Sponsorship
National Cancer Institute (U19CA148065)
Medical Research Council (G1000143)
European Commission (223175)
Cancer Research UK (16565)
Medical Research Council (G0401527)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research UK (A10710)
Cancer Research UK (A12014)
Cancer Research UK (A10118)
BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note.