title: Genome-wide association study identifies novel breast cancer susceptibility loci.
abstract: Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
authors.affiliation: CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. d.easton@srl.cam.ac.uk
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mesh_terms: D000483:Alleles; D051017:Apoptosis Regulatory Proteins; D001210:Asia, Southeastern; D001315:Australia; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005060:Europe / Q000208:ethnology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D005838:Genotype; D006609:High Mobility Group Proteins; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D009656:North America; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D015534:Trans-Activators
chemical_list: D051017:Apoptosis Regulatory Proteins; D006609:High Mobility Group Proteins; C489183:LSP1 protein, human; D008840:Microfilament Proteins; D011980:Receptors, Progesterone; C521752:TOX3 protein, human; D015534:Trans-Activators; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human