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Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Original publication

DOI

10.1038/nature24284

Type

Journal article

Journal

Nature

Publication Date

11/2017

Volume

551

Pages

92 - 94

Addresses

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Keywords

NBCS Collaborators, ABCTB Investigators, ConFab/AOCS Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Transcription Factors, Risk Assessment, Binding Sites, Regulatory Sequences, Nucleic Acid, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Computer Simulation, Asian Continental Ancestry Group, European Continental Ancestry Group, Asia, Europe, Female, Genome-Wide Association Study, Genetic Loci