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Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

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SGUL Authors: Snape, Katie Mairwen Greenwood

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Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Item Type: Article
Additional Information: This is a post-peer-review, pre-copyedit version of an article published in Nature Research. The final authenticated version is available online at: http://dx.doi.org/10.1038/s41588-019-0537-1
Keywords: Bayes Theorem, Biomarkers, Tumor, Breast Neoplasms, Chromosome Mapping, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, Risk Factors, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Bayes Theorem, Biomarkers, Tumor, Breast Neoplasms, Chromosome Mapping, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, Risk Factors, Developmental Biology, 11 Medical and Health Sciences, 06 Biological Sciences
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Journal or Publication Title: Nat Genet
ISSN: 1546-1718
Language: eng
Dates:
DateEvent
January 2020Published
7 January 2020Published Online
24 October 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
MC_PC_14105Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
P30 CA008748NCI NIH HHSUNSPECIFIED
P20 GM130423NIGMS NIH HHSUNSPECIFIED
R01 CA204954NCI NIH HHSUNSPECIFIED
203477/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
P30 ES010126NIEHS NIH HHSUNSPECIFIED
UL1 TR001863NCATS NIH HHSUNSPECIFIED
C8197/A16565Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
U19 CA148065National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
K08 CA234394NCI NIH HHSUNSPECIFIED
C1287/A16563Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
C1287/A10118Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
C1287/A10710Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
656144Horizon 2020UNSPECIFIED
X01HG007492National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
223175Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
633784Horizon 2020UNSPECIFIED
634935Horizon 2020UNSPECIFIED
HEALTH-F2-2009-223175European UnionUNSPECIFIED
PSR-SIIRI-701Ministry of Economic Development, Innovation and Export Trade of QuebecUNSPECIFIED
PubMed ID: 31911677
Web of Science ID: WOS:000508163500002
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112634
Publisher's version: https://doi.org/10.1038/s41588-019-0537-1

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