Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
Author(s)
Type
Journal Article
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.
Date Issued
2020-01-07
Date Acceptance
2019-10-24
Citation
Nature Genetics, 2020, 52 (1), pp.56-73
ISSN
1061-4036
Publisher
Nature Research
Start Page
56
End Page
73
Journal / Book Title
Nature Genetics
Volume
52
Issue
1
Copyright Statement
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2020.
The final publication is available at Springer via https://doi.org/10.1038/s41588-019-0537-1
The final publication is available at Springer via https://doi.org/10.1038/s41588-019-0537-1
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000508163500002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
COMPREHENSIVE MOLECULAR PORTRAITS
ESTROGEN-RECEPTOR
INTEGRATIVE ANALYSIS
FUNCTIONAL VARIANTS
SUSCEPTIBILITY LOCI
PROTEIN FUNCTION
CHROMATIN
ENHANCER
REVEALS
Publication Status
Published
Date Publish Online
2020-01-07