期刊
BMC GENOMICS
卷 18, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s12864-017-3620-y
关键词
BRD4; Genome-wide association studies; SNPs; Functional annotation; Chromatin; Risk loci; Prostate cancer risk; breast cancer risk; schizophrenia; super-enhancer
资金
- South-East Norway Health Authorities at the Oslo University Hospital [2014040]
- Norwegian Centre for Molecular Medicine
- Research Council of Norway (RCN)
- University of Oslo through the Centre for Molecular Medicine (Norway)
- Norwegian Cancer Society
- EU
- SENHA at the Oslo University Hospital
- Centre for Molecular Medicine (Norway)
- Norwegian Centre of Research in Mental Disorders (NORMENT)
- RCN
- SENHA
- Norwegian Health Association
- KG Jebsen Foundation
- Kristian Gerhard Jebsen Foundation
- Centre for Molecular Medicine Norway
- Research Council of Norway [213837, 223273]
- South-East Norway Health Authorities [2013-123]
- National Institutes of Health [R01AG031224, R01EB000790, RC2DA29475]
- Cancer Research UK [C5047/A3354]
- Prostate Cancer Research Foundation
- National Cancer Research Network UK
- National Cancer Research Institute (NCRI) UK
- Health Technology Assessment Programme [96/20/06, 96/20/99]
- Department of Health, UK, Cancer Research UK [C522/A8649]
- Medical Research Council (UK) [G0500966, 75466]
- NCRI, UK
- Southwest National Health Service Research and Developmen
- Institute of Cancer Research
- Everyman Campaign
- Prostate Cancer UK
- South East Norway Health Authority (SENHA)
- Oslo University Hospitals
- South-East Norway Health Authorities at the Oslo University Hospital [2014040]
- Norwegian Centre for Molecular Medicine
- Research Council of Norway (RCN)
- University of Oslo through the Centre for Molecular Medicine (Norway)
- Norwegian Cancer Society
- EU
- SENHA at the Oslo University Hospital
- Centre for Molecular Medicine (Norway)
- Norwegian Centre of Research in Mental Disorders (NORMENT)
- RCN
- SENHA
- Norwegian Health Association
- KG Jebsen Foundation
- Kristian Gerhard Jebsen Foundation
- Centre for Molecular Medicine Norway
- Research Council of Norway [213837, 223273]
- South-East Norway Health Authorities [2013-123]
- National Institutes of Health [R01AG031224, R01EB000790, RC2DA29475]
- Cancer Research UK [C5047/A3354]
- Prostate Cancer Research Foundation
- National Cancer Research Network UK
- National Cancer Research Institute (NCRI) UK
- Health Technology Assessment Programme [96/20/06, 96/20/99]
- Department of Health, UK, Cancer Research UK [C522/A8649]
- Medical Research Council (UK) [G0500966, 75466]
- NCRI, UK
- Southwest National Health Service Research and Developmen
- Institute of Cancer Research
- Everyman Campaign
- Prostate Cancer UK
- South East Norway Health Authority (SENHA)
- Oslo University Hospitals
- MRC [MR/N003284/1, G0500966] Funding Source: UKRI
- Cancer Research UK [14136, 16561, 19170, 16565] Funding Source: researchfish
- Cancer Research UK
- The Francis Crick Institute [10124] Funding Source: researchfish
- Medical Research Council [MR/N003284/1, G0500966, G0401527, G1000143] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10114] Funding Source: researchfish
Background: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. Results: Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. Conclusions: This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.
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