Camp, N.J., Lin, W.Y., Bigelow, A. et al. (23 more authors) (2016) Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus. Cancer Research, 76 (7). pp. 1916-1925. ISSN 0008-5472
Abstract
The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low risk association signals to their underlying functional sequence variants (FSVs). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of non-coding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof of principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate-FSVs. Our results were consistent with those from a 2000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus (eQTL) analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 American Association for Cancer Research. This is an author produced version of a paper subsequently published in Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number YORKSHIRE CANCER RESEARCH S295 YORKSHIRE CANCER RESEARCH S299 CANCER RESEARCH UK (CRUK) C9528/A11292 YORKSHIRE CANCER RESEARCH SPP060 MEDICAL RESEARCH COUNCIL NONE CANCER RESEARCH UK (CRUK) C5410/A7315. |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 07 Mar 2016 13:54 |
Last Modified: | 05 Nov 2017 22:49 |
Published Version: | http://dx.doi.org/10.1158/0008-5472.CAN-15-1629 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Refereed: | Yes |
Identification Number: | 10.1158/0008-5472.CAN-15-1629 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:94772 |