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Lookup NU author(s): Dr Sarah RiceORCiD, Dr Colin Shepherd, Professor John LoughlinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
To date, genome-wide association studies have implicated at least 35 loci in osteoarthritis but, due to linkage disequilibrium, the specific variants underlying these associations and the mechanisms by which they contribute to disease risk have yet to be pinpointed. Here, we functionally test 1,605 single nucleotide variants associated with osteoarthritis for regulatory activity using a massively parallel reporter assay. We identify six single nucleotide poly- morphisms (SNPs) with differential regulatory activity between the major and minor alleles. We show that the most significant SNP, rs4730222, exhibits differential nuclear protein binding in electrophoretic mobility shift assays and drives increased expression of an alter- native isoform of HBP1 in a heterozygote chondrosarcoma cell line, in a CRISPR-edited osteosarcoma cell line, and in chondrocytes derived from osteoarthritis patients. This study provides a framework for prioritization of GWAS variants and highlights a role of HBP1 and Wnt signaling in osteoarthritis pathogenesis.
Author(s): Klein JC, Keith A, Rice SJ, Shepherd C, Agarwal V, Loughlin J, Shendure J
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2019
Volume: 10
Print publication date: 04/06/2019
Online publication date: 04/06/2019
Acceptance date: 03/05/2019
Date deposited: 06/06/2019
ISSN (electronic): 2041-1723
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41467-019-10439-y
DOI: 10.1038/s41467-019-10439-y
PubMed id: 31164647
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