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Functional testing of thousands of osteoarthritis-associated variants for regulatory activity

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.

Publication metadata

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


DOI: 10.1038/s41467-019-10439-y

PubMed id: 31164647


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Funder referenceFunder name
20771VERSUS Arthritis (formerly Arthritis Research UK)
JXR 10641