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

Jason C. Klein, Aidan Keith, Sarah J. Rice, Colin Shepherd, Vikram Agarwal, John Loughlin and Jay Shendure ()
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Jason C. Klein: University of Washington
Aidan Keith: University of Washington
Sarah J. Rice: Newcastle University, International Centre for Life
Colin Shepherd: Newcastle University, International Centre for Life
Vikram Agarwal: University of Washington
John Loughlin: Newcastle University, International Centre for Life
Jay Shendure: University of Washington

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract 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 polymorphisms (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 alternative 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.

Date: 2019
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DOI: 10.1038/s41467-019-10439-y

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