Functional Testing of Thousands of Osteoarthritis-Associated Variants for Regulatory Activity

bioRxiv (Cold Spring Harbor Laboratory) 2018 14 cites
2018:12019:12020:12021:22022:22023:22024:22025:22026:1
2018 2026
14

Jason C. Klein, Aidan Keith, Sarah J. Rice, Colin Shepherd, Vikram Agarwal et al.

Abstract

Abstract

              To date, genome-wide association studies have implicated at least 35 loci in osteoarthritis, but due to linkage disequilibrium, we have yet to pinpoint the specific variants that underlie these associations, nor the mechanisms by which they contribute to disease risk. Here we functionally tested 1,605 single nucleotide variants associated with osteoarthritis for regulatory activity using a massively parallel reporter assay. We identified six single nucleotide polymorphisms (SNPs) with differential regulatory activity between the major and minor alleles. We show that our most significant hit, rs4730222, drives increased expression of an alternative isoform of
              HBP1
              in a heterozygote chondrosarcoma cell line, a CRISPR-edited osteosarcoma cell line, and in chondrocytes derived from osteoarthritis patients.
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