Annotating Transcriptional Effects of Genetic Variants in Disease-Relevant Tissue: Transcriptome-Wide Allelic Imbalance in Osteoarthritic Cartilage

Arthritis Rheumatol. 2019 Apr;71(4):561-570. doi: 10.1002/art.40748. Epub 2019 Feb 23.


Objective: Multiple single-nucleotide polymorphisms (SNPs) conferring susceptibility to osteoarthritis (OA) mark imbalanced expression of positional genes in articular cartilage, reflected by unequally expressed alleles among heterozygotes (allelic imbalance [AI]). We undertook this study to explore the articular cartilage transcriptome from OA patients for AI events to identify putative disease-driving genetic variation.

Methods: AI was assessed in 42 preserved and 5 lesioned OA cartilage samples (from the Research Arthritis and Articular Cartilage study) for which RNA sequencing data were available. The count fraction of the alternative alleles among the alternative and reference alleles together (φ) was determined for heterozygous individuals. A meta-analysis was performed to generate a meta-φ and P value for each SNP with a false discovery rate (FDR) correction for multiple comparisons. To further validate AI events, we explored them as a function of multiple additional OA features.

Results: We observed a total of 2,070 SNPs that consistently marked AI of 1,031 unique genes in articular cartilage. Of these genes, 49 were found to be significantly differentially expressed (fold change <0.5 or >2, FDR <0.05) between preserved and paired lesioned cartilage, and 18 had previously been reported to confer susceptibility to OA and/or related phenotypes. Moreover, we identified notable highly significant AI SNPs in the CRLF1, WWP2, and RPS3 genes that were related to multiple OA features.

Conclusion: We present a framework and resulting data set for researchers in the OA research field to probe for disease-relevant genetic variation that affects gene expression in pivotal disease-affected tissue. This likely includes putative novel compelling OA risk genes such as CRLF1, WWP2, and RPS3.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Allelic Imbalance / genetics*
  • Cartilage, Articular / metabolism*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Osteoarthritis / genetics*
  • Polymorphism, Single Nucleotide*
  • Receptors, Cytokine / genetics
  • Ribosomal Proteins / genetics
  • Risk Factors
  • Sequence Analysis, RNA
  • Transcriptome / genetics*
  • Ubiquitin-Protein Ligases / genetics


  • RPS3 protein, human
  • Receptors, Cytokine
  • Ribosomal Proteins
  • cytokine-like factor-1
  • WWP2 protein, human
  • Ubiquitin-Protein Ligases