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Objective  Multiple single‐nucleotide polymorphisms ( SNP s) 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  SNP s 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 SNP s in the   CRLF 1 ,   WWP 2 , and   RPS 3  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   CRLF 1 ,   WWP 2 , and   RPS 3 .

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