Cindy Boer

172 | Chapter 4.1 Of note is the high correlation between osteoarthritis and sciatica, fibromyalgia, headaches and other pain phenotypes, where the highest correlation is with spine os- teoarthritis (rg = 0.61, 0.87, 0.39, 0.79, respectively). SOX5 , one of the new signals iden- tified in this study, has been previously reported to be associated with back pain and with imaging-detected lumbar intervertebral disc degeneration, attributing the pain to possible structural problems of the spine[18]. These findings are supported by animal model data where inactivation of SOX5 leads to defects in cartilage and skeletogenesis in mice[19]. We also observed strong correlation between osteoarthritis and pain phe- notypes in the LD-Hub database (all derived from the UK Biobank dataset), in particular between spine osteoarthritis and dorsalgia (rg=0.87), leg pain on walking (rg=0.82), knee pain (rg=0.63), hip pain (rg=0.76) back pain (rg=0.75) and neck/shoulder pain (rg=0.74) ( Supplementary Table 6 ). Pain is the most disabling symptom experienced by osteoarthritis patients, one of the main reasons to proceed to total joint replacement[20] and the main reason for physician consultation. The aetiology of pain in osteoarthritis is multifactorial including significant soft tissue inflammation, the sensitisation of pain pathways involving the joint nociceptors, the nociceptive processing in the central nervous system and neuro- pathic pain components in osteoarthritis models[21-24]. Although a main symptom, no genetic determinants of osteoarthritis pain have been discovered before. Our data suggest that part of the identified signals are also associated with osteoarthritis pain. Resolution of GWAS Signals Identification of putative causal variants and involved tissues We employed complementary computational approaches ( Methods ) to fine-map the GWAS signals to a small set of likely causal variants, identify relevant tissues based on signal enrichment, and provide mechanistic insights based on expression quantitative trait locus colocalization. 12 signals were fine-mapped to variant sets contained entire- ly within the transcript of a single gene with >95% posterior probability (PP), although we note that this does not provide conclusive evidence for the effector gene. However, of note, ALDH1A2 , which fine maps to 6 intronic variants with 99% PP, is currently the target of approved drugs in use for other indications, providing a potential opportunity for drug repositioning ( Table 3 , Supplementary Table 8 ).