Cindy Boer

Genetics of Osteoarthritis Consortium GWAS Meta-Analyses | 177 4.1 Amassing evidence to identify effector genes From the 376 genes (mentioned above, Supplementary Table 8 ) we combined sup- portive information from the fine-mapping and eQTL colocalization analyses, ani- mal model data, human musculoskeletal phenotype, functional genomics and plasma pQTL causal inference analysis and identify 38 genes that have at least three different lines of evidence pointing to them as a putative effector gene ( Table 3 ). Of these 38 genes, 23 provide strong additional supportive evidence for known osteoarthritis-as- sociated genes ( Table 3 ) and 15 reside in newly-associated signals: C2orf40 (lead SNV rs66989638), TSEN15 (rs1327123), VGLL4 (rs2276749), RNF144B (rs9396861), CHST3 (rs3740129), TRIOBP (rs12160491), CUX1 (rs116934101), FBN2 (rs17615906), IGF1R (rs12914479), COL2A1, PFKM and WNT10B (rs7967762), PTCH1 (rs76340814), TNFSF11 (rs58973023) and SNAP47 (rs11588850). We discuss the 15 genes associated with the new signals here. Four of the putative osteoarthritis causal genes are involved in developmental pathways: PTCH1 , WNT10B , CHST3 and VGLL4. Developmental pathways, particularly for skeletal, bone and cartilage development, are known to be involved in osteoarthri- tis pathology[13]. Mutations and deficiency of carbohydrate sulfotransferase 3 protein ( CHST3 ) , an enzyme involved in the metabolism of the major proteoglycan present in cartilage chondroitin sulphate, have been previously associated with short stature, congenital joint dislocations, clubfoot and elbow joint dysplasia[44]. CHST3 has been shown to be associated with lumbar disc degeneration[45]. In addition, mutations in CHST3 have been observed in patients diagnosed with autosomal recessive Larsen syn- drome, which affects bone development[46]. PTCH1 (Patched 1) is a member of the hedgehog (Hh) signaling pathway, im- portant in embryonic development and tissue maintenance and regulation. PTCH1 is a receptor for Hh ligands and regulates the activity of SMO. When bound, PTCH1 re- linquishes its inhibitory effect on SMO and activates the Hh signalling cascade. The Hh pathway plays an important role in the longitudinal growth of long bones during devel- opment[47] and there are currently drug repurposing opportunities for this pathway (see SMO below). WNT10B (Wnt family member 10B) is involved in the Wnt signalling pathway, which has an established role in osteoarthritis pathogenesis[48]. Mutations in WNT10B have been linked to limb defects and dental abnormalities[49-51]. Downregulation of VGLL4 is linked to the upregulation of Wnt/β-catenin pathway target genes[52]. VGLL4 functions via interacting with TEA domain (TEAD) transcription factors[52, 53].