Cindy Boer

Genetics of Osteoarthritis Consortium GWAS Meta-Analyses | 169 4.1 further identified a signal associated with total hip replacement with opposite direc- tion of effects between men and women, rs10282983 (p-value sex-diff =4.93x10 -16 , p-val- ue het-diff =7.66x10 -14 ; female OR=1.15, 95% CI=1.11-1.19, p-value female =2.21x10 -14 ; male OR=0.92, 95% CI=0.88-0.96, p-value male =5.16x10 -04 ). rs10282983 resides in an intron of C8orf34 and has also been associated with waist-to-hip ratio[11] and heel bone mineral density[12]. Similarities and differences of signals across phenotypes We observed that some variants demonstrate a joint-specific effect (within the pow- er bracket afforded by the study). We found that the majority of SNVs, 60 out of the 100, were genome-wide significantly associated with more than one osteoarthritis phe- notype ( Figure 2, Supplementary Information ). 40 of the identified SNVs show ge- nome-wide significant associations with weight-bearing joints only (spine, knee and/ or hip), and four display associations with non weight-bearing joints only (hand, finger and thumb) ( Figure 2 ). Although several core pathways are known to underpin osteo- arthritis pathology, regardless of joint site affected, no common genetic osteoarthritis SNVs have been found previously, with the exception of the GDF5 locus[13, 14]. Here, we have identified 42 SNVs with strong association across both weight-bearing and non weight-bearing joints. Several of these SNVs, rs3771501 ( TGFA ), rs3993110 ( TEAD1/ DKK3 ), rs72979233 ( CHRDL 2), rs7967762 ( FPKM / WNT10B ) ( Figure 2, a panel 2,4 ) are strongly associated with multiple osteoarthritis joint sites. These SNVs likely repre- sent a common underlying mechanism in osteoarthritis pathology and could therefore be prime candidates for drug development. Novel insights may be gleaned from the comparison of association signals across osteoarthritis phenotypes. For example, most of the SNVs associated with knee, hip, and knee and/or hip osteoarthritis have a larger effect size on the respective joint replace- ment-defined phenotypes, all of which are notably of smaller sample size. This could be driven by homogeneity of phenotype definition ( Supplementary Table 1 ), or can rep-resent an actual biological and functional relevance of the association, indicating that these loci might play more important roles in receiving a joint replacement (i.e., pain and inflammation) than in osteoarthritis pathology itself. For example, rs76340814 ( PTCH1 ) and rs28929474 (missense variant in SERPINA1 ) have stronger associations and larger effect sizes with THR, TKR and TJR, than with hip or knee osteoarthritis ( Figure 2, panel 2 ). Indeed, PTCH1 is thought to function in neurogenetic/brain de-velopment (PMID 20583177, 16405370) and SERPINA1 in inflammation. Studies in rat osteoarthritis models have shown that early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase and caused lasting improvements in joint inflammation, pain and saphenous nerve damage[15].