Cindy Boer

Hand Osteoarthritis Phenotypes | 99 2.2 Results Patterns of osteoarthritis severity in joints of the hand We used hierarchal cluster analysis on the KL-grades of all 32 hand joints of the left hand and right hand to identify clusters ( Figure 1 ). Tight symmetric clustering between the left and right joints was seen, in addition to clustering based on joint group, which is in line with previous findings [19, 38, 39] ( Figure 1a – b ). Clustering based on individual radiographic features, joint space narrowing (JSN) and number of osteophytes (OST), produced similar symmetric and joint group clusters ( online S upplementary Figures S1 and S2 ). We observed consistent clustering of the PIP with the DIP joints and the TS with the CMC joints ( Figure 1, online S upplementary Figure S1 and S2 ). Based on these analyses, we created three semi-quantitative hand OA phenotypes: hand KLsum, thumb KLsum and finger KLsum ( Table 1 ). Identification of genetic hand osteoarthritis loci We conducted genome-wide association studies (GWAS) on each of the three iden- tified hand OA phenotypes in a discovery sample that included RS-I, RS-II and RS-III cohorts (n~ 8,700) ( Table S1 ). In total, we identified seven independent signals with genome-wide suggestive association (p-value<1x10 -06 ) which were taken forward for replication in the Framingham Heart Study (FHS, n=1,203) ( Figure 2, Table 2 ). In to- tal, four independent signals were genome-wide significant in the meta-analysis (p-val- ue≤5x10 -08 ), of which three were significantly replicated (p-value<0.05) ( Table 2 ). Two of these signals were novel osteoarthritis associated loci. The first and most significant novel locus was located on chromosome 1 near the ZNF678 , WNT3A and WNT9A genes, with rs10916199 as the lead single nucleotide variant (SNV). This signal is replicated (p-value<0.05) and genome-wide significantly associated with thumb KLsum (beta=- 0.31, p-value=2.36x10 -13 ). The second replicated novel locus is located on chromosome 11 containing the F2, LRP4 and CREB3L1 genes, and is associated with thumb KLsum (beta=-0.19, p-value=4.7x10 -08 ). We also identified two known OA associated loci. The first locus was located near the MGP gene, with rs4767133 as the lead SNV. This locus was previously found to be associated with hand KLsum [16]. The second known OA locus, also located on chromosome 12, is the CCDC91 -locus, which was also previously found to be associated with hand KLsum, though it did not reach genome-wide sig- nificance[16]. Here, the lead variant rs12049916, was genome-wide significantly asso- ciated with hand KLsum (beta=0.78, p-value=1.5x10 -08 ) and finger KLsum (beta=0.58, p-value=2.0x10 -08 ), but did not reach nominal significance in the replication cohort, though the direction of effect was the same between discovery and replication cohorts ( Table 2 ).