Cindy Boer

Hand Osteoarthritis Phenotypes | 101 2.2 1 0 2 4 6 10 12 8 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 [CCDC91] STXBP6---[]---NOVA1 ETS2---[]---PSMG1 MGP--[]-ERP27 [ZNF678] [F2] UVRAG-[]--WNT11 Chromosome -log 10 (P-value) Thumb Hand Finger Thumb HAND Finger ▲ Figure 2: Combined Manhattan-plot of GWAS discovery results of all radiographic hand OA struc- tural phenotypes. thumb= thumb KLsum score, finger= finger KLsum score and hand: handklsum score. GWAS discovery consists of RSI, RSII and RSIII, and was adjusted for age, sex, and the first four genetic principle components. The −log10 p-values, for each of the ~11million SNPs analyzed (remaining after EASYQC quality control) from the association studies is plotted against their position per chromosome. The dotted red horizontal line corresponds to the genome-wide significant threshold (p-vslur=5*10−08). The solid grey line corresponds to the selection for replication threshold (p-value=5*10−06). Lead SNP location is represented by [] (intronic), if the SNP is localized intergenic the dashes denotes the distance, -≤10kb,--≤100kb,----≤1Mkb,----≥1Mkb. GWAS, genome-wide association studies. For plots of the indi- vidual GWAS see Supplementary Figures 3-5. To examine if replicated loci were also associated with clinically defined OA, we looked up findings in GWAS summary statistics froma recent large-scale OAmeta-analy- sis that included the UK Biobank and deCODE populations[14, 15]( Table 3 ). Of the nov- el signals, only rs10916199 (thumb KLsum) was significantly associated with its match- ing clinical OA phenotype (thumb OA: OR=0.9, 95%CI=0.86-0.95, p-value=5.7x10 -05 ). Of the known signals, rs4764133 was significantly associated with multiple clinical OA phenotypes: thumb OA (OR=1.07, 95%CI= 1.03-1.12, p-value=6.3x10 -04 ), finger OA (OR=1.12, 95%CI=1.07-1.17, p-value=5.7-10 -07 ), hand OA (OR=1.09, 95%CI=1.04-1.13, p-value=6.7x10 -05 ), and nominal significantly with knee OA (OR=0.99, 95%CI=0.96- 1.00, p-value 1.8x10 -02 )( Table 3 ). WNT9A as potential causal gene for thumb OA We examined the rs10916199 locus in more detail given the strong and consistent as- sociation with thumb OA. Different levels of information were leveraged for all genes within 1Mb surrounding rs10916199 in order to prioritize a putative causal gene ( Fig- ure 3, online supplementary text ). First, we meta-analyzed two human osteoarthritic cartilage expression quantitative trait loci (eQTL) datasets (n=116, hip/knee joints, on- line supplementary Table S1 )[40, 41] and found no significant effect of rs10916199