Cindy Boer

102 | Chapter 2.2 Table 3: Association with xosteoarthritis phenotypes Thumb OA (7,280 cases; 605,132 controls) Finger OA (7,037 cases; 222,772 controls) rsID EA EAF OR 95%CI P-value OR 95%CI P-value rs10916199 A 0.81 0.91 0.86-0.95 5.7x10 -05 0.98 0.93-1.04 0.57 rs2070852 C 0.69 0.97 0.89-1.05 0.47 0.99 0.94-103 0.58 rs4764133 T 0.39 1.07 1.03-1.12 6.3x10 -04 1.12 1.07-1.17 5.7x10 -07 rs12049916 A 0.77 1.00 0.96-1.05 0.87 0.99 0.94-1.04 0.67 Hand OA (8,591 cases; 224,326 controls) Hip OA (17,151 cases, 613,790) rsID EA EAF OR 95%CI P-value OR 95%CI P-value rs10916199 A 0.81 1.03 0.98-1.08 0.32 1.00 0.98-1.03 0.95 rs2070852 C 0.69 0.99 0.96-103 0.80 0.98 0.96-1.01 0.22 rs4764133 T 0.39 1.09 1.04-1.13 6.7x10 -04 0.99 0.96-1.01 0.30 rs12049916 A 0.77 0.99 0.94-1.04 0.68 0.96 0.93-0.99 2.9x10 -03 KneeOA (24,919 cases, 613,702 controls) rsID EA EAF OR 95%CI P-value rs10916199 A 0.81 0.99 0.97-1.02 0.59 rs2070852 C 0.69 0.99 0.97-1.01 0.40 rs4764133 T 0.39 0.98 0.96-1.00 0.018 rs12049916 A 0.77 0.99 0.97-1.01 0.27 Thumb OA, Finger OA, HandOA GWAS summary statistics are from the DECODE cohort, Hip OA and Knee OA summary statistics are from a meta-analysis of DECODE and UKbiobank cohorts. OA: osteoarthritis, EA: Effect Allele, NEA: Non Effect Allele, EAF: Effect Allele Frequency, SE: Standard Error, OR: odds ratio, CI: Confidence Interval on gene expression in these datasets. Next, there were significant methylation quantitative trait loci (meQTL) associated with rs10916109 and two CpG sites in human osteoar-thritic cartilage (knee/hip joints): CpG09796739 (beta=0.39, FDR p- value=8.3x10-07) and CpG11520395 (beta=0.21, FDR p-value=5.5x10 -03 ) ( Figure 3e, zone 2 ). These methylation sites are located in a region flanking an active transcriptional start site in primary osteoblasts and chondrogenic cells ( Figure 3b ). To further assess co-localization of the identified genetic loci with regulatory function during cartilage differentiation, we intersected the GWAS signals in the lo-cus with accessible chromatin regions (ATAC-seq peaks) in rare human fetal cartilage acquired from proximal and distal long bones from gestational day(E) 59 of development[42]. Two of the SNVs in high LD (r2≥0.8) with rs10916199 (rs74140304 and rs11588850) intersected with accessible chromatin regions across multiple human long bone cartilage ( Figure 3c ). In addition, rs74140304 also intersected with an active transcription start site in osteoblast and chondrogenic cells ( Figure 3b )[28]. Next, we examined 3D chromatin conformation in the locus.