Cindy Boer

Cartilage Thickness and Hip Osteoarthritis | 85 2.1 Phenotype description of radiographic hip OA Radiographic hip OA was defined in the RS-I, RS-II, RSIII, Twins-UK, Chingford, and JoCo studies using Kellgren and Lawrence (KL) grade. Hip OA cases were defined as a KL grade≥2 on either side of the hip or THR due to OA. Hip OA controls were defined as no THR for OA and KL grade≤1 and JSN≤1. In MrOS and SOF cohorts, radiographic hip OA case-control was defined by a modified Croft grade, as previously described[44], where cases were defined as a Croft score ≥ 2 on either side of the hip or THR due to OA and controls were defined as a Croft score ≤ 1 on both sides of the hip and no THR. Hip OA cases in the GOAL and Nottingham OA studies were defined by having THR, and controls were radiographically free of hip OA, as previously described [45]. In GARP, hip osteoarthritis was defined as pain or stiffness in the groin and hip region on most days of the preceding month in addition to femoral or acetabular osteophytes or axial joint space narrowing on radiography or prosthesis due to osteoarthritis. In GOGO, hip OA was defined as KL grade>=2, or minimal joint space width<=2.5 mm, or the combina- tion of joint space narrowing grade>=2 and any osteophyte of grade>=1, or history of joint replacement for OA. In JoCo, hip OA cases were defined as KL grade>=2 or THR in at least one hip. Hip OA controls were defined as KL grade<= 1 in both hips. Gene prioritization analysis We have used several available tools and publicly available databases to prioritize genes in known and newly discovered osteoarthritis associated regions. Locus gene sets were constructed by taking a region of 500Kb upstream and 500Kb downstream of the lead SNP of that locus. We analysed 152 genes in 13 independent loci associated with mini- mal joint space width in the hip joint (mJSW) for 7 loci, hip OA for 4 loci, total joint re- placement (TJR) for 1 locus and total hip replacement (THR) for 1 locus[2]. We analysed the following biological evidence for each gene at all loci; Nearest located genes: Taken from the UCSC genome browser, GRCh37/hg19[46]. DEPICT gene prioritization: Da- ta-driven Expression-Prioritized Integration for Complex Traits, a novel tool designed to identify the most likely causal gene in a given locus and to gene sets that are enriched in the genetic associations[21]. DEPICT was used to prioritize genes in a 1MB region around the found SNPs that were significant associated with the osteoarthritis pheno- type, taking a region of 500Kb upstream and 500Kb downstream of the lead SNP of that locus. Gene prioritization analysis was performed to directly investigate functional similarities among genes from different associated regions, significance was defined by false discovery rate (FDR ≤ 5%). GRAIL gene prioritization: Gene Relationships Across Implicated Loci (GRAIL), was used to determine connectively between genes across OA implicated loci based on literature associations [22]. A GRAIL analysis was performed