Novel susceptability loci for osteoarthritis of the hand: Variants in coding EN GENE regulatory regions

Abstract

Purpose: Osteoarthritis (OA) of the hand, is to a large extend, genetically determined. However, despite the large GWAS efforts into OA over the last years only one locus has been found to be associated to hand OA. We here aim to identify novel genes and pathways involved in the etiology of hand OA. Methods: We conducted a genome-wide association study of hand OA in a discovery set of 10,155 participants from the three Rotterdam Study cohorts (RS1, RS2 and RS3) using standardized age and gender adjustments. We have used a quantitative bilateral hand OA phenotype, summing all KL-scores of the hand joints for both hands (min score: 0, max score: 128). EasyQC was used to conduct quality control across cohorts. Results were combined in a jointed meta-analysis using inverse variance weighting. Genome-wide significant signals were analyzes for enrichment in genomic regulatory regions, using data from the ENCODE and Roadmap epigenetics project. Results: The discovery analysis yielded 16 loci with suggestive evidence for association (P<5*10-6 ) and another 3 loci with genome-wide significant association (p<5*10-8). These novel genome-wide significant loci include SNPs in or near the MGP, PTHLH and APBB2 genes. The risk alleles of MGP, PTHLH and APBB2 genes had a higher KL-sum score compared to the reference allele (delta KL-score was 7, 6, and 23 respectively) MGP codes for Matrix Gla Protein and is important for limiting calcification in tissues. Mutations in the MGP gene have been associated to Keutel Syndrome, which is characterized by abnormal mineralization of cartilage tissue. We here identified a SNP resulting in a protein-change to be associated with hand OA. The identified SNPs in the PTHLH-locus and the APBB2-locus co-localize with enhancer histone markers in osteoblast and chondrogenic cells from the Roadmap and ENCODE database, suggesting a potential gene regulatory function for these SNPs. Conclusions: We identified 3 loci to be associated to hand OA, a coding variant in the MPG gene and two intronic variants in APBB2 and CCDC91 located near gene regulatory marks specific for bone and/or cartilage. In addition, we have also found 16 loci suggestively associated to hand OA. Future analysis will consist of validation of our findings in other cohorts and further functional assessment and pathway analyses of the identified variants