Cindy Boer

118 | Chapter 3.1 Abstract Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12,784 individuals (discovery: 8,743, replication: 4,011). Genome-wide sig- nificant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p-val- ue=3.5x10 −10 ) near the matrix Gla protein (MGP) gene and at chr12 (p-value=6.1x10 −9 ) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three addi- tional studies, which resulted in a highly significant association between the MGP vari- ant and hand OA (rs4764133, Beta meta =0.83, p-value meta =1.8x10 −15 ). This variant is high linkage disequilibriumwith a coding variant in MGP , a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was sig- nificantly lower compared with the MGP RNA expression of the reference allele (40.7%, p-value<5x10 −16 ). Conclusions Our results indicate that the association between the MGP variant and in- creased risk for hand OA is caused by a lower expression of MGP , which may increase the burden of hand OA by decreased inhibition of cartilage calcification.