A Variant in MCF2L Is Associated with Osteoarthritis

Aaron G. Day-Williams, Lorraine Southam, Kalliope Panoutsopoulou, Nigel W. Rayner, Tonu Esko, Karol Estrada, Hafdis T. Helgadottir, Albert Hofman, Throvaldur Ingvarsson, Helgi Jonsson, Aime Keis, Hanneke J.M. Kerkhof, Gudmar Thorleifsson, Nigel K. Arden, Andrew Carr, Kay Chapman, Panos Deloukas, John Loughlin, Andrew McCaskie, William E.R. Ollier, Stuart H. Ralston, Timothy D. Spector, Gillian A. Wallis, J. Mark Wilkinson, Nadim Aslam, Fraser Birell, Ian Carluke, John Joseph, Ashok Rai, Mike Reed, Kirsten Walker, arcOGEN Consortium, Sally A. Doherty, Ingileif Jonsdottir, Rose A. Maciewicz, Kenneth R. Muir, Andres Metspalu, Fernando Rivadeneira, Kari Stefansson, Unnur Styrkarsdottir, Andre G. Uitterlinden, Joyce B.J. van Meurs, Weiya Zhang, Ana M. Valdes, Michael Doherty, Eleftheria Zeggini

Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 × 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.