Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Funding Information: T.R.G. and J.Z. receive research funding from GlaxoSmithKline. T.R.G. receives research funding from Biogen. U.S., K.S., L. Stefánsdóttir, G.B., S.H.L., U.T., and G. T. are employed by deCODE genetics/Amgen Inc. A.M.V. is a consultant for Zoe Global Ltd. All other authors report no competing interests. All Regeneron Genetics Center banner authors are current employees and/or stockholders of Regeneron Pharmaceuticals. Funding Information: We thank Nigel W. Rayner and Ahmed Elhakeem for their input. This research was conducted using the UK Biobank Resource under application numbers 9979 and 23359. G.D.S. and T.R.G. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol MC_UU_00011/1&4. A.M.V. is funded by the NIHR Nottingham BRC. J.Z. is funded by a Vice-Chancellor Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). Study design and project coordination, E. Zeggini; Writing Group, U.S. J.B.J.v.M. J.M.W. M.T.M.L. K.S.E.C. L.S. C.G.B. K.H. Y.Z. R.C.d.A. L. Stef?nsd?ttir, E. Zeggini, A.P.M. G.T. P.C.S. J.Z. and T.R.G.; Core Analyses, C.G.B. K. Hatzikotoulas, L. Southam, L. Stef?nsd?ttir, Y.Z. R.C.d.A. T.T.W. J.Z. A.H. M.T.-L. and J.M.W.; Individual Study Design and Principal Investigators, E. Zeggini, U.S. J.B.J.v.M. M.T.M.L. I.M. J.M.W. T.E. K. Hveem, S.I. K.S.E.C. A.T. A.M.V. K.S. P.E.S. P.C. G.D.S. J.H.T. T.R.G. S.A.L. G.C.B. A.G.U. U.T. P.K. J.H.K. arcOGEN Consortium, HUNT All-In Pain, ARGO Consortium, and Regeneron Genetics Center; Analyses, Genotyping, and Phenotyping in Individual Studies, C.G.B. K.H. L. Southam, J.M.W. L. Stef?nsd?ttir, Y.Z. R.C.d.A. T.T.W. J.Z. A.H. M.T.-L. A.H.S. C.T. E. Zengini, A.B. G.T. G.B. H.J. T.I. R.M. H.T. M.K. M.T. R.R.G.H.H.N. M.M. J.P.Y.C. D.S. J.-A.Z. A.L. M.B.J. L.F.T. B.W. M.E.G. J.S. M.S. G.A. A.G. S.H.L. arcOGEN Consortium, HUNT All-In Pain, ARGO Consortium, and Regeneron Genetics Center. All authors contributed to the final version of the manuscript. T.R.G. and J.Z. receive research funding from GlaxoSmithKline. T.R.G. receives research funding from Biogen. U.S. K.S. L. Stef?nsd?ttir, G.B. S.H.L. U.T. and G. T. are employed by deCODE genetics/Amgen Inc. A.M.V. is a consultant for Zoe Global Ltd. All other authors report no competing interests. All Regeneron Genetics Center banner authors are current employees and/or stockholders of Regeneron Pharmaceuticals. Funding Information: We thank Nigel W. Rayner and Ahmed Elhakeem for their input. This research was conducted using the UK Biobank Resource under application numbers 9979 and 23359. G.D.S. and T.R.G. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol MC_UU_00011/1&4. A.M.V. is funded by the NIHR Nottingham BRC . J.Z. is funded by a Vice-Chancellor Fellowship from the University of Bristol . This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit ( MC_UU_00011/4 ). Publisher Copyright: © 2021 The Authors Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.Peer reviewe