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.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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TitleDeciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
DateSeptember 2nd, 2021
Issue nameCell
Issue numberv184.18:4784-4818.e17
DOI10.1016/j.cell.2021.07.038
AuthorsBoer CG, Hatzikotoulas K, Southam L, Stefánsdóttir L, Zhang Y, Coutinho de Almeida R, Wu TT, Zheng J, Hartley A, Teder-Laving M, Skogholt AH, Terao C, Zengini E, Alexiadis G, Barysenka A, Bjornsdottir G, Gabrielsen ME, Gilly A, Ingvarsson T, Johnsen MB, Jonsson H, Kloppenburg M, Luetge A, Lund SH, Mägi R, Mangino M, Nelissen RRGHH, Shivakumar M, Steinberg J, Takuwa H, Thomas LF, Tuerlings M, Babis GC, Cheung JPY, Kang JH, Kraft P, Lietman SA, Samartzis D, Slagboom PE, Stefansson K, Thorsteinsdottir U, Tobias JH, Uitterlinden AG, Winsvold B, Zwart JA, Davey Smith G, Sham PC, Thorleifsson G, Gaunt TR, Morris AP, Valdes AM, Tsezou A, Cheah KSE, Ikegawa S, Hveem K, Esko T, Wilkinson JM, Meulenbelt I, Lee MTM, van Meurs JBJ, Styrkársdóttir U & Zeggini E
InfoLoughlin J, Arden N, Birrell F, Carr A, Deloukas P, Doherty M, McCaskie AW, Ollier WER, Rai A, Ralston SH, Spector TD, Wallis GA, Martinsen AE, Willer C, Fors EA, Mundal I, Hagen K, Nilsen KB, Lie MU, Børte S, Brumpton B, Nielsen JB, Fritsche LG, Zhou W, Heuch I, Storheim K, Tyrpenou E, Koukakis A, Chytas D, Evangelopoulos DS, Efstathios C, Pneumaticos S, Nikolaou VS, Malizos K, Anastasopoulou L, Abecasis G, Baras A, Cantor M, Coppola G, Deubler A, Economides A, Lotta LA, Overton JD, Reid JG, Shuldiner A, Karalis K, Siminovitch K, Beechert C, Forsythe C, Fuller ED, Gu Z, Lattari M, Lopez A, Schleicher TD, Padilla MS, Widom L, Wolf SE, Pradhan M, Manoochehri K, Bai X, Balasubramanian S, Boutkov B, Eom G, Habegger L, Hawes A, Krasheninina O, Lanche R, Mansfield AJ, Maxwell EK, Nafde M, O'Keeffe S, Orelus M, Panea R, Polanco T, Rasool A, Salerno W, Staples JC, Li D, Sharma D, Banerjee I, Bovijn J, Locke A, Verweij N, Haas M, Hindy G, De T, Akbari P, Sosina O, Ferreira MAR, Jones MB, Mighty J, LeBlanc MG, Mitnaul LJ
Keywordsdrug targets, effector genes, functional genomics, genetic architecture, genome-wide association meta-analysis, osteoarthritis
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