Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

arcOGEN Consortium; HUNT All-In Pain; ARGO Consortium; Regeneron Genetics Center

doi:10.1016/j.cell.2021.07.038

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

arcOGEN Consortium, HUNT All-In Pain, ARGO Consortium, Regeneron Genetics Center

Research output: Contribution to journal › Article › peer-review

214 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	4784-4818.e17
Journal	Cell
Volume	184
Issue number	18
DOIs	https://doi.org/10.1016/j.cell.2021.07.038
Publication status	Published - 2 Sept 2021

Keywords

drug targets
effector genes
functional genomics
genetic architecture
genome-wide association meta-analysis
osteoarthritis

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10.1016/j.cell.2021.07.038

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@article{bbd04b9e312f403d90a221a1e59353c2,

title = "Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations",

abstract = "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.",

keywords = "drug targets, effector genes, functional genomics, genetic architecture, genome-wide association meta-analysis, osteoarthritis",

author = "{arcOGEN Consortium} and {HUNT All-In Pain} and {ARGO Consortium} and {Regeneron Genetics Center} and Boer, {Cindy G.} and Konstantinos Hatzikotoulas and Lorraine Southam and Lilja Stef{\'a}nsd{\'o}ttir and Yanfei Zhang and {Coutinho de Almeida}, Rodrigo and Wu, {Tian T.} and Jie Zheng and April Hartley and Maris Teder-Laving and Skogholt, {Anne Heidi} and Chikashi Terao and Eleni Zengini and George Alexiadis and Andrei Barysenka and Gyda Bjornsdottir and Gabrielsen, {Maiken E.} and Arthur Gilly and Thorvaldur Ingvarsson and Johnsen, {Marianne B.} and Helgi Jonsson and Margreet Kloppenburg and Almut Luetge and Lund, {Sigrun H.} and Reedik M{\"a}gi and Massimo Mangino and Nelissen, {Rob R.G.H.H.} and Manu Shivakumar and Julia Steinberg and Hiroshi Takuwa and Thomas, {Laurent F.} and Margo Tuerlings and John Loughlin and Nigel Arden and Fraser Birrell and Andrew Carr and Panos Deloukas and Michael Doherty and McCaskie, {Andrew W.} and Ollier, {William E.R.} and Ashok Rai and Ralston, {Stuart H.} and Spector, {Tim D.} and Wallis, {Gillian A.} and Martinsen, {Amy E.} and Cristen Willer and Fors, {Egil Andreas} and Ingunn Mundal and Knut Hagen and Valdes, {Ana M.}",

note = "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. Stef{\'a}nsd{\'o}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). 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: {\textcopyright} 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

day = "2",

doi = "10.1016/j.cell.2021.07.038",

language = "English",

volume = "184",

pages = "4784--4818.e17",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "18",

}

TY - JOUR

T1 - Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

AU - arcOGEN Consortium

AU - HUNT All-In Pain

AU - ARGO Consortium

AU - Regeneron Genetics Center

AU - Boer, Cindy G.

AU - Hatzikotoulas, Konstantinos

AU - Southam, Lorraine

AU - Stefánsdóttir, Lilja

AU - Zhang, Yanfei

AU - Coutinho de Almeida, Rodrigo

AU - Wu, Tian T.

AU - Zheng, Jie

AU - Hartley, April

AU - Teder-Laving, Maris

AU - Skogholt, Anne Heidi

AU - Terao, Chikashi

AU - Zengini, Eleni

AU - Alexiadis, George

AU - Barysenka, Andrei

AU - Bjornsdottir, Gyda

AU - Gabrielsen, Maiken E.

AU - Gilly, Arthur

AU - Ingvarsson, Thorvaldur

AU - Johnsen, Marianne B.

AU - Jonsson, Helgi

AU - Kloppenburg, Margreet

AU - Luetge, Almut

AU - Lund, Sigrun H.

AU - Mägi, Reedik

AU - Mangino, Massimo

AU - Nelissen, Rob R.G.H.H.

AU - Shivakumar, Manu

AU - Steinberg, Julia

AU - Takuwa, Hiroshi

AU - Thomas, Laurent F.

AU - Tuerlings, Margo

AU - Loughlin, John

AU - Arden, Nigel

AU - Birrell, Fraser

AU - Carr, Andrew

AU - Deloukas, Panos

AU - Doherty, Michael

AU - McCaskie, Andrew W.

AU - Ollier, William E.R.

AU - Rai, Ashok

AU - Ralston, Stuart H.

AU - Spector, Tim D.

AU - Wallis, Gillian A.

AU - Martinsen, Amy E.

AU - Willer, Cristen

AU - Fors, Egil Andreas

AU - Mundal, Ingunn

AU - Hagen, Knut

AU - Valdes, Ana M.

N1 - 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: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9/2

Y1 - 2021/9/2

N2 - 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.

AB - 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.

KW - drug targets

KW - effector genes

KW - functional genomics

KW - genetic architecture

KW - genome-wide association meta-analysis

KW - osteoarthritis

UR - http://www.scopus.com/inward/record.url?scp=85114044916&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.07.038

DO - 10.1016/j.cell.2021.07.038

M3 - Article

AN - SCOPUS:85114044916

SN - 0092-8674

VL - 184

SP - 4784-4818.e17

JO - Cell

JF - Cell

IS - 18

ER -

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Abstract

Keywords

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