Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
drug targets
effector genes
functional genomics
genetic architecture
genome-wide association meta-analysis
osteoarthritis
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
02 09 2021
02 09 2021
Historique:
received:
09
10
2020
revised:
26
03
2021
accepted:
30
07
2021
pubmed:
28
8
2021
medline:
5
1
2022
entrez:
27
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34450027
pii: S0092-8674(21)00941-7
doi: 10.1016/j.cell.2021.07.038
pmc: PMC8459317
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4784-4818.e17Subventions
Organisme : Medical Research Council
ID : MC_UU_00011/1&4
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/4
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K017047/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R015635/1
Pays : United Kingdom
Investigateurs
John Loughlin
(J)
Nigel Arden
(N)
Fraser Birrell
(F)
Andrew Carr
(A)
Panos Deloukas
(P)
Michael Doherty
(M)
Andrew W McCaskie
(AW)
William E R Ollier
(WER)
Ashok Rai
(A)
Stuart H Ralston
(SH)
Tim D Spector
(TD)
Gillian A Wallis
(GA)
Amy E Martinsen
(AE)
Cristen Willer
(C)
Egil Andreas Fors
(EA)
Ingunn Mundal
(I)
Knut Hagen
(K)
Kristian Bernhard Nilsen
(KB)
Marie Udnesseter Lie
(MU)
Sigrid Børte
(S)
Ben Brumpton
(B)
Jonas Bille Nielsen
(JB)
Lars G Fritsche
(LG)
Wei Zhou
(W)
Ingrid Heuch
(I)
Kjersti Storheim
(K)
Evangelos Tyrpenou
(E)
Athanasios Koukakis
(A)
Dimitrios Chytas
(D)
Dimitrios Stergios Evangelopoulos
(DS)
Chronopoulos Efstathios
(C)
Spiros Pneumaticos
(S)
Vasileios S Nikolaou
(VS)
Konstantinos Malizos
(K)
Lydia Anastasopoulou
(L)
Goncalo Abecasis
(G)
Aris Baras
(A)
Michael Cantor
(M)
Giovanni Coppola
(G)
Andrew Deubler
(A)
Aris Economides
(A)
Luca A Lotta
(LA)
John D Overton
(JD)
Jeffrey G Reid
(JG)
Alan Shuldiner
(A)
Katia Karalis
(K)
Katherine Siminovitch
(K)
Christina Beechert
(C)
Caitlin Forsythe
(C)
Erin D Fuller
(ED)
Zhenhua Gu
(Z)
Michael Lattari
(M)
Alexander Lopez
(A)
Thomas D Schleicher
(TD)
Maria Sotiropoulos Padilla
(MS)
Louis Widom
(L)
Sarah E Wolf
(SE)
Manasi Pradhan
(M)
Kia Manoochehri
(K)
Xiaodong Bai
(X)
Suganthi Balasubramanian
(S)
Boris Boutkov
(B)
Gisu Eom
(G)
Lukas Habegger
(L)
Alicia Hawes
(A)
Olga Krasheninina
(O)
Rouel Lanche
(R)
Adam J Mansfield
(AJ)
Evan K Maxwell
(EK)
Mona Nafde
(M)
Sean O'Keeffe
(S)
Max Orelus
(M)
Razvan Panea
(R)
Tommy Polanco
(T)
Ayesha Rasool
(A)
William Salerno
(W)
Jeffrey C Staples
(JC)
Dadong Li
(D)
Deepika Sharma
(D)
Ilanjana Banerjee
(I)
Jonas Bovijn
(J)
Adam Locke
(A)
Niek Verweij
(N)
Mary Haas
(M)
George Hindy
(G)
Tanima De
(T)
Parsa Akbari
(P)
Olukayode Sosina
(O)
Manuel A R Ferreira
(MAR)
Marcus B Jones
(MB)
Jason Mighty
(J)
Michelle G LeBlanc
(MG)
Lyndon J Mitnaul
(LJ)
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests 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.
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