TY - JOUR
T1 - Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data
AU - Tachmazidou, Ioanna
AU - Hatzikotoulas, Konstantinos
AU - Southam, Lorraine
AU - Esparza-Gordillo, Jorge
AU - Haberland, Valeriia
AU - Zheng, Jie
AU - Johnson, Toby
AU - arcOGEN Consortium
AU - Koprulu, Mine
AU - Zengini, Eleni
AU - Steinberg, Julia
AU - Wilkinson, Jeremy M
AU - Bhatnagar, Sahir
AU - Hoffman, Joshua D
AU - Buchan, Natalie
AU - Süveges, Dániel
AU - Yerges-Armstrong, Laura
AU - Smith, George Davey
AU - Gaunt, Tom R
AU - Scott, Robert A
AU - McCarthy, Linda C
AU - Zeggini, Eleftheria
PY - 2019/2
Y1 - 2019/2
N2 - Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.
AB - Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.
KW - Adult
KW - Aged
KW - Biological Specimen Banks
KW - Case-Control Studies
KW - Female
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study/methods
KW - Humans
KW - Male
KW - Middle Aged
KW - Osteoarthritis, Hip/genetics
KW - Polymorphism, Single Nucleotide/genetics
KW - Quantitative Trait Loci/genetics
KW - United Kingdom
U2 - 10.1038/s41588-018-0327-1
DO - 10.1038/s41588-018-0327-1
M3 - Article
C2 - 30664745
SN - 1061-4036
VL - 51
SP - 230
EP - 236
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -