title: Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.
abstract: Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Martha C
authors.initials: MC
authors.lastname: Castaño-Betancourt
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
authors.forename: Dan S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology. Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yolande F M
authors.initials: YF
authors.lastname: Ramos
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Cindy G
authors.identifier: http://orcid.org/0000-0003-4809-0044
authors.initials: CG
authors.lastname: Boer
authors.affiliation: Department of Twins Research and Genetic Epidemiology Unit, King's College London, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Metrustry
authors.affiliation: Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Youfang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology. Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: den Hollander
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.identifier: http://orcid.org/0000-0001-9754-073X
authors.initials: J
authors.lastname: van Rooij
authors.affiliation: Duke Molecular Physiology Institute and Division of Rheumatology. Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Kraus
authors.affiliation: Departments of Medicine and Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Yau
authors.affiliation: Departments of Medicine and Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, United States of America.
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.affiliation: Health Sciences Research Institute, University of Warwick, Warwick, United Kingdom.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Muir
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Harvard T.H. School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.affiliation: School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Doherty
authors.affiliation: School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Weiya
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Kraaij
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Epidemiology Division, Family Medicine and Public Health Department, University of California, San Diego, La Jolla, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Barrett-Connor
authors.affiliation: Respiratory, Inflammation, Autoimmunity Innovative Medicines, AstraZeneca AB, Mölndal, Sweden.
authors.forename: Rose A
authors.initials: RA
authors.lastname: Maciewicz
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and musculoskeletal sciences, University of Oxford, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Arden
authors.affiliation: Department of Orthopaedics, Leiden University Medical Center, Leiden The Netherlands.
authors.forename: Rob G H H
authors.initials: RG
authors.lastname: Nelissen
authors.affiliation: Department of Rheumatology and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Margreet
authors.initials: M
authors.lastname: Kloppenburg
authors.affiliation: Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Jordan
authors.affiliation: University of California at San Francisco, San Francisco, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Nevitt
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology. Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Eline P
authors.initials: EP
authors.lastname: Slagboom
authors.affiliation: Department of Twins Research and Genetic Epidemiology Unit, King's College London, London, United Kingdom.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Hart
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Floris
authors.initials: F
authors.lastname: Lafeber
authors.affiliation: Decode Genetics, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Styrkarsdottir
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: Department of Hygiene & Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.|Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Evangelou
authors.affiliation: Department of Twins Research and Genetic Epidemiology Unit, King's College London, London, United Kingdom.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: University of California at San Francisco, San Francisco, California.|School of Medicine, University of California, Davis, Sacramento, California.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology. Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
authors.affiliation: School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002356:Cartilage / Q000473:pathology; D058543:Class Ia Phosphatidylinositol 3-Kinase; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006621:Hip Joint / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D014198:Trehalase / Q000235:genetics*
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D016211:Transforming Growth Factor alpha; D014198:Trehalase; C587886:TGFA protein, human; C588001:PIK3R1 protein, human; C496365:FGFR3 protein, human