title: Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis.
abstract: OBJECTIVE
  Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA.
  
  
  METHODS
  A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage.
  
  
  RESULTS
  We report suggestive evidence (p<5×10-6) of association at 6 variants with OA endophenotypes that would have been missed by using presence of hip OA as the disease end point. For example, in the analysis of hip OA cases with superior maxJSN versus cases with non-superior maxJSN we detected association with a variant in theLRCH1gene (rs754106, p=1.49×10-7, OR (95% CIs) 0.70 (0.61 to 0.80)). In the comparison of hypertrophic with non-hypertrophic OA the most significant variant was located betweenSTT3BandGADL1(rs6766414, p=3.13×10-6, OR (95% CIs) 1.45 (1.24 to 1.69)). Both of these associations were fully attenuated in non-stratified analyses of all hip OA cases versus population controls (p>0.05).STT3Bwas significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10-4).
  
  
  CONCLUSIONS
  Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity.
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Kalliope
authors.initials: K
authors.lastname: Panoutsopoulou
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
authors.forename: Shankar
authors.initials: S
authors.lastname: Thiagarajah
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.|5th Psychiatric Department, Dromokaiteio Psychiatric Hospital of Athens, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Zengini
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.|Department of Genomics and Computational Biology, Biogen Idec, Cambridge, Massachusetts, USA.
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Day-Williams
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands.
authors.forename: Yolande Fm
authors.initials: YF
authors.lastname: Ramos
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands.|Department of Orthopaedics, LUMC, Leiden, The Netherlands.
authors.forename: Jennifer Mta
authors.initials: JM
authors.lastname: Meessen
authors.affiliation: Department of Orthopaedics, LUMC, Leiden, The Netherlands.
authors.forename: Kasper
authors.initials: K
authors.lastname: Huetink
authors.affiliation: Department of Orthopaedics, LUMC, Leiden, The Netherlands.
authors.forename: Rob Ghh
authors.initials: RG
authors.lastname: Nelissen
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.|Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.|Wellcome Trust Centre for Human Genetics, Oxford, UK.|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: N William
authors.initials: NW
authors.lastname: Rayner
authors.affiliation: Academic Rheumatology, University of Nottingham, Nottingham, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Wilkinson
mesh_terms: D001284:Atrophy; D016723:Bone Remodeling / Q000235:genetics; D002358:Cartilage, Articular / Q000000981:diagnostic imaging* / Q000378:metabolism; D058068:Endophenotypes; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006602:Hexosyltransferases / Q000235:genetics*; D006621:Hip Joint / Q000000981:diagnostic imaging* / Q000473:pathology; D006801:Humans; D006984:Hypertrophy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D015207:Osteoarthritis, Hip / Q000000981:diagnostic imaging* / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D044465:White People
chemical_list: C508643:LRCH1 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D006602:Hexosyltransferases; C551978:STT3B protein, human
keywords: Chondrocytes; Gene Polymorphism; Osteoarthritis