title: Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis.
abstract: OBJECTIVE
  The aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families.
  
  
  METHODS
  Genome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family.
  
  
  RESULTS
  Genome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele.
  
  
  CONCLUSIONS
  A potentially novel functional OA susceptibility variant was identified by targeted re-sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis.
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Center for Life Course Epidemiology and Systems Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Taipale
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Jakkula
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland.
authors.forename: O-P
authors.initials: OP
authors.lastname: Kämäräinen
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Gao
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Center for Life Course Epidemiology and Systems Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Skarp
authors.affiliation: Gertrude H. Sergievsky Center, College for Physicians and Surgeons, Columbia University, New York, USA.
authors.forename: S
authors.initials: S
authors.lastname: Barral
authors.affiliation: Department of Orthopaedics and Traumatology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Department of Orthopaedics and Traumatology, Jyväskylä Central Hospital, Jyväskylä, Finland.
authors.forename: I
authors.initials: I
authors.lastname: Kiviranta
authors.affiliation: Department of Orthopaedics and Traumatology, Kuopio University Hospital, Kuopio, Finland; Bone and Cartilage Research Unit, University of Eastern Finland, Kuopio, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Kröger
authors.affiliation: Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Ott
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland.
authors.forename: G-H
authors.initials: GH
authors.lastname: Wei
authors.affiliation: Connective Tissue Gene Tests, Allentown, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ala-Kokko
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Center for Life Course Epidemiology and Systems Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland. Electronic address: minna.mannikko@oulu.fi.
authors.forename: M
authors.initials: M
authors.lastname: Männikkö
mesh_terms: D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000235:genetics*; D020370:Osteoarthritis, Knee / Q000235:genetics*; D010375:Pedigree
keywords: Enhancer element; Hip; Knee; Linkage analysis; Next generation sequencing; Osteoarthritis