title: Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31.
abstract: Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10(-10)) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10(-10)). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10(-11) (rs3204689).
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Unnur
authors.identifier: 0000000181468278
authors.initials: U
authors.lastname: Styrkarsdottir
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Hafdis T
authors.initials: HT
authors.lastname: Helgadottir
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nils
authors.initials: N
authors.lastname: Bomer
authors.affiliation: Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Metrustry
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Bierma-Zeinstra
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annelieke M
authors.initials: AM
authors.lastname: Strijbosch
authors.affiliation: 1] Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. [2] Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Evangelou
authors.affiliation: Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hart
authors.affiliation: 1] Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. [2] Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, The Netherlands. [3] Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: Arctic Mass, Reykjavik, Iceland.
authors.forename: Finnur F
authors.initials: FF
authors.lastname: Eiriksson
authors.affiliation: 1] Arctic Mass, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Margret
authors.initials: M
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Frigge
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Nigel K
authors.initials: NK
authors.lastname: Arden
authors.affiliation: 1] Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland. [2] Institution of Health Science, University of Akureyri, Akureyri, Iceland.
authors.forename: Thorvaldur
authors.initials: T
authors.lastname: Ingvarsson
authors.affiliation: Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lohmander
authors.affiliation: 1] Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. [2] Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Margreet
authors.initials: M
authors.lastname: Kloppenburg
authors.affiliation: 1] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Deptartment 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 Twin Research, King's College London, St. Thomas' Hospital, London, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Spector
authors.affiliation: 1] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Andre
authors.initials: A
authors.lastname: Uitterlinden
authors.affiliation: 1] Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. [2] Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, The Netherlands. [3] Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jonsdottir
authors.affiliation: 1] Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK. [2] Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.affiliation: 1] Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. [2] Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: van Meurs
authors.affiliation: 1] Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [2] Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Helgi
authors.initials: H
authors.lastname: Jonsson
authors.affiliation: 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D001483:Base Sequence; D002356:Cartilage / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D019295:Computational Biology; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006225:Hand / Q000473:pathology*; D006801:Humans; D007055:Iceland; D008969:Molecular Sequence Data; D009426:Netherlands; D010003:Osteoarthritis / Q000235:genetics* / Q000473:pathology; D050697:Retinal Dehydrogenase / Q000235:genetics*; D017422:Sequence Analysis, DNA; D006113:United Kingdom
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase
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