Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

Unnur Styrkarsdottir¹, Gudmar Thorleifsson¹, Hafdis T Helgadottir¹, Nils Bomer², Sarah Metrustry³, S Bierma-Zeinstra⁴, Annelieke M Strijbosch², Evangelos Evangelou⁵, Deborah Hart³, Marian Beekman⁶, Aslaug Jonasdottir¹, Asgeir Sigurdsson¹, Finnur F Eiriksson⁷, Margret Thorsteinsdottir⁸, Michael L Frigge¹, Augustine Kong¹, Sigurjon A Gudjonsson¹, Olafur T Magnusson¹, Gisli Masson¹; TREAT-OA Consortium; arcOGEN Consortium; Albert Hofman⁹, Nigel K Arden¹⁰, Thorvaldur Ingvarsson¹¹, Stefan Lohmander¹², Margreet Kloppenburg¹³, Fernando Rivadeneira¹⁴, Rob G H H Nelissen¹⁵, Tim Spector³, Andre Uitterlinden¹⁴, P Eline Slagboom⁶, Unnur Thorsteinsdottir¹⁶, Ingileif Jonsdottir¹⁶, Ana M Valdes¹⁷, Ingrid Meulenbelt¹⁸, Joyce van Meurs⁴, Helgi Jonsson¹⁹, Kari Stefansson¹⁶

Affiliations

¹ deCODE Genetics/Amgen, Reykjavik, Iceland.
² Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.
⁴ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁵ 1] Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. [2] Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁶ 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.
⁷ Arctic Mass, Reykjavik, Iceland.
⁸ 1] Arctic Mass, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁹ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁰ National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK.
¹¹ 1] Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland. [2] Institution of Health Science, University of Akureyri, Akureyri, Iceland.
¹² Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden.
¹³ 1] Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. [2] Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁴ 1] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁵ Deptartment of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁶ 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁷ 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.
¹⁸ 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.
¹⁹ 1] Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [2] Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.

PMID: 24728293
DOI: 10.1038/ng.2957

Meta-Analysis

Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

Unnur Styrkarsdottir et al. Nat Genet. 2014 May.

. 2014 May;46(5):498-502.

doi: 10.1038/ng.2957. Epub 2014 Apr 13.

Authors

Affiliations

¹ deCODE Genetics/Amgen, Reykjavik, Iceland.
² Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.
⁴ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁵ 1] Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. [2] Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁶ 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.
⁷ Arctic Mass, Reykjavik, Iceland.
⁸ 1] Arctic Mass, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁹ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁰ National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK.
¹¹ 1] Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland. [2] Institution of Health Science, University of Akureyri, Akureyri, Iceland.
¹² Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden.
¹³ 1] Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. [2] Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁴ 1] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁵ Deptartment of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁶ 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁷ 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.
¹⁸ 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.
¹⁹ 1] Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [2] Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.

PMID: 24728293
DOI: 10.1038/ng.2957

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).

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Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

Affiliations

Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

Authors

Affiliations

Abstract

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Medical