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

Unnur Styrkarsdottir*, Gudmar Thorleifsson, Hafdis T. Helgadottir, Nils Bomer, Sarah Metrustry, S. Bierma-Zeinstra, Annelieke M. Strijbosch, Evangelos Evangelou, Deborah Hart, Marian Beekman, Aslaug Jonasdottir, Asgeir Sigurdsson, Finnur F. Eiriksson, Margret Thorsteinsdottir, Michael L. Frigge, Augustine Kong, Sigurjon A. Gudjonsson, Olafur T. Magnusson, Gisli Masson, Albert HofmanNigel K. Arden, Thorvaldur Ingvarsson, Stefan Lohmander, Margreet Kloppenburg, Fernando Rivadeneira, Rob G.H.H. Nelissen, Tim Spector, Andre Uitterlinden, P. Eline Slagboom, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Ana M. Valdes, Ingrid Meulenbelt, Joyce Van Meurs, Helgi Jonsson, Kari Stefansson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)498-502
Number of pages5
JournalNature Genetics
Volume46
Issue number5
DOIs
Publication statusPublished - May 2014

Bibliographical note

Funding Information:
1deCODE Genetics/Amgen, Reykjavik, Iceland. 2Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3Department of Twin Research, King’s College London, St. Thomas’ Hospital, London, UK. 4Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 5Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. 6Department of Epidemiology and Biostatistics, Imperial College London, London, UK. 7Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, The Netherlands. 8Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands. 9Arctic Mass, Reykjavik, Iceland. 10Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 11Full list of members and affiliations appears in the Supplementary Note. 12Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 13National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK. 14Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland. 15Institution of Health Science, University of Akureyri, Akureyri, Iceland. 16Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden. 17Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 18Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. 19Deptartment of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands. 20Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK. 21Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. Correspondence should be addressed to K.S. (kstefans@decode.is) or U.S. (unnur.styrkarsdottir@decode.is).

Funding Information:
We thank the subjects of the deCODE study, the Rotterdam study, the GARP, LLS, RAAK and PAPRIKA studies, the TwinsUK and Chingford studies, and the MDC study for their valuable participation. This work was supported by European Union Framework Programme 7 grant 200800 TREAT-OA. Full acknowledgments are given in the Supplementary Note.

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