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

Nature Genetics volume 46, pages 498–502 (2014)Cite this article

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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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Figure 1: Regional association plot for the 15q22 ALDH1A2 locus.
Figure 2: Genotype-dependent expression of ALDH1A2 in adipose and cartilage tissues.
Figure 3: Pedigree of a family segregating the rare variants at 1p31.

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Acknowledgements

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.

Author information

Authors and Affiliations

  1. deCODE Genetics/Amgen, Reykjavik, Iceland

    Unnur Styrkarsdottir, Gudmar Thorleifsson, Hafdis T Helgadottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Michael L Frigge, Augustine Kong, Sigurjon A Gudjonsson, Olafur T Magnusson, Gisli Masson, Unnur Thorsteinsdottir, Ingileif Jonsdottir & Kari Stefansson

  2. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    Nils Bomer, Annelieke M Strijbosch, Marian Beekman, P Eline Slagboom & Ingrid Meulenbelt

  3. Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK

    Sarah Metrustry, Deborah Hart, Tim Spector & Ana M Valdes

  4. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    S Bierma-Zeinstra, Fernando Rivadeneira, Andre Uitterlinden & Joyce van Meurs

  5. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece

    Evangelos Evangelou

  6. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    Evangelos Evangelou

  7. Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, The Netherlands

    Marian Beekman & P Eline Slagboom

  8. Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands

    Marian Beekman, P Eline Slagboom & Ingrid Meulenbelt

  9. Arctic Mass, Reykjavik, Iceland

    Finnur F Eiriksson & Margret Thorsteinsdottir

  10. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Margret Thorsteinsdottir, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Helgi Jonsson & Kari Stefansson

  11. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

    Albert Hofman, Fernando Rivadeneira & Andre Uitterlinden

  12. National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK

    Nigel K Arden

  13. Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland

    Thorvaldur Ingvarsson

  14. Institution of Health Science, University of Akureyri, Akureyri, Iceland

    Thorvaldur Ingvarsson

  15. Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden

    Stefan Lohmander

  16. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    Margreet Kloppenburg

  17. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

    Margreet Kloppenburg

  18. Deptartment of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands

    Rob G H H Nelissen

  19. Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK

    Ana M Valdes

  20. Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland

    Helgi Jonsson

Authors
  1. Unnur Styrkarsdottir
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  2. Gudmar Thorleifsson
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  3. Hafdis T Helgadottir
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  7. Annelieke M Strijbosch
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  9. Deborah Hart
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Consortia

The TREAT-OA Consortium

arcOGEN Consortium

Contributions

The study was designed and results were interpreted by U.S., G.T., I.M., U.T., I.J., H.J. and K.S. Phenotype data and Icelandic subject recruitment were coordinated and managed by T.I. and H.J. D.H., S.M., N.K.A., T.S. and A.M.V. coordinated, managed, genotyped and analyzed the TwinsUK and Chingford cohort samples. M.B., M.K., P.E.S. and I.M. coordinated, managed, genotyped and analyzed the samples from the GARP, LLS, PAPRIKA and RAAK studies. A.H., F.R., A.U., S.B.-Z. and J.v.M. coordinated, managed, genotyped and analyzed the samples from the Rotterdam cohorts. S.L. coordinated and managed the samples from the MDC study. E.E. undertook the meta-analysis for the TreatOA consortium. G.M., U.T., G.T. and U.S. coordinated sequence data analysis, imputation and association analysis in the Icelandic data set. O.T.M. and S.A.G. performed exome sequencing and analysis. S.A.G., A.J. and A.S. carried out bioinformatics analysis for 1p31. Shared haplotype analysis was performed by M.L.F. and A.K. Sanger sequencing of Icelandic samples and Centaurus genotyping of Icelandic and Swedish samples were carried out and analyzed by H.T.H. and U.S. Expression experiments were carried out and analyzed by N.B., A.M.S., R.G.H.H.N., A.J., A.S., F.F.E. and M.T. The manuscript was drafted by U.S., G.T. and K.S. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Unnur Styrkarsdottir or Kari Stefansson.

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Competing interests

U.S., G.T., H.T.H., A.J., A.S., S.A.G., M.L.F., A.K., O.T.M., G.M., U.T., I.J. and K.S. are employed by deCODE Genetics/Amgen.

Additional information

Full list of members and affiliations appears in the Supplementary Note.

Full list of members and affiliations appears in the Supplementary Note.

Integrated supplementary information

Supplementary Figure 1 Manhattan plot of the discovery GWAS.

P values (–log10) are plotted against their respective positions on each chromosome. P = 5 × 10−8 is indicated by the horizontal pink line.

Supplementary Figure 2 Differential allelic expression of ALDH1A2 transcript in cartilage according to genotype at rs3204689.

Allelic imbalance depicted by allele ratios (G/C) plotted as log2 values for 22 individuals heterozygous for the rs3204689 SNP. Cartilage was isolated from the hip or knee joints of individuals with osteoarthritis. (a) Preserved (macroscopically normal) articular cartilage samples (N = 15). (b) Osteoarthritis-affected articular cartilage samples (N = 17). *P < 0.0005, **P < 0.0001, ***P < 0.00001.

Supplementary Figure 3 Genes in the 1p31 locus region.

Locations of genes in the region on 1p31 that is shared by all the affected carriers and the locations of the three associated markers and the LD blocks are shown. The genes are LINC00466 (long intergenic non-protein-coding RNA 466), FOXD3 (forkhead box D3), ALG6 (α-1,3-glucosyltransferase), ITGB3BP (integrin β3–binding protein), EFCAB7 (EF-hand calcium-binding domain 7), PGM1 (phosphoglucomutase 1) and ROR1 (receptor tyrosine kinase–like orphan receptor 1), and the pseudogene is DLEU2L (deleted in lymphocytic leukemia 2-like). All positions are in NCBI Build 36 coordinates. The plot was created using a stand-alone version of LocusZoom software35 (http://csg.sph.umich.edu/locuszoom/).

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Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–3 (PDF 1727 kb)

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Styrkarsdottir, U., Thorleifsson, G., Helgadottir, H. et al. Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nat Genet 46, 498–502 (2014). https://doi.org/10.1038/ng.2957

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