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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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.
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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.
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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.
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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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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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DOI: https://doi.org/10.1038/ng.2957
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