Abstract
We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10−12, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10−18, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.
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Change history
17 April 2017
In the version of this article initially published online, the name of author Maryam S. Daneshpour was spelled incorrectly. The error has been corrected in the print, PDF and HTML versions of this article.
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Acknowledgements
We thank all the study subjects for their valuable participation, the staff from all studies and the participating physicians. Full acknowledgments are given in the Supplementary Note.
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U.S., H.H., U.T., P.S., J.L. and K.S. designed the study and interpreted the results. T.I., H.J. and U.S. managed the phenotype data, recruitment and coordination of Icelandic subjects. O.A.A., I.S.A., A.B., T.F., G. Selbæk, H.S., C.C., L.S.L., I.J., N.J.S., P.S.B., A. Helgadottir, U.T., J.L., the arcOGEN consortium, L.A.K., J.I.M., T.R., C.W., F.H., F.A., M.S.D., N.L.S.T., J.M.K. and U.S. performed subject ascertainment, recruitment, management and coordination of samples from non-Icelandic populations. T.I. analyzed hip radiographs. H.S.J. and O.M. performed the genotyping. A.S., A.J., A.B.A., L.N.R., A.V., J.L., G.H.H. and H.H. carried out the expression experiments and analyzed the results. G.L.N. and A.B.A. designed and performed the NMD experiments. G.M., O.M., A.O., G. Sveinbjornsson, F.Z., G. Sulem, A. Helgason, A.K., D.G. and P.S. performed the bioinformatics analysis, whole-genome sequencing, genealogy, imputation and association analysis in the Icelandic data set. All authors contributed to the final version of the manuscript.
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U.S., H.H., A.S., G.L.N., A.B.A., G.H.H., A.J., A.M., A.O., G. Sveinbjornsson, F.Z., G. Sulem, A. Helgadottir, H.S.J., A. Helgason, H.S., S.G., T.R., O.M., G.M., A.K., I.J., D.G., P.S., U.T. and K.S. are employed by deCODE Genetics/Amgen, Inc.
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Styrkarsdottir, U., Helgason, H., Sigurdsson, A. et al. Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis. Nat Genet 49, 801–805 (2017). https://doi.org/10.1038/ng.3816
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DOI: https://doi.org/10.1038/ng.3816
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