| Literature DB >> 28319091 |
Unnur Styrkarsdottir1, Hannes Helgason1,2, Asgeir Sigurdsson1, Gudmundur L Norddahl1, Arna B Agustsdottir1, Louise N Reynard3, Amanda Villalvilla3, Gisli H Halldorsson1, Aslaug Jonasdottir1, Audur Magnusdottir1, Asmundur Oddson1, Gerald Sulem1, Florian Zink1, Gardar Sveinbjornsson1, Agnar Helgason1,4, Hrefna S Johannsdottir1, Anna Helgadottir1, Hreinn Stefansson1, Solveig Gretarsdottir1, Thorunn Rafnar1, Ina S Almdahl5, Anne Brækhus6,7, Tormod Fladby5,8, Geir Selbæk6,9,10, Farhad Hosseinpanah11, Fereidoun Azizi12, Jung Min Koh13, Nelson L S Tang14, Maryam S Daneshpour15, Jose I Mayordomo16, Corrine Welt17, Peter S Braund18,19, Nilesh J Samani18,19, Lambertus A Kiemeney20, L Stefan Lohmander21, Claus Christiansen22, Ole A Andreassen23, Olafur Magnusson1, Gisli Masson1, Augustine Kong1, Ingileif Jonsdottir1,24,25, Daniel Gudbjartsson1,2, Patrick Sulem1, Helgi Jonsson24,26, John Loughlin3, Thorvaldur Ingvarsson24,27,28, Unnur Thorsteinsdottir1,24, Kari Stefansson1,24.
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.Entities:
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Year: 2017 PMID： 28319091 DOI： 10.1038/ng.3816
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330