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Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis

Lookup NU author(s): Dr Louise Reynard, Dr Amanda Villalvilla Garcia, Professor John LoughlinORCiD



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2017.

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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.

Publication metadata

Author(s): Styrkarsdottir U, Helgason H, Sigurdsson A, Norddahl GL, Agustsdottir AB, Reynard LN, Villalvilla A, Halldorsson GH, Jonasdottir A, Magnusdottir A, Oddson A, Sulem G, Zink F, Sveinbjornsson G, Helgason A, Johannsdottir HS, Helgadottir A, Stefansson H, Gretarsdottir S, Rafnar T, Almdahl IS, Brækhus A, Fladby T, Selbæk G, Hosseinpana F, Azizi F, Koh JM, Tang NL, Danesphour M, Mayordomo JI, Welt C, Braund PS, Samani NJ, Kiemeney LA, Lohmander LS, Christiansen C, Andreassen OA, arcOGEN consortium, Magnusson O, Masson G, Kong A, Jonsdottir I, Gudbjartsson D, Sulem P, Jonsson H, Loughlin J, Ingvarsson T, Thorsteinsdottir U, Stefansson K

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2017

Volume: 49

Issue: 5

Pages: 801-805

Print publication date: 01/05/2017

Online publication date: 20/03/2017

Acceptance date: 23/02/2017

Date deposited: 11/06/2018

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group


DOI: 10.1038/ng.3816

PubMed id: 28319091


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