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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Unnur Styrkarsdottir
  • Hannes Helgason
  • Asgeir Sigurdsson
  • Gudmundur L. Norddahl
  • Arna B. Agustsdottir
  • Louise N. Reynard
  • Amanda Villalvilla
  • Gisli H. Halldorsson
  • Aslaug Jonasdottir
  • Audur Magnusdottir
  • Asmundur Oddson
  • Gerald Sulem
  • Florian Zink
  • Gardar Sveinbjornsson
  • Agnar Helgason
  • Hrefna S. Johannsdottir
  • Anna Helgadottir
  • Hreinn Stefansson
  • Solveig Gretarsdottir
  • Thorunn Rafnar
  • Ina S. Almdahl
  • Anne Brækhus
  • Tormod Fladby
  • Geir Selbæk
  • Farhad Hosseinpanah
  • Fereidoun Azizi
  • Jung Min Koh
  • Nelson L.S. Tang
  • Maryam S. Daneshpour
  • Jose I. Mayordomo
  • Corrine Welt
  • Peter S. Braund
  • Nilesh J. Samani
  • Lambertus A. Kiemeney
  • L. Stefan Lohmander
  • Claus Christiansen
  • Ole A. Andreassen
  • Olafur Magnusson
  • Gisli Masson
  • Augustine Kong
  • Ingileif Jonsdottir
  • Daniel Gudbjartsson
  • Patrick Sulem
  • Helgi Jonsson
  • John Loughlin
  • Thorvaldur Ingvarsson
  • Unnur Thorsteinsdottir
  • Kari Stefansson
  • arcOGEN consortium
Enheter & grupper
Externa organisationer
  • deCODE Genetics/Amgen, Inc.
  • University of Iceland
  • University of Newcastle upon Tyne
  • Akershus University Hospital
  • Vestfold Hospital
  • Oslo university hospital
  • University of Oslo
  • Innlandet Hospital Trust
  • University of Ulsan
  • Chinese University of Hong Kong
  • Shahid Beheshti University of Medical Sciences
  • Lozano Blesa University Hospital
  • University of Utah
  • University of Leicester
  • Glenfield Hospital
  • Radboud University Medical Center
  • Nordic Bioscience AS
  • National University Hospital of Iceland
  • University of Akureyri
  • Akureyri Central Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
  • Ortopedi
Originalspråkengelska
Sidor (från-till)801-805
Antal sidor5
TidskriftNature Genetics
Volym49
Utgåva nummer5
StatusPublished - 2017
PublikationskategoriForskning
Peer review utfördJa