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

Styrkarsdottir, Unnur ; Helgason, Hannes ; Sigurdsson, Asgeir ; Norddahl, Gudmundur L. LU ; Agustsdottir, Arna B. ; Reynard, Louise N. ; Villalvilla, Amanda ; Halldorsson, Gisli H. ; Jonasdottir, Aslaug and Magnusdottir, Audur , et al. (2017) In Nature Genetics 49(5). p.801-805
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... (More)

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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type
Contribution to journal
publication status
published
subject
in
Nature Genetics
volume
49
issue
5
pages
5 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:28319091
  • scopus:85015667730
ISSN
1061-4036
DOI
10.1038/ng.3816
language
English
LU publication?
yes
id
e53ff083-1adc-4d4d-b234-bb6c24bc63c0
date added to LUP
2020-04-23 11:38:20
date last changed
2025-03-06 15:48:05
@article{e53ff083-1adc-4d4d-b234-bb6c24bc63c0,
  abstract     = {{<p>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&gt;C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10<sup>-12</sup>, 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<sup>-18</sup>, OR = 7.71). On average, c.1141G&gt;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.</p>}},
  author       = {{Styrkarsdottir, Unnur and Helgason, Hannes and Sigurdsson, Asgeir and Norddahl, Gudmundur L. and Agustsdottir, Arna B. and Reynard, Louise N. and Villalvilla, Amanda and Halldorsson, Gisli H. and Jonasdottir, Aslaug and Magnusdottir, Audur and Oddson, Asmundur and Sulem, Gerald and Zink, Florian and Sveinbjornsson, Gardar and Helgason, Agnar and Johannsdottir, Hrefna S. and Helgadottir, Anna and Stefansson, Hreinn and Gretarsdottir, Solveig and Rafnar, Thorunn and Almdahl, Ina S. and Brækhus, Anne and Fladby, Tormod and Selbæk, Geir and Hosseinpanah, Farhad and Azizi, Fereidoun and Koh, Jung Min and Tang, Nelson L.S. and Daneshpour, Maryam S. and Mayordomo, Jose I. and Welt, Corrine and Braund, Peter S. and Samani, Nilesh J. and Kiemeney, Lambertus A. and Lohmander, L. Stefan and Christiansen, Claus and Andreassen, Ole A. and Magnusson, Olafur and Masson, Gisli and Kong, Augustine and Jonsdottir, Ingileif and Gudbjartsson, Daniel and Sulem, Patrick and Jonsson, Helgi and Loughlin, John and Ingvarsson, Thorvaldur and Thorsteinsdottir, Unnur and Stefansson, Kari}},
  issn         = {{1061-4036}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{801--805}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis}},
  url          = {{http://dx.doi.org/10.1038/ng.3816}},
  doi          = {{10.1038/ng.3816}},
  volume       = {{49}},
  year         = {{2017}},
}