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Nat Genet. 2017 May;49(5):801-805. doi: 10.1038/ng.3816. Epub 2017 Mar 20.

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

Author information

1
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
2
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
3
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
4
Department of Anthropology, University of Iceland, Reykjavik, Iceland.
5
Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
6
Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
7
Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
8
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
9
Faculty of Medicine, University of Oslo, Oslo, Norway.
10
Centre for Old Age Psychiatry Research, Innlandet Hospital Trust, Ottestad, Norway.
11
Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
12
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
13
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
14
Department of Chemical Pathology and Laboratory for Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, and School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
15
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
16
Division of Medical Oncology, Lozano Blesa University Hospital, Zaragoza, Spain.
17
Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, USA.
18
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
19
NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
20
Radboud University Medical Center, Radboud Institute for Health Science, Nijmegen, the Netherlands.
21
Orthopaedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
22
Nordic Bioscience, Herlev, Denmark.
23
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
24
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
25
Department of Immunology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
26
Department of Medicine, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
27
Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland.
28
Institution of Health Science, University of Akureyri, Akureyri, Iceland.

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.

PMID:
28319091
DOI:
10.1038/ng.3816
[Indexed for MEDLINE]

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