Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis.
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.
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Unnur
http://orcid.org/0000-0001-8146-8278
U
Styrkarsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Hannes
H
Helgason
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Asgeir
A
Sigurdsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gudmundur L
GL
Norddahl
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Arna B
AB
Agustsdottir
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
Louise N
LN
Reynard
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
Amanda
A
Villalvilla
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gisli H
GH
Halldorsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Aslaug
A
Jonasdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Audur
A
Magnusdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Asmundur
http://orcid.org/0000-0002-4606-5163
A
Oddson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gerald
G
Sulem
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Florian
F
Zink
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gardar
G
Sveinbjornsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Department of Anthropology, University of Iceland, Reykjavik, Iceland.
Agnar
A
Helgason
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Hrefna S
HS
Johannsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Anna
A
Helgadottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Hreinn
H
Stefansson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Solveig
S
Gretarsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Thorunn
T
Rafnar
Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
Ina S
IS
Almdahl
Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.|Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
Anne
A
Brækhus
Department of Neurology, Akershus University Hospital, Lørenskog, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Tormod
T
Fladby
Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.|Faculty of Medicine, University of Oslo, Oslo, Norway.|Centre for Old Age Psychiatry Research, Innlandet Hospital Trust, Ottestad, Norway.
Geir
G
Selbæk
Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Farhad
F
Hosseinpanah
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Fereidoun
F
Azizi
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Jung Min
JM
Koh
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.
Nelson L S
http://orcid.org/0000-0002-3607-5819
NLS
Tang
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Maryam S
MS
Daneshpour
Division of Medical Oncology, Lozano Blesa University Hospital, Zaragoza, Spain.
Jose I
JI
Mayordomo
Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, USA.
Corrine
C
Welt
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.|NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Peter S
PS
Braund
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.|NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Nilesh J
NJ
Samani
Radboud University Medical Center, Radboud Institute for Health Science, Nijmegen, the Netherlands.
Lambertus A
LA
Kiemeney
Orthopaedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
L Stefan
http://orcid.org/0000-0002-5424-9448
LS
Lohmander
Nordic Bioscience, Herlev, Denmark.
Claus
C
Christiansen
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.
Ole A
http://orcid.org/0000-0002-4461-3568
OA
Andreassen
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Olafur
O
Magnusson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gisli
G
Masson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Augustine
A
Kong
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Immunology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
Ingileif
http://orcid.org/0000-0001-8339-150X
I
Jonsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Daniel
http://orcid.org/0000-0002-5222-9857
D
Gudbjartsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Patrick
http://orcid.org/0000-0001-7123-6123
P
Sulem
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Medicine, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
Helgi
H
Jonsson
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
John
J
Loughlin
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland.|Institution of Health Science, University of Akureyri, Akureyri, Iceland.
Thorvaldur
T
Ingvarsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Unnur
U
Thorsteinsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Kari
K
Stefansson
D019644:Arthroplasty, Replacement, Hip; D064236:Cartilage Oligomeric Matrix Protein / Q000235:genetics*; D002478:Cells, Cultured; D018389:Codon, Nonsense; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D016368:Frameshift Mutation; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007055:Iceland; D053208:Kaplan-Meier Estimate; D020125:Mutation, Missense; D015207:Osteoarthritis, Hip / Q000235:genetics* / Q000601:surgery; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods*
D064236:Cartilage Oligomeric Matrix Protein; D018389:Codon, Nonsense; D016326:Extracellular Matrix Proteins; C000596977:CHADL protein, human; C577553:TSP5 protein, human