Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus

Hackinger, Sophie, Trajanoska, Katerina, Styrkarsdottir, Unnur, Zengini, Eleni, Steinberg, Julia, Ritchie, Graham R.S., Hatzikotoulas, Konstantinos, Gilly, Arthur, Evangelou, Evangelos, Kemp, John P., Evans, David, Ingvarsson, Thorvaldur, Jonsson, Helgi, Thorsteinsdottir, Unnur, Stefansson, Kari, McCaskie, Andrew W., Brooks, Roger A., Wilkinson, Jeremy M., Rivadeneira, Fernando and Zeggini, Eleftheria (2017) Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus. Human Molecular Genetics, 26 19: 3850-3858. doi:10.1093/hmg/ddx285


Author Hackinger, Sophie
Trajanoska, Katerina
Styrkarsdottir, Unnur
Zengini, Eleni
Steinberg, Julia
Ritchie, Graham R.S.
Hatzikotoulas, Konstantinos
Gilly, Arthur
Evangelou, Evangelos
Kemp, John P.
Evans, David
Ingvarsson, Thorvaldur
Jonsson, Helgi
Thorsteinsdottir, Unnur
Stefansson, Kari
McCaskie, Andrew W.
Brooks, Roger A.
Wilkinson, Jeremy M.
Rivadeneira, Fernando
Zeggini, Eleftheria
Title Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 1460-2083
0964-6906
Publication date 2017-10-01
Sub-type Article (original research)
DOI 10.1093/hmg/ddx285
Open Access Status Not yet assessed
Volume 26
Issue 19
Start page 3850
End page 3858
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 1312 Molecular Biology
1311 Genetics
2716 Genetics (clinical)
Abstract Osteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n=31,800) and femoral neck (n=32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, n=3,498; knee, n=3,266; hip and/or knee, n=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (r=0.18, P=2.23×10), which may be driven by the presence of spinal osteophytes.We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.0895% CI 1.05-1.11, P=3.12×10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID U01 DK062418
WT098051
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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Created: Sat, 16 Dec 2017, 20:59:12 EST