Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus
arcOGEN Consortium, GEFOS Consortium,
Human Molecular Genetics
Oxford University Press
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Hackinger, S., Trajanoska, K., Styrkarsdottir, U., Zengini, E., Steinberg, J., Ritchie, G., Hatzikotoulas, K., et al. (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. https://doi.org/10.1093/hmg/ddx285
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, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=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 (rg=0.18, P = 2.23 × 10-2), 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 1.08 95% CI 1.05-1.11, Pmeta=3.12 × 10-10), 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.
phenotype, bone mineral density, bone remodeling, cartilage, exostoses, neck of femur, genes, genome, hip region, introns, knee region, knee joint, lumbar vertebra, osteoarthritis, single nucleotide polymorphism, genetics, pleiotropism, causality, smad3 gene, datasets
This work was funded by the Wellcome Trust (WT098051).
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK062418)
National Institute for Health Research (NIHR) (unknown)
External DOI: https://doi.org/10.1093/hmg/ddx285
This record's URL: https://www.repository.cam.ac.uk/handle/1810/269460
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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