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Analysis of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis threat locus.
Hum Mol Genet. 2017 Oct 01;26(19):3850-3858
Authors: Hackinger S, Trajanoska Ok, Styrkarsdottir U, Zengini E, Steinberg J, Ritchie GRS, Hatzikotoulas Ok, Gilly A, Evangelou E, Kemp JP, arcOGEN Consortium, GEFOS Consortium, Evans D, Ingvarsson T, Jonsson H, Thorsteinsdottir U, Stefansson Ok, McCaskie AW, Brooks RA, Wilkinson JM, Rivadeneira F, Zeggini E
Summary
Osteoarthritis (OA) is a typical complicated illness with excessive public well being burden and no healing remedy. Excessive bone mineral density (BMD) is related to an elevated threat of creating OA, suggesting a shared underlying biology. Right here, we carried out the primary systematic overlap evaluation of OA and BMD on a genome broad scale. We used abstract statistics from the GEFOS consortium for lumbar backbone (n?=?31,800) and femoral neck (n?=?32,961) BMD, and from the arcOGEN consortium for 3 OA phenotypes (hip, ncases=three,498; knee, ncases=three,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD rating regression we discovered a major genetic correlation between the mixed OA phenotype (hip and/or knee) and lumbar backbone BMD (rg=zero.18, P?=?2.23?×?10-2), which can be pushed by the presence of spinal osteophytes. We recognized 143 variants with proof for cross-phenotype affiliation which we took ahead for replication in unbiased large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a complete pattern dimension of as much as 23,425 circumstances and 236,814 controls. We discovered robustly replicating proof for affiliation with OA at rs12901071 (OR 1.08?95% CI 1.05-1.11, Pmeta=three.12?×?10-10), an intronic variant within the SMAD3 gene, which is understood to play a task in bone transforming and cartilage upkeep. We have been capable of affirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings present the primary systematic analysis of pleiotropy between OA and BMD, spotlight genes with organic relevance to each traits, and set up a strong new OA genetic threat locus at SMAD3.
PMID: 28934396 [PubMed – indexed for MEDLINE]