Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis

Styrkársdóttir, Unnur; Lund, Sigrún H.; Þorleifsson, Guðmar; Zink, Florian; Stefansson, Olafur A.; Sigurdsson, Jon K.; Juliusson, Kristinn; Bjarnadóttir, Kristbjörg; Sigurbjörnsdóttir, Sara; Jönsson, Stefan; Norland, Kristjan; Stefánsdóttir, Lilja; Sigurðsson, Ásgeir; Sveinbjörnsson, Garðar; Oddsson, Ásmundur; Björnsdóttir, Gyða; Gudmundsson, Reynir L.; Halldorsson, Gisli H.; Rafnar, Thorunn; Jónsdóttir, Ingileif; Steingrímsson, Eiríkur; Norddahl, Gudmundur L.; Másson, Gísli; Sulem, Patrick; Jónsson, Helgi; Ingvarsson, Þorvaldur; Guðbjartsson, Daníel F.; Þorsteinsdóttir, Unnur; Stefánsson, Kāri

doi:10.1038/s41588-018-0247-0

Cited by 134 publications

(160 citation statements)

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“…The two largest OA analyses were published within the last year and together they identified 56 new loci ( Fig. 1(B) and (C); 28,29 ). Unlike the majority of previous OA studies, which have employed the traditional GWAS design of signal discovery followed by replication, both studies performed a meta-analysis of the UKBB data together with the Icelandic deCODE genetics 28 or UK arcOGEN datasets 29 .…”

Section: Identification Of New Oa Genetic Risk Locimentioning

confidence: 99%

Osteoarthritis year in review 2019: genetics, genomics and epigenetics

Reynard

Barter

2020

Osteoarthritis and Cartilage

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s u m m a r yAlthough osteoarthritis (OA) aetiology is complex, genetic, genomic and epigenetic studies published within the last decade have advanced our understanding of the molecular processes underlying this common musculoskeletal disease. The purpose of this narrative review is to highlight the key research articles within the OA genetics, genomics and epigenetics fields that were published between April 2018 and April 2019. The review focuses on the identification of new OA genetic risk loci, genomics techniques that have been used for the first time in human cartilage and new publicly available databases, and datasets that will aid OA functional studies.Fifty-six new OA susceptibility loci were identified by two large scale genome wide association study meta-analyses, increasing the number of genome-wide significant risk loci to 90. OA risk variants are enriched near genes involved in skeletal development and morphology, and show genetic overlap with height, hip shape, bone area and developmental dysplasia of the hip. Several functional studies of OA loci were published, including a genome-wide analysis of genetic variation on cartilage gene expression. A specialised data portal for exploring cross-species skeletal transcriptomic datasets has been developed, and the first use of cartilage single cell RNAseq analysis reported. This year also saw the systematic identification of all microRNAs, long non-coding RNAs and circular RNAs expressed in human OA cartilage. Putative transcriptional regulatory regions have been mapped in human chondrocytes genome-wide, providing a dataset that will facilitate the prioritisation and characterisation of OA genetic and epigenetic loci.

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Section: Identification Of New Oa Genetic Risk Locimentioning

confidence: 99%

Osteoarthritis year in review 2019: genetics, genomics and epigenetics

Reynard

Barter

2020

Osteoarthritis and Cartilage

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“…In recent genome-wide association studies (GWAS) of hip and knee OA [5,6], 27 new loci conferring risk to OA were identified ( Table 2). To see whether those OA susceptibility genes are sensitive to OA pathophysiology in either the articular cartilage, the subchondral bone or both, we explored the expression levels and the differential expression between lesioned and preserved tissue of those genes in our data sets.…”

Section: Differential Expression Of Previously Identified Risk Genesmentioning

confidence: 99%

“…To find genes that are most likely causal to OA, we explored 27 previously published genes in which single nucleotide polymorphisms (SNPs) were identified as being genome-wide significantly associated with OA ( Table 2), suggesting that those genes have a more causal relationship to OA and making them attractive potential drug targets [5,6]. To see whether the previously identified OA risk genes are involved in the OA pathophysiological process in both tissues, we compared the expression levels and the differential expression between the preserved and lesioned samples ( Table 2).…”

Section: Differential Expression Analysis Of the Gene Expression Levementioning

confidence: 99%

“…CHADL, encoding Chondroadherin-Like Protein, is involved in collagen binding and is a negative modulator of chondrocyte differentiation. The OA susceptibility allele rs117018441-T, located in an intron of CHADL, marks higher expression of CHADL compared to rs117018441-G in skeletal muscle and adipose tissue (GTEx) [5,35]. This may indicate that increased expression of CHADL has a negative regulatory role both in bone and cartilage and that a therapeutic strategy could be the inhibition of this gene.…”

Section: Differential Expression Analysis Of the Gene Expression Levementioning

confidence: 99%

“…Development of OA is dependent on multiple factors, with both environmental and genetic components [2,3]. To discover genes and underlying disease pathways genetic studies, such as large genome wide association studies (GWAS), have been performed that identified compelling OA risk single nucleotide polymorphisms (SNPs) [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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RNA sequencing reveals interacting key determinants of osteoarthritis acting in subchondral bone and articular cartilage

Tuerlings

Hoolwerff

Houtman

et al. 2020

Preprint

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Objective: The aim of this study was to identify key determinants of the interactive osteoarthritis (OA) pathophysiological processes of subchondral bone and cartilage. Methods:We performed RNA sequencing on macroscopically preserved and lesioned OA subchondral bone of patients that underwent joint replacement surgery due to OA (N=24 pairs; 6 hips, 18 knees, RAAK-study). Unsupervised hierarchical clustering and differential expression analyses were performed. Results were combined with previously identified, differentially expressed genes in cartilage (partly overlapping samples) as well as with recently identified OA risk genes . Results:We identified 1569 genes significantly differentially expressed between lesioned and preserved subchondral bone, including CNTNAP2 (FC=2.4, FDR=3.36x10 -5 ) and STMN2 (FC=9.6, FDR=3.36x10 -3 ). Among the identified genes, 305 were also differentially expressed and with same direction of effects in cartilage, including IL11 and CHADL, recently acknowledged OA susceptibility genes. Upon differential expression analysis stratifying for joint site, we identified 509 genes exclusively differentially expressed in subchondral bone of the knee, such as KLF11 and WNT4. These exclusive knee genes were enriched for involvement in epigenetic processes, characterized by for instance HIST1H3J and HIST1H3H. Conclusion:To our knowledge, we are the first to report on differential gene expression patterns of paired OA subchondral bone tissue using RNA sequencing. Among the most consistently differentially expressed genes with OA pathophysiology in both bone and cartilage were IL11 and CHADL. As these genes were recently also identified as robust OA risk genes they classify as attractive druggable targets acting on two OA disease relevant tissues.

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Capturing Essential Physiological Aspects of Interacting Cartilage and Bone Tissue with Osteoarthritis Pathophysiology: A Human Osteochondral Unit‐on‐a‐Chip Model

Tuerlings

Boone

Amirabadi

et al. 2022

Adv Materials Technologies

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Given the multi‐tissue aspects of osteoarthritis (OA) pathophysiology, translation of OA susceptibility genes towards underlying biological mechanism and eventually drug target discovery requires appropriate human in vitro OA models that incorporate both functional bone and cartilage tissue units. Therefore, a microfluidic chip is developed with an integrated fibrous polycaprolactone matrix in which neo‐bone and cartilage are produced, that could serve as a tailored human in vitro disease model of the osteochondral unit of joints. The model enables to evaluate OA‐related environmental perturbations to (individual) tissue units by controlling environmental cues, for example by adding biochemical agents. After establishing the co‐culture in the system, a layer of cartilaginous matrix is deposited in the chondrogenic compartment, while a bone‐like matrix is deposited between the fibers, indicated by both histology and gene expression levels of collagen type 2 and osteopontin, respectively. As proof‐of‐principle, the bone and cartilaginous tissue are exposed to active thyroid hormone, creating an OA disease model. This results in increased expression levels of hypertrophy markers integrin‐binding sialoprotein and alkaline phosphatase in both cartilage and bone, as expected. Altogether, this model could contribute to enhanced translation from OA risk genes towards novel OA therapies.

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Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis

Cited by 134 publications

References 64 publications

Osteoarthritis year in review 2019: genetics, genomics and epigenetics

Osteoarthritis year in review 2019: genetics, genomics and epigenetics

RNA sequencing reveals interacting key determinants of osteoarthritis acting in subchondral bone and articular cartilage

Capturing Essential Physiological Aspects of Interacting Cartilage and Bone Tissue with Osteoarthritis Pathophysiology: A Human Osteochondral Unit‐on‐a‐Chip Model

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