Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis

Styrkársdóttir, Unnur; Helgason, Hannes; Sigurðsson, Ásgeir; Norddahl, Gudmundur L.; Agustsdottir, Arna B; Reynard, Louise N.; Villalvilla, A.; Halldorsson, Gisli H.; Jónasdóttir, Áslaug; Magnusdottir, Audur; Oddson, Asmundur; Sulem, Gerald; Zink, Florian; Sveinbjörnsson, Garðar; Helgason, Agnar; Johannsdottir, Hrefna; Helgadóttir, Anna; Stefánsson, Hreinn; Grétarsdóttir, Sólveig; Rafnar, Thorunn; Almdahl, Ina Selseth; Brækhus, Anne; Fladby, Tormod; Selbæk, Geir; Hosseinpanah, Farhad; Azizi, Fereidoun; Koh, Jung Min; Tang, Nelson L.S.; Daneshpour, Maryam S.; Mayordomo, J. I.; Welt, Corrine K.; Braund, Peter S.; Samani, Nilesh J.; Kiemeney, Lambertus A.; Lohmander, L. Stefan; Christiansen, Claus; Andreassen, Ole A.; Magnússon, Ólafur Þ.; Másson, Gísli; Kong, Augustine; Jónsdóttir, Ingileif; Guðbjartsson, Daníel F.; Sulem, Patrick; Jónsson, Helgi; Loughlin, John; Ingvarsson, Þorvaldur; Þorsteinsdóttir, Unnur; Stefánsson, Kāri

doi:10.1038/ng.3816

Cited by 80 publications

(69 citation statements)

References 42 publications

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“…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%

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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Section: Differential Expression Analysis Of the Gene Expression Levementioning

confidence: 99%

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

Tuerlings

Hoolwerff

Houtman

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…This year, five large genome-wide association study (GWAS) added to our knowledge regarding OA genetic risk. These included one hand OA study 1 , one hip OA study 2 , and two knee OA studies in Chinese cohorts 3,4 . One additional study examined variation associated with neuropathic pain following total joint replacement 5 (summarized in Table II).…”

Section: Geneticsmentioning

confidence: 99%

Osteoarthritis year in review 2018: genetics and epigenetics

Jeffries

2019

Osteoarthritis and Cartilage

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Objective: This review was designed to identify highlights of the osteoarthritis (OA) genetics and epigenetics literature published between April 2017 and January 2018. Design: A Pubmed literature search was conducted using the keywords 'osteoarthritis' and each of the following: 'genomic', 'genetic', 'epigenomic', 'epigenetic', 'histone', 'noncoding RNA', 'miRNA', 'lncRNA', 'DNA methylation', 'DNA hydroxymethylation', 'DNMT', and 'TET'. The dates of publication were restricted to 4/1/2017e1/15/2018. Results were compared to the same search terms limited to 4/1/2016e1/15/2017. Results: Virtually all search term combinations demonstrated a decrease in papers published this year compared to last, with epigenetic and miRNA/lncRNA research being stable. Despite this, numerous advances were made this year, including the second large genome-wide association study (GWAS) study of hand OA, a new twin study of hip and knee OA concordance, an extensive study of GDF5 evolution, analyses of the contribution of Dnmt3a to OA, a description of DNA methylation in a nonhuman primate model of OA, and an integrated, multi-omics analysis of DNA methylation, mRNA, and protein expression in human OA samples, among others. A variety of micro-and a few circular-RNA studies were also published, highlighting the importance of noncoding RNA in both the pathogenesis and potential treatment of OA. Conclusion: Although publications have decreased slightly in the last year, genetics and epigenetics continue to be a topic of substantial research in OA, and considerable progress continues to be made in the field.

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“…With the rapid development of genetic epidemiology and genetic assay technologies, gene polymorphisms are found to play a crucial role in the initiation and progression of OA and have received more and more attentions over recent years . So far, genome‐wide association studies have demonstrated that single nucleotide polymorphisms (SNPs) in a range of genes, such as growth differentiation factor 5 gene, Frizzled‐related protein gene, cartilage oligomeric matrix protein gene and chondroadherin‐like gene, and fat mass and obesity‐associated gene, are associated with susceptibility to OA. Apart from that, increasing literature elucidated a vital role of inflammation during the pathogenesis of OA, and various inflammatory cytokine genes which conferred susceptibility to OA are still being investigated .…”

Section: Introductionmentioning

confidence: 99%

Association of IL‐17A‐197G/A and IL‐17F‐7488T/C polymorphisms and osteoarthritis susceptibility: A meta‐analysis

et al. 2019

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Aim This meta‐analysis was conducted with the aim of collecting and synthesizing the existing evidence on the association of interleukin‐17A (IL‐17A)‐197G/A and IL‐17F‐7488T/C gene polymorphisms and osteoarthritis (OA) susceptibility. Methods Six electronic databases including PubMed, EMBASE, Web of Science, Cochrane Library, CNKI, and Wanfang were systematically searched for potentially relevant studies previous to June 2019. The strengths of association were estimated by summary odds ratios (ORs) and 95% confidence intervals (95%CIs) in a model‐free approach. Heterogeneity test and sensitivity analysis were also conducted to guarantee the reliability of this study. Results Six eligible case‐control studies comprising 1989 OA patients and 2116 healthy controls were obtained for the meta‐analysis. Dominant model was confirmed to be the optimal genetic model (MM + Mm vs mm). The pooled estimate supported that IL‐17A‐197G/A and IL‐17F‐7488T/C polymorphisms were significantly associated with OA susceptibility in the overall population (IL‐17A‐197G/A: GG + GA vs AA, OR = 0.69, 95%CI 0.57‐0.80; P < .001; IL‐17F‐7488T/C, TT + TC vs CC, OR = 0.46, 95%CI 0.29‐0.71, P < .001). However, subgroup analyses suggested the association only existed in Asians and knee OA. Conclusion The findings of the present study indicate that IL‐17A‐197G/A and IL‐17F‐7488T/C polymorphisms are positively associated to reduced risk of knee OA, especially in Asian populations.

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Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis

Cited by 80 publications

References 42 publications

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

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

Osteoarthritis year in review 2018: genetics and epigenetics

Association of IL‐17A‐197G/A and IL‐17F‐7488T/C polymorphisms and osteoarthritis susceptibility: A meta‐analysis

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