Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identify<i>WNT9A</i>as novel osteoarthritis gene

Boer, Cindy G.; Yau, Michelle S.; Rice, S.J.; Almeida, Rodrigo Coutinho de; Cheung, Kathleen; Styrkársdóttir, Unnur; Southam, Lorraine; Broer, Linda; Wilkinson, J. Mark; Uitterlinden, André G.; Zeggini, Eleftheria; Felson, David T.; Loughlin, John; Young, Mariel; Capellini, Terence D.; Meulenbelt, Ingrid; Meurs, Joyce B. J. van

doi:10.1136/annrheumdis-2020-217834

Cited by 32 publications

(38 citation statements)

References 51 publications

(51 reference statements)

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“…There are three main mechanisms of epigenetic regulation of gene expression: post-translational modification of histones, noncoding RNAs (ncRNAs, such as miRNAs), and DNAm, of which the latter is the most well-studied. Studies of the cartilage DNA methylome have led to the discovery of OA-associated methylation quantitative trait loci (mQTLs), at which there is a correlation between genotype at an OA risk SNP and cis DNAm 25,54,63,64 . DNAm is thought to act as a conduit through which the functional effect of A STRING proteineprotein interaction network of OA risk gene products.…”

Section: Interaction Between Oa Genetics and Epigeneticsmentioning

confidence: 99%

“…DOT1L expression is essential for cartilage homeostasis, and the identification of this region as a risk locus strongly supports the requirement for tight regulation of chromatin state to maintain cartilage integrity 62 . Similarly, OA risk SNPs have been identified in the region of cartilage-specific ncRNAs that are known to be vital for homeostasis of the articular joint surface and are dysregulated in OA, including the miRNAs miR-140 and miR-455 23,25 .…”

Section: Table IIImentioning

confidence: 99%

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Genetics of osteoarthritis

Aubourg

Rice

Bruce-Wootton

et al. 2022

Osteoarthritis and Cartilage

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Osteoarthritis genetics has been transformed in the past decade through the application of large-scale genome-wide association scans. So far, over 100 polymorphic DNA variants have been associated with this common and complex disease. These genetic risk variants account for over 20% of osteoarthritis heritability and the vast majority map to non-protein coding regions of the genome where they are presumed to act by regulating the expression of target genes. Statistical fine mapping, in silico analyses of genomics data, and laboratory-based functional studies have enabled the identification of some of these targets, which encode proteins with diverse roles, including extracellular signaling molecules, intracellular enzymes, transcription factors, and cytoskeletal proteins. A large number of the risk variants correlate with epigenetic factors, in particular cartilage DNA methylation changes in cis, implying that epigenetics may be a conduit through which genetic effects on gene expression are mediated. Some of the variants also appear to have been selected as humans adapted to bipedalism, suggesting that a proportion of osteoarthritis genetic susceptibility results from antagonistic pleiotropy, with risk variants having a positive role in joint formation but a negative role in the long-term health of the joint. Although data from an osteoarthritis genetic study has not yet directly led to a novel treatment, some of the osteoarthritis associated genes code for proteins that have available therapeutics. Genetic investigations are therefore revealing fascinating fundamental insights into osteoarthritis and can expose options for translational intervention.

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Section: Interaction Between Oa Genetics and Epigeneticsmentioning

confidence: 99%

Section: Table IIImentioning

confidence: 99%

Genetics of osteoarthritis

Aubourg

Rice

Bruce-Wootton

et al. 2022

Osteoarthritis and Cartilage

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“…Due to the genetic complexity of the reported regions, the identification of functional SNPs and effector genes at the majority of OA risk loci remains elusive (16,17). In recent years, post-GWAS | 1857 integration of epigenetic data sets has increasingly been conducted to colocalize genetic risk loci with changes to the cartilage epigenome (18)(19)(20)(21). Correlations between genotypes at OA association SNPs and DNA methylation have been identified in cartilage, marking methylation quantitative trait loci (QTLs) (19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Genetic and Epigenetic Interplay Within a COLGALT2 Enhancer Associated With Osteoarthritis

Kehayova

Watson

Wilkinson

et al. 2021

Arthritis & Rheumatology

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Objective The osteoarthritis (OA)–associated single‐nucleotide polymorphism (SNP) rs11583641 is located in COLGALT2, encoding a posttranslational modifier of collagen. In cartilage, the SNP genotype correlates with DNA methylation in a putative enhancer. This study was undertaken to characterize the mechanistic relationship between rs11583641, the putative enhancer, and COLGALT2 expression using cartilage samples from human patients and a chondrocyte cell model. Methods Nucleic acids were extracted from articular cartilage samples obtained from patients with OA (n = 137). Samples were genotyped, and DNA methylation was quantified at 12 CpGs using pyrosequencing. The putative enhancer was deleted in Tc28a2 chondrocytes using clustered regularly interspaced short palindromic repeat/Cas9, and the impact on nearby gene expression was determined using real‐time quantitative polymerase chain reaction. Targeted modulation of the epigenome using catalytically dead Cas9 (dCas9) constructs fused to DNA methyltransferase 3a or ten–eleven translocase 1 allowed for the investigation of a causal relationship between DNA methylation and enhancer activity. Results The genotype at rs11583641 correlated with DNA methylation at 3 CpGs, and the presence of the OA risk allele, C, corresponded to reduced levels of methylation. Deletion of the enhancer resulted in a 2.7‐fold reduction in COLGALT2 expression. Targeted methylation and demethylation of the CpGs had antagonistic effects on COLGALT2 expression. An allelic imbalance in the expression of COLGALT2 was identified in the cartilage from patients with OA, with relative overexpression of the OA risk allele. Allelic expression ratios correlated with DNA methylation at 4 CpGs. Conclusion COLGALT2 is a target of OA genetic risk at this locus. The genotype at rs11583641 impacts DNA methylation in a gene enhancer, which, in turn, modulates COLGALT2 expression. COLGALT2 encodes an enzyme that initiates posttranslational glycosylation of collagens and is therefore a compelling OA susceptibility target.

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“…Current GWAS have included thousands of patients with OA 21,23,67 , but a full metaanalysis of multiple populations will likely lead to the identification of further risk variants. This year Boer et al, elegantly demonstrated how analysis of well-characterized patient cohorts, where patients were segregated into distinct disease sub-types (in this case of hand OA), could increase the discovery power of a relatively modestly sized GWAS 15 . An expectation in the coming year(s) would be that further patient or disease stratification could improve GWASderived knowledge of disease-associated loci for OA of the other joint sites.…”

Section: Future Approaches and Summarymentioning

confidence: 99%

Osteoarthritis year in review: genetics, genomics, epigenetics

Young

Barter

Soul

2022

Osteoarthritis and Cartilage

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Summary Objective In this review, we have highlighted the advances over the past year in genetics, genomics and epigenetics in the ﬁeld of osteoarthritis (OA). Methods A literature search of PubMed was performed using the criteria: “osteoarthritis” and one of the following terms “genetic(s), genomic(s), epigenetic(s), polymorphism, noncoding ribonucleic acid (RNA), microRNA, long noncoding RNA, lncRNA, circular RNA, RNA sequencing (RNA-seq), single cell sequencing, transcriptomics, or deoxyribonucleic acid (DNA) methylation between April 01, 2020 and April 30, 2021. Results In total we identiﬁed 765 unique publications, which eventually reduced to 380 of relevance to the field as judged by two assessors. Many of these studies included multiple search terms. We summarised advances relating to genetics, functional genetics, genomics and epigenetics, focusing on our personal key papers during the year. Conclusions This year few studies have identiﬁed new genetic variants contributing to OA susceptibility, but a focus has been on refining risk loci or their functional validation. The use of new technologies together with investigating the cross-talk between multiple tissue types, greater sample sizes and/or better patient classification (OA subtypes) will continue to increase our knowledge of disease mechanisms and progress towards understanding and treating OA.

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Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identifyWNT9Aas novel osteoarthritis gene

Cited by 32 publications

References 51 publications

Genetics of osteoarthritis

Genetics of osteoarthritis

Genetic and Epigenetic Interplay Within a COLGALT2 Enhancer Associated With Osteoarthritis

Osteoarthritis year in review: genetics, genomics, epigenetics

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