Accelerating functional gene discovery in osteoarthritis

Butterfield, Natalie C.; Curry, Katherine F; Steinberg, Julia; Dewhurst, Hannah; Komla‐Ebri, Davide; Mannan, Naila S.; Adoum, Anne‐Tounsia; Leitch, Victoria; Logan, John G.; Waung, Julian A.; Ghirardello, Elena J.; Southam, Lorraine; Youlten, Scott E.; Wilkinson, J. Mark; McAninch, Elizabeth A.; Vancollie, Valerie E.; Kussy, Fiona; White, Jacqueline K.; Adams, David J.; Lelliott, Christopher J.; Jacques, Richard; Bianco, Antonio C.; Boyde, A.; Zeggini, Eleftheria; Williams, Graham R.; Bassett, J H Duncan

doi:10.1101/836221

Cited by 7 publications

(8 citation statements)

References 102 publications

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“…A complementary approach to such in vitro functional studies is the investigation of risk alleles in mice. This has so far proven particularly insightful for the OA risk that maps to the GDF5 locus 41 and similar reports are appearing in the literature 88 . A recent database of genes associated with OA in animal models can complement these investigations 89 .…”

Section: Discussionsupporting

confidence: 53%

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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: Discussionsupporting

confidence: 53%

“…A recent database of genes associated with OA in animal models can complement these investigations 89 . The degree to which the functional characterization of OA GWAS signals will benefit from animal models is open to debate, but clearly there are grounds for optimism 88,90 .…”

Section: Discussionmentioning

confidence: 99%

Genetics of osteoarthritis

Aubourg

Rice

Bruce-Wootton

et al. 2022

Osteoarthritis and Cartilage

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“…Luciferase reporter assays in these cells for rs6060369 found that the risk allele ''T'' drove reduced expression (Figure 6C, p = 0.000044; Fisher-combined p = 8.79EÀ09). We computationally predicted that Pituitary homeobox 1 (PITX1), a major TF in knee formation (Nemec et al, 2017) and OA factor (Butterfield et al, 2019;Picard et al, 2007), binds to this variant position. Using ChIP on T/C-28a2 cells (Figure 6D), E15.5 distal femur and proximal tibia cartilage, and PITX1 ChIPseq data (Figure 6E), we validated PITX1 binding at this position, indicating that it likely mediates the cis-acting effects of rs6060369 in R4 on GDF5 expression.…”

Section: Functional Interrogation Of An Oa Risk Locusmentioning

confidence: 99%

Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk

Richard¹,

Liu²,

Cao³

et al. 2020

Cell

110

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During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5-UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis.

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“…Studies from April 12,020 to April 30 2021 performing functional analysis of genetic variants for OA risk are summarized above With the intention of improving functional gene discovery in OA, Butterfield et al developed a three-mode imaging pipeline to comprehensively phenotype the mouse knee joint and its diseaserelated changes 27 . Iodine-contrast-enhancer (ICE) mCT determines several cartilage and bone volume, thickness and density characteristics, joint surface replication (JSR) quantifies cartilage surface damage, and subchondral bone X-ray microradiography (scXRM) determines mineral density.…”

Section: Osteoarthritis and Cartilagementioning

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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Accelerating functional gene discovery in osteoarthritis

Cited by 7 publications

References 102 publications

Genetics of osteoarthritis

Genetics of osteoarthritis

Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk

Osteoarthritis year in review: genetics, genomics, epigenetics

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