{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:53Z","timestamp":1785410573725,"version":"3.56.0"},"reference-count":82,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82405121"],"award-info":[{"award-number":["82405121"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82074287"],"award-info":[{"award-number":["82074287"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274232"],"award-info":[{"award-number":["82274232"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274376"],"award-info":[{"award-number":["82274376"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82405121"],"award-info":[{"award-number":["82405121"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82074287"],"award-info":[{"award-number":["82074287"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82274232"],"award-info":[{"award-number":["82274232"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82274376"],"award-info":[{"award-number":["82274376"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Joint Funds of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U24A6013"],"award-info":[{"award-number":["U24A6013"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["U24A6013"],"award-info":[{"award-number":["U24A6013"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2018YFC2002500"],"award-info":[{"award-number":["2018YFC2002500"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007162","name":"Science and Technology Program Project of Guangdong Province\u2014Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization","doi-asserted-by":"publisher","award":["2021B1212040007"],"award-info":[{"award-number":["2021B1212040007"]}],"id":[{"id":"10.13039\/501100007162","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Basic and Applied Basic Research Fund of Guangdong Province","award":["2022B1515120022"],"award-info":[{"award-number":["2022B1515120022"]}]},{"name":"Basic and Applied Basic Research Fund of Guangdong Province","award":["2025A1515012368"],"award-info":[{"award-number":["2025A1515012368"]}]},{"name":"Basic and Applied Basic Research Fund of Guangdong Province","award":["2026A1515012784"],"award-info":[{"award-number":["2026A1515012784"]}]},{"name":"Postdoctoral Fellowship Program of CPSF","award":["2025M783886"],"award-info":[{"award-number":["2025M783886"]}]},{"name":"Construction Project of Guangdong Famous Traditional Chinese Medicine Inheritance Studio","award":["108"],"award-info":[{"award-number":["108"]}]},{"name":"Excellent Graduate Student Cultivation Program of Jinan University","award":["61"],"award-info":[{"award-number":["61"]}]},{"name":"MCMIA"},{"id":[{"id":"https:\/\/ror.org\/05pf8rm83","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: The directional relationship between epigenetic age acceleration (EAA) and musculoskeletal disease remains unresolved. This study integrated bidirectional Mendelian randomization (MR) with multi-layer genomic evidence to evaluate directionality, shared genetic architecture, and robustness to instrument definition. Methods: Four EAA clocks (IEAA, PhenoAA, HannumAA, and GrimAA) and ten musculoskeletal phenotypes were analyzed in a 10 \u00d7 4 bidirectional two-sample MR design. EAA instruments underwent GRCh37 functional annotation, genome-wide-significant external-association screening for the index variants and European linkage-disequilibrium proxies, pair-specific Steiger filtering, and conservative Set A\/B\/C sensitivity analyses. The juvenile-arthritis reverse models underwent instrument-flow reconstruction, strength assessment, liability-scale directionality testing, and minimum-detectable-effect analysis. Additional analyses comprised LD score regression (LDSC), PLACO+ cross-trait locus mapping, Bayesian colocalization, multivariable MR (MVMR) with exact-SNP matched univariable comparators, and integrated evidence synthesis. Results: Forward MR yielded two nominal HannumAA associations. The inverse HannumAA\u2013spondyloarthritis estimate remained directionally consistent across the original, Steiger-filtered, and conservative external-association-filtered sets, whereas the HannumAA\u2013pain-in-thoracic-spine estimate lost nominal significance in the conservative set; no forward result survived correction across 40 tests. GrimAA forward estimates were sensitive to use of the fallback instrument threshold. Reverse MR identified ten nominal associations. For juvenile arthritis, three harmonized instruments had F statistics of 51.25\u2013102.35; liability-scale Steiger comparisons supported the tested direction under all 16 outcome-by-prevalence combinations, although the 788-case discovery GWAS and possible winner\u2019s curse remained important limitations. LDSC identified FDR-significant positive genetic correlations of GrimAA with hip osteoarthritis (r_g = 0.267, p = 8.49 \u00d7 10\u22125, q = 0.0019) and knee osteoarthritis (r_g = 0.269, p = 9.52 \u00d7 10\u22125, q = 0.0019). PLACO+ identified 738 genome-wide-significant cross-trait variants and 65 independent loci; six of 37 evaluable loci showed strong colocalization. Of 96 MVMR models, 43 had primary-exposure conditional F \u2265 10, and 32 also had candidate-trait conditional F \u2265 10. After exact-SNP matching, the 43 primary-strength models were operationally classified as 35 partially attenuated and eight independent-signal models, with no fully attenuated model; no adjusted association survived multiplicity correction. Conclusions: The results support a prioritized genomic map with substantial instrument- and model-specific uncertainty. Disease-to-clock signals were richer than clock-to-disease signals, GrimAA shared polygenic architecture with osteoarthritis, and selected loci showed strong shared-variant evidence, while the MR and MVMR findings remained unsuitable for definitive causal or mediation claims.<\/jats:p>","DOI":"10.3390\/genes17080878","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T11:45:26Z","timestamp":1785239126000},"page":"878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Shared Genetic Architecture Between Epigenetic Aging and Musculoskeletal Diseases"],"prefix":"10.3390","volume":"17","author":[{"given":"Wei","family":"Xu","sequence":"first","affiliation":[{"name":"College of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1902-5921","authenticated-orcid":false,"given":"Xuanyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, Zhongshan School of Medicine, Sun Yat-sen University, Shenzhen Campus, Shenzhen 518107, China"},{"name":"Department of Medical Informatics and Neurobiology Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Shenzhen 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biyi","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4732-8073","authenticated-orcid":false,"given":"Xiaoyun","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Guangzhou 510632, China"},{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1016\/S0140-6736(18)30480-X","article-title":"What low back pain is and why we need to pay attention","volume":"391","author":"Hartvigsen","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/978-981-13-3681-2_16","article-title":"Osteoporosis and the ageing skeleton","volume":"91","author":"Aspray","year":"2019","journal-title":"Sub-Cell. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"M146","DOI":"10.1093\/gerona\/56.3.M146","article-title":"Frailty in older adults: Evidence for a phenotype","volume":"56","author":"Fried","year":"2001","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1016\/S0140-6736(08)60599-1","article-title":"Bone mineral density, osteoporosis, and osteoporotic fractures: A genome-wide association study","volume":"371","author":"Richards","year":"2008","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1016\/S0020-1383(16)47004-X","article-title":"Fracture healing in osteoporotic bone","volume":"47","author":"Cheung","year":"2016","journal-title":"Injury"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s11914-017-0413-9","article-title":"Effects of aging on fracture healing","volume":"15","author":"Clark","year":"2017","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.joca.2012.11.012","article-title":"Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!)","volume":"21","author":"Berenbaum","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1097\/BOR.0000000000000353","article-title":"Role of low-grade inflammation in osteoarthritis","volume":"29","author":"Scanzello","year":"2017","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00281-022-00912-0","article-title":"Genetics of rheumatoid arthritis","volume":"44","author":"Padyukov","year":"2022","journal-title":"Semin. Immunopathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0140-6736(16)31591-4","article-title":"Axial spondyloarthritis","volume":"390","author":"Sieper","year":"2017","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s11926-018-0716-6","article-title":"Peripheral mechanisms contributing to osteoarthritis pain","volume":"20","author":"Syx","year":"2018","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/s41576-018-0004-3","article-title":"DNA methylation-based biomarkers and the epigenetic clock theory of ageing","volume":"19","author":"Horvath","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.molcel.2018.08.008","article-title":"DNA methylation clocks in aging: Categories, causes, and consequences","volume":"71","author":"Field","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1186\/s13059-019-1824-y","article-title":"DNA methylation aging clocks: Challenges and recommendations","volume":"20","author":"Bell","year":"2019","journal-title":"Genome Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R115","DOI":"10.1186\/gb-2013-14-10-r115","article-title":"DNA methylation age of human tissues and cell types","volume":"14","author":"Horvath","year":"2013","journal-title":"Genome Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.molcel.2012.10.016","article-title":"Genome-wide methylation profiles reveal quantitative views of human aging rates","volume":"49","author":"Hannum","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"573","DOI":"10.18632\/aging.101414","article-title":"An epigenetic biomarker of aging for lifespan and healthspan","volume":"10","author":"Levine","year":"2018","journal-title":"Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"303","DOI":"10.18632\/aging.101684","article-title":"DNA methylation GrimAge strongly predicts lifespan and healthspan","volume":"11","author":"Lu","year":"2019","journal-title":"Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s42003-024-06609-4","article-title":"Development of an epigenetic clock resistant to changes in immune cell composition","volume":"7","author":"Tomusiak","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1093\/gerona\/glu057","article-title":"Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases","volume":"69","author":"Franceschi","year":"2014","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Paul, K.C., Binder, A.M., Horvath, S., Kusters, C., Yan, Q., Rosario, I.D., Yu, Y., Bronstein, J., and Ritz, B. (2021). Accelerated hematopoietic mitotic aging measured by DNA methylation, blood cell lineage, and parkinson\u2019s disease. BMC Genom., 22.","DOI":"10.1186\/s12864-021-08009-y"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s13059-021-02398-9","article-title":"Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging","volume":"22","author":"McCartney","year":"2021","journal-title":"Genome Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1111\/acel.12349","article-title":"DNA methylation and healthy human aging","volume":"14","author":"Jones","year":"2015","journal-title":"Aging Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101755","DOI":"10.1016\/j.molmet.2023.101755","article-title":"Chronic inflammation and the hallmarks of aging","volume":"74","author":"Baechle","year":"2023","journal-title":"Mol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1749-6632.2000.tb06651.x","article-title":"Inflamm-aging. An evolutionary perspective on immunosenescence","volume":"908","author":"Franceschi","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: A new immune-metabolic viewpoint for age-related diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s00439-007-0448-6","article-title":"Mendelian randomization: Can genetic epidemiology help redress the failures of observational epidemiology?","volume":"123","author":"Ebrahim","year":"2008","journal-title":"Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/ije\/dyv108","article-title":"Mendelian randomization: Where are we now and where are we going?","volume":"44","author":"Burgess","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_30","first-page":"a41302","article-title":"Mendelian randomization","volume":"12","author":"Birney","year":"2022","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: Genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Hemani","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1093\/ije\/dyr036","article-title":"Avoiding bias from weak instruments in Mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int. J. Epidemiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Loh","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ng.3406","article-title":"An atlas of genetic correlations across human diseases and traits","volume":"47","author":"Finucane","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ray, D., and Chatterjee, N. (2020). A powerful method for pleiotropic analysis under composite null hypothesis identifies novel shared loci between type 2 diabetes and prostate cancer. PLoS Genet., 16.","DOI":"10.1101\/2020.04.11.037630"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Giambartolomei, C., Vukcevic, D., Schadt, E.E., Franke, L., Hingorani, A.D., Wallace, C., and Plagnol, V. (2014). Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004383"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"a38984","DOI":"10.1101\/cshperspect.a038984","article-title":"Multivariable Mendelian randomization and mediation","volume":"11","author":"Sanderson","year":"2021","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e335","DOI":"10.1002\/cpz1.335","article-title":"Two-sample multivariable Mendelian randomization analysis using r","volume":"1","author":"Rasooly","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5434","DOI":"10.1002\/sim.9133","article-title":"Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization","volume":"40","author":"Sanderson","year":"2021","journal-title":"Stat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/s41588-018-0327-1","article-title":"Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data","volume":"51","author":"Tachmazidou","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: The STROBE-MR statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"1000 Genomes Project Consortium (2015). A global reference for human genetic variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: Rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"D1005","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Hemani, G., Tilling, K., and Davey Smith, G. (2017). Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet., 13.","DOI":"10.1101\/117101"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet. Epidemiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1002\/gepi.21614","article-title":"A better coefficient of determination for genetic profile analysis","volume":"36","author":"Lee","year":"2012","journal-title":"Genet. Epidemiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1136\/ard.46.4.277","article-title":"Incidence and prevalence of juvenile chronic arthritis: A population survey","volume":"46","author":"Fasth","year":"1987","journal-title":"Ann. Rheum. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.jbspin.2013.09.003","article-title":"Prevalence and incidence of juvenile idiopathic arthritis: A systematic review","volume":"81","author":"Thierry","year":"2014","journal-title":"Jt. Bone Spine"},{"key":"ref_57","first-page":"649","article-title":"Prevalence and short-term outcome of juvenile idiopathic arthritis: A population-based study in Estonia","volume":"25","author":"Pruunsild","year":"2007","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1097\/EDE.0b013e318181b865","article-title":"Curses\u2014Winner\u2019s and otherwise\u2014In genetic epidemiology","volume":"19","author":"Kraft","year":"2008","journal-title":"Epidemiology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.joca.2021.03.002","article-title":"Genetics of osteoarthritis","volume":"30","author":"Aubourg","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cytogfr.2018.10.002","article-title":"Pro-inflammatory cytokines: The link between obesity and osteoarthritis","volume":"44","author":"Wang","year":"2018","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/art.39842","article-title":"Review: Metabolic regulation of inflammation in osteoarthritis","volume":"69","author":"Berenbaum","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1097\/BOR.0000000000000373","article-title":"Metabolic syndrome-associated osteoarthritis","volume":"29","author":"Courties","year":"2017","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1097\/BOR.0000000000000094","article-title":"Genetics of juvenile idiopathic arthritis: New tools bring new approaches","volume":"26","author":"Moncrieffe","year":"2014","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jaut.2015.08.002","article-title":"Immunogenetics of juvenile idiopathic arthritis: A comprehensive review","volume":"64","author":"Hersh","year":"2015","journal-title":"J. Autoimmun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"11063","DOI":"10.1038\/srep11063","article-title":"DNA methylation at IL32 in juvenile idiopathic arthritis","volume":"5","author":"Meyer","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jaut.2017.09.010","article-title":"The DNA methylation landscape of CD4+ t cells in oligoarticular juvenile idiopathic arthritis","volume":"86","author":"Martino","year":"2018","journal-title":"J. Autoimmun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1097\/BOR.0000000000000471","article-title":"Epigenetics of inflammatory arthritis","volume":"30","author":"Hammaker","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1093\/rheumatology\/keaa232","article-title":"The genetics of rheumatoid arthritis","volume":"59","author":"Dedmon","year":"2020","journal-title":"Rheumatology"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Sharip, A., and Kunz, J. (2020). Understanding the pathogenesis of spondyloarthritis. Biomolecules, 10.","DOI":"10.3390\/biom10101461"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1097\/BOR.0000000000000128","article-title":"Epigenetics in rheumatoid arthritis","volume":"27","author":"Klein","year":"2015","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/s41584-020-0413-5","article-title":"Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes","volume":"16","author":"Nygaard","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.2174\/1381612821666150310143332","article-title":"Interleukin-6 in rheumatoid arthritis\u2014From the laboratory to the bedside","volume":"21","author":"Liu","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev-immunol-032414-112110","article-title":"HLA-B27","volume":"33","author":"Bowness","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1002\/art.24616","article-title":"Functional analysis of the osteoarthritis susceptibility-associated GDF5 regulatory polymorphism","volume":"60","author":"Egli","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Pan, F., Tian, J., Winzenberg, T., Ding, C., and Jones, G. (2014). Association between GDF5 rs143383 polymorphism and knee osteoarthritis: An updated meta-analysis based on 23,995 subjects. BMC Musculoskelet. Disord., 15.","DOI":"10.1186\/1471-2474-15-404"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Huang, X., Zhang, W., and Shao, Z. (2018). Association between GDF5 rs143383 genetic polymorphism and musculoskeletal degenerative diseases susceptibility: A meta-analysis. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0685-7"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1136\/ard.2010.134619","article-title":"GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changes","volume":"70","author":"Daans","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Kan, A., Ikeda, T., Fukai, A., Nakagawa, T., Nakamura, K., Chung, U., Kawaguchi, H., and Tabin, C.J. (2013). SOX11 contributes to the regulation of GDF5 in joint maintenance. BMC Dev. Biol., 13.","DOI":"10.1186\/1471-213X-13-4"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41584-022-00749-9","article-title":"Synovial inflammation in osteoarthritis progression","volume":"18","author":"Coras","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1007\/s13679-023-00520-5","article-title":"Obesity, metabolic syndrome, and osteoarthritis\u2014An updated review","volume":"12","author":"Sampath","year":"2023","journal-title":"Curr. Obes. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41588-018-0302-x","article-title":"An atlas of genetic influences on osteoporosis in humans and mice","volume":"51","author":"Morris","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s13148-021-01150-1","article-title":"Epigenetic age is associated with baseline and 3-year change in frailty in the Canadian longitudinal study on aging","volume":"13","author":"Verschoor","year":"2021","journal-title":"Clin. Epigenet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/878\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T04:14:37Z","timestamp":1785384877000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":82,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["genes17080878"],"URL":"https:\/\/doi.org\/10.3390\/genes17080878","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]}}}