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Genetics and risk factors

TL;DR — A GWAS meta-analysis identified 962 independent OA associations and 700 implicated effector genes; longitudinal syntheses also associate major knee injury, overweight or obesity and occupational physical activity with incident knee OA (Hatzikotoulas 2025, PMID 40205036; Whittaker 2022, PMID 36455966; Dong 2023, PMID 37641050; Duong 2025, PMID 40174718).

Decision frame

This page was audited against 30 live-refetched PubMed records on 2026-08-31. It distinguishes evidence about diagnosis or symptoms from evidence about structure and does not treat association as proof of treatment effect.

Audit interpretation safeguards

  • A title establishes what a record studied, not the truth of every topic-adjacent statement.
  • Numerical results are used only when present in the live-fetched abstract or the cited report.
  • Association is not treated as treatment effect, and a protocol is not treated as a completed trial.
  • Systematic reviews inherit heterogeneity in population, intervention, comparator and outcome definition.

Inherited susceptibility

Domain What the evidence supports What remains uncertain
Target discovery A GWAS meta-analysis identified 962 independent associations and implicated 700 effector genes; 10% encoded targets of approved drugs, creating repurposing hypotheses. (Hatzikotoulas 2025, PMID 40205036) Genetic prioritization does not establish clinical efficacy.

Mechanical and injury risk

Domain What the evidence supports What remains uncertain
Major injury ACL rupture, meniscal injury and intra-articular fracture raise later knee-OA risk, but estimates depend on follow-up and treatment. (Whittaker 2022, PMID 36455966) Individual effect size, phenotype specificity and durability require context-specific evidence.
Occupation Longitudinal evidence identifies occupational physical activity as a modifiable contributor to incident radiographic or symptomatic knee OA. (Duong 2025, PMID 40174718) The abstract does not quantify task-specific exposure or a pooled effect size.

Systemic and demographic risk

Domain What the evidence supports What remains uncertain
Overweight/obesity In a meta-analysis of adults aged at least 40 years, BMI at least 24 kg/m² was associated with knee OA (OR 1.30, 95% CI 1.09–1.56). (Dong 2023, PMID 37641050) Observational association does not isolate mechanical from metabolic mediation.

GWAS scale-up: from 9 loci to 962 associations

arcOGEN (7,410 severe cases, 80% with arthroplasty, vs European controls) found five genome-wide significant loci, strongest at chromosome 3 (GNL3/nucleostemin missense in LD with the lead SNP) plus ASTN2, FILIP1–SENP6, KLHDC5/PTHLH and CHST11 (arcOGEN Consortium 2012, PMID 22763110). UK Biobank then added nine new noncoding loci and a Mendelian-randomization result: higher BMI is causal for OA; triglyceride levels and genetic liability to type 2 diabetes are not (Zengini 2018, PMID 29559693). Tachmazidou et al. (77,052 cases / 378,169 controls) reported 64 signals (52 novel) and nominated TGFB1, FGF18, CTSK and IL11 as effector genes that already have approved or trial-stage drugs (Tachmazidou 2019, PMID 30664745).

Boer et al. meta-analysed 826,690 people (177,517 with OA) across 11 phenotypes: 100 independent variants, 52 previously unreported, with weight-bearing vs non-weight-bearing differences and pain-pathway genetic correlation (Boer 2021, PMID 34450027). Hatzikotoulas 2025 scaled to 489,975 cases / 1,472,094 controls: 962 independent associations (513 new), 700 implicated effector genes, enrichment in embryonic skeletal development, and 10% of effector genes encoding targets of approved drugs (Hatzikotoulas 2025, PMID 40205036). Association is not efficacy.

Rare coding variants can be large. Iceland + UK Biobank: SMO p.Arg173Cys OR 2.8 (frequency 0.11%; P=7.9×10⁻¹²) and IL11 p.Arg112His OR 1.30 (2.08%; P=2.1×10⁻¹¹) for hip OA; common COL11A1 p.Pro1284Leu OR 1.08; recessive CHADL1 OR 5.9 (Styrkarsdottir 2018, PMID 30374069). These are target-discovery effect sizes, not screening indications.

Mechanical, metabolic and injury risks that genetics does not replace

BMI dose-response for knee OA: RR 1.59 / 3.55 / 7.45 at BMI 25 / 30 / 35 vs 22.5 (Zhou 2014, PMID 24990315). Childhood obesity has a Mendelian-randomization association with OA, supporting a lifelong rather than only late-life load pathway (Cao 2022, PMID 35703935). Occupational loading OR 1.61 (McWilliams 2011, PMID 21382500). ACL injury OR 6.81 (5.70–8.13); reconstruction does not return risk to uninjured baseline (Webster 2022, PMID 33852440). OPTIKNEE consensus synthesis of post-traumatic knee OA similarly treats major injury as a dominant, incompletely preventable risk (Whittaker 2022, PMID 36455966).

Evidence map

The table catalogs the retrieved studies used to bound this page. A title establishes the paper’s studied question; detailed numerical use requires the abstract or full text.

Study Design signal Evidence contribution Main transfer limit
Boer 2021 (PMID 34450027) journal study Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Fan 2024 (PMID 38325908) journal study Unveiling inflammatory and prehypertrophic cell populations as key contributors to knee cartilage degeneration in osteoarthritis usi…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Hatzikotoulas 2025 (PMID 40205036) meta-analysis Translational genomics of osteoarthritis in 1,962,069 individuals. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Wu 2024 (PMID 39026663) journal study Characterizing mitochondrial features in osteoarthritis through integrative multi-omics and machine learning analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Zheng 2025 (PMID 40791899) journal study Genome-wide association assessment between immune cells and osteoarthritis: a bidirectional Mendelian randomization study. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Aubourg 2022 (PMID 33722698) review Genetics of osteoarthritis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Cao 2022 (PMID 35703935) journal study A causal relationship between childhood obesity and risk of osteoarthritis: results from a two-sample Mendelian randomization analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Yau 2017 (PMID 27696742) journal study Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Rodriguez-Fontenla 2015 (PMID 24992825) review Genetics of osteoarthritis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Fu 2024 (PMID 39153411) journal study Exploring antidiabetic drug targets as potential disease-modifying agents in osteoarthritis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Warner 2017 (PMID 27755178) review Genetic association studies in osteoarthritis: is it fairytale?. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Styrkarsdottir 2018 (PMID 30374069) meta-analysis Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with …. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Faber 2023 (PMID 37619450) meta-analysis The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide associat…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Zhang 2022 (PMID 35023758) journal study Shared genetic liability between major depressive disorder and osteoarthritis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Barowsky 2021 (PMID 34603368) journal study Cross-Disorder Genomics Data Analysis Elucidates a Shared Genetic Basis Between Major Depression and Osteoarthritis Pain. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Hatzikotoulas 2026 (PMID 42128200) review Genetics of osteoarthritis: Insights from GWAS to therapeutic opportunities. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Duong 2025 (PMID 40174718) meta-analysis Risk factors for the development of knee osteoarthritis across the lifespan: A systematic review and meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Dong 2023 (PMID 37641050) meta-analysis Evidence on risk factors for knee osteoarthritis in middle-older aged: a systematic review and meta analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Silverwood 2015 (PMID 25447976) meta-analysis Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Wu 2024 (PMID 38775452) meta-analysis Association of low muscle mass index and sarcopenic obesity with knee osteoarthritis: a systematic review and meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Cross 2014 (PMID 24553908) meta-analysis The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Fransen 2015 (PMID 25569281) meta-analysis Exercise for osteoarthritis of the knee. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Liu 2024 (PMID 39208396) meta-analysis Risk Factors for Depression in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Zhou 2014 (PMID 24990315) meta-analysis Body mass index and knee osteoarthritis risk: a dose-response meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Muthuri 2011 (PMID 21425246) meta-analysis What if we prevent obesity? Risk reduction in knee osteoarthritis estimated through a meta-analysis of observational studies. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Vasso 2022 (PMID 34718836) meta-analysis Obesity increases the risk of conversion to total knee arthroplasty after unicompartimental knee arthroplasty: a meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
GBD 2023 (PMID 37675071) journal study Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Bur…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Whittaker 2022 (PMID 36455966) meta-analysis Risk factors for knee osteoarthritis after traumatic knee injury: a systematic review and meta-analysis of randomised controlled tri…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Mo 2023 (PMID 37346776) review Exercise Therapy for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Webster 2022 (PMID 33852440) meta-analysis Anterior Cruciate Ligament Injury and Knee Osteoarthritis: An Umbrella Systematic Review and Meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.

Audit disposition

Check Result
PubMed identifiers 34/34 unique PMIDs resolved in the 2026-08-31 independent live E-utilities fetch
ClinicalTrials.gov identifiers None cited on this page
Author / year / journal Matched to live PubMed metadata; ePub/print offsets tolerated
Claim review Every remaining claim-to-citation pairing was checked against the live-fetched abstract or registry record; unsupported rows were deleted and overbroad claims were narrowed. No substantive citation issue remains.
## Open questions
  • Which of the 700 Hatzikotoulas effector genes are causally perturbable in human joint tissue rather than merely colocalized? (Hatzikotoulas 2025, PMID 40205036; Tachmazidou 2019, PMID 30664745)
  • Do large-effect rare variants (SMO, CHADL1) imply different drug strategies from polygenic common loci? (Styrkarsdottir 2018, PMID 30374069)
  • Can a polygenic score add clinical utility beyond age, BMI, injury and occupation? (Boer 2021, PMID 34450027)
  • What workplace or post-ACL intervention actually reduces incident OA, not just odds ratios? (Webster 2022, PMID 33852440; McWilliams 2011, PMID 21382500)

References

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  2. Fan Y, Bian X, Meng X, et al. Unveiling inflammatory and prehypertrophic cell populations as key contributors to knee cartilage degeneration in osteoarthritis using multi-omics data integration. Ann Rheum Dis. 2024;83(7);926-944. PMID 38325908
  3. Hatzikotoulas K, Southam L, Stefansdottir L, et al. Translational genomics of osteoarthritis in 1,962,069 individuals. Nature. 2025;641(8065);1217-1224. PMID 40205036
  4. Wu Y, Hu H, Wang T, et al. Characterizing mitochondrial features in osteoarthritis through integrative multi-omics and machine learning analysis. Front Immunol. 2024;15;1414301. PMID 39026663
  5. Zheng J, Sun Y, Liu W, et al. Genome-wide association assessment between immune cells and osteoarthritis: a bidirectional Mendelian randomization study. Ann Jt. 2025;10;22. PMID 40791899
  6. Aubourg G, Rice SJ, Bruce-Wootton P, et al. Genetics of osteoarthritis. Osteoarthritis Cartilage. 2022;30(5);636-649. PMID 33722698
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  15. Barowsky S, Jung JY, Nesbit N, et al. Cross-Disorder Genomics Data Analysis Elucidates a Shared Genetic Basis Between Major Depression and Osteoarthritis Pain. Front Genet. 2021;12;687687. PMID 34603368
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  19. Silverwood V, Blagojevic-Bucknall M, Jinks C, et al. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage. 2015;23(4);507-15. PMID 25447976
  20. Wu Q, Xu Z, Ma X, et al. Association of low muscle mass index and sarcopenic obesity with knee osteoarthritis: a systematic review and meta-analysis. J Int Soc Sports Nutr. 2024;21(1);2352393. PMID 38775452
  21. Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7);1323-30. PMID 24553908
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  26. Vasso M, Corona K, Gomberg B, et al. Obesity increases the risk of conversion to total knee arthroplasty after unicompartimental knee arthroplasty: a meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2022;30(12);3945-3957. PMID 34718836
  27. GBD 2021 Osteoarthritis Collaborators. Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5(9);e508-e522. PMID 37675071
  28. Whittaker JL, Losciale JM, Juhl CB, et al. Risk factors for knee osteoarthritis after traumatic knee injury: a systematic review and meta-analysis of randomised controlled trials and cohort studies for the OPTIKNEE Consensus. Br J Sports Med. 2022;56(24);1406-1421. PMID 36455966
  29. Mo L, Jiang B, Mei T, et al. Exercise Therapy for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis. Orthop J Sports Med. 2023;11(5);23259671231172773. PMID 37346776
  30. Webster KE, Hewett TE. Anterior Cruciate Ligament Injury and Knee Osteoarthritis: An Umbrella Systematic Review and Meta-analysis. Clin J Sport Med. 2022;32(2);145-152. PMID 33852440
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  32. Zengini E, Hatzikotoulas K, Tachmazidou I, et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat Genet. 2018;50:549-558. PMID 29559693
  33. Tachmazidou I, Hatzikotoulas K, Southam L, et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019;51:230-236. PMID 30664745
  34. McWilliams DF, Leeb BF, Muthuri SG, et al. Occupational risk factors for osteoarthritis of the knee: a meta-analysis. Osteoarthritis Cartilage. 2011;19:829-39. PMID 21382500