We primarily aimed to investigate whether there are phenotypic and genetic links underlying body mass index (BMI) and overall osteoarthritis (OA). We then intended to explore whether the relationships differ across sexes and sites.
We first evaluated the phenotypic association between BMI and overall OA using data from the UK Biobank. We then investigated the genetic relationship leveraging summary statistics of the hitherto largest genome-wide association studies performed for BMI and overall OA. Finally, we repeated all analyses in a sex- (female, male) and site- (knee, hip, spine) specific manner.
Observational analysis suggested an increased hazard of diagnosed OA per 5 kg/m2 increment in BMI (hazard ratio = 1.38, 95% confidence interval (CI) = 1.37–1.39). A positive overall genetic correlation was observed for BMI and OA ( = 0.43, P = 4.72 × 10−133), corroborated by 11 significant local signals. Cross-trait meta-analysis identified 34 pleiotropic loci shared between BMI and OA, of which seven were novel. Transcriptome-wide association study revealed 29 shared gene–tissue pairs, targeting nervous, digestive, and exo/endocrine systems. Mendelian randomization demonstrated a robust BMI-OA causal relationship (odds ratio = 1.47, 95% CI = 1.42–1.52). A similar pattern of effects was observed in sex- and site-specific analyses, with BMI affecting OA comparably in both sexes and most strongly in the knee.
Our work demonstrates an intrinsic relationship underlying BMI and overall OA, reflected by a pronounced phenotypic association, significant biological pleiotropy, and a putative causal link. Stratified analysis further reveals that the effects are distinct across sites and comparable across sexes.
Abbreviations:BMI (body mass index), OA (osteoarthritis), MR (mendelian randomization), LDSC (linkage-disequilibrium score regression), CPASSOC (Cross-Phenotype Association), TWAS (transcriptome-wide association study)
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Osteoarthritis and Cartilage
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Body mass index and risk of knee osteoarthritis: systematic review and meta-analysis of prospective studies.BMJ Open. 2015; 5e007568https://doi.org/10.1136/bmjopen-2014-007568
- Body mass index and susceptibility to knee osteoarthritis: a systematic review and meta-analysis.Jt Bone Spine. 2012; 79: 291-297https://doi.org/10.1016/j.jbspin.2011.05.015
- The relationship between body mass index and hip osteoarthritis: a systematic review and meta-analysis.Jt Bone Spine. 2011; 78: 150-155https://doi.org/10.1016/j.jbspin.2010.04.011
- Investigating asthma heterogeneity through shared and distinct genetics: insights from genome-wide cross-trait analysis.J Allergy Clin Immunol. 2021; 147: 796-807https://doi.org/10.1016/j.jaci.2020.07.004
- Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis.Nat Genet. 2018; 50: 549-558https://doi.org/10.1038/s41588-018-0079-y
- Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.Cell. 2021; 184: 4784-4818 e17https://doi.org/10.1016/j.cell.2021.07.038
- Evaluation of the genetic overlap between osteoarthritis with body mass index and height using genome-wide association scan data.Ann Rheum Dis. 2013; 72: 935-941https://doi.org/10.1136/annrheumdis-2012-202081
- Causal Factors for knee, hip, and hand osteoarthritis: a Mendelian randomization study in the UK biobank.Arthritis Rheumatol. 2019; 71: 1634-1641https://doi.org/10.1002/art.40928
- The causal relationship between body mass index and the risk of osteoarthritis.Int J Gen Med. 2021; 14: 2227-2237https://doi.org/10.2147/IJGM.S314180
- Cardiometabolic polygenic risk scores and osteoarthritis outcomes: a Mendelian randomization study using data from the Malmo Diet and cancer study and the UK biobank.Arthritis Rheumatol. 2019; 71: 925-934https://doi.org/10.1002/art.40812
- Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry.Hum Mol Genet. 2019; 28: 166-174https://doi.org/10.1093/hmg/ddy327
- UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.PLoS Med. 2015; 12e1001779https://doi.org/10.1371/journal.pmed.1001779
- Safety and efficacy of omadacycline by BMI categories and diabetes history in two Phase III randomized studies of patients with acute bacterial skin and skin structure infections.J Antimicrob Chemother. 2021; 76: 1315-1322https://doi.org/10.1093/jac/dkaa558
- An atlas of genetic correlations across human diseases and traits.Nat Genet. 2015; 47: 1236-1241https://doi.org/10.1038/ng.3406
- Local genetic correlation Gives insights into the shared genetic architecture of complex traits.Am J Hum Genet. 2017; 101: 737-751https://doi.org/10.1016/j.ajhg.2017.09.022
- Cross-phenotype association analysis using summary statistics from GWAS.Statistical Human Genetics. Methods in Molecular Biology. 2017: 455-467
- PLINK: a tool set for whole-genome association and population-based linkage analyses.Am J Hum Genet. 2007; 81: 559-575https://doi.org/10.1086/519795
- The Ensembl variant effect predictor.Genome Biol. 2016; 17: 122https://doi.org/10.1186/s13059-016-0974-4
- Genetic and epigenetic fine mapping of causal autoimmune disease variants.Nature. 2015; 518: 337-343https://doi.org/10.1038/nature13835
- Bayesian test for colocalisation between pairs of genetic association studies using summary statistics.PLoS Genet. 2014; 10e1004383https://doi.org/10.1371/journal.pgen.1004383
- Investigating the shared genetic architecture of uterine leiomyoma and breast cancer: a genome-wide cross-trait analysis.Am J Hum Genet. 2022; 109: 1272-1285https://doi.org/10.1016/j.ajhg.2022.05.015
- Phenotypic and genotypic associations between migraine and lipoprotein subfractions.Neurology. 2021; 97: e2223-e2235https://doi.org/10.1212/wnl.0000000000012919
- Integrative approaches for large-scale transcriptome-wide association studies.Nat Genet. 2016; 48: 245-252https://doi.org/10.1038/ng.3506
- Mendelian randomization analysis with multiple genetic variants using summarized data.Genet Epidemiol. 2013; 37: 658-665https://doi.org/10.1002/gepi.21758
- Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.Int J Epidemiol. 2015; 44: 512-525https://doi.org/10.1093/ije/dyv080
- The MR-base platform supports systematic causal inference across the human phenome.Elife. 2018; 7https://doi.org/10.7554/eLife.34408
- Genetic studies of body mass index yield new insights for obesity biology.Nature. 2015; 518: 197-206https://doi.org/10.1038/nature14177
- Avoiding bias from weak instruments in Mendelian randomization studies.Int J Epidemiol. 2011; 40: 755-764https://doi.org/10.1093/ije/dyr036
- Dipeptidase-1 is an adhesion receptor for neutrophil recruitment in lungs and liver.Cell. 2019; 178: 1205-1221 e17https://doi.org/10.1016/j.cell.2019.07.017
- Adipocyte hypertrophy and improved postprandial lipid response in beta 2 syntrophin deficient mice.Cell Physiol Biochem. 2019; 52: 1151-1165https://doi.org/10.33594/000000078
- Pro-inflammatory cytokines: the link between obesity and osteoarthritis.Cytokine Growth Factor Rev. 2018; 44: 38-50https://doi.org/10.1016/j.cytogfr.2018.10.002
- The utrophin-beta 2 syntrophin complex regulates adipocyte lipid droplet size independent of adipogenesis.Mol Cell Biochem. 2019; 452: 29-39https://doi.org/10.1007/s11010-018-3409-6
- Obesity and inflammation: the linking mechanism and the complications.Arch Med Sci. 2017; 13: 851-863https://doi.org/10.5114/aoms.2016.58928
- An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).Semin Arthritis Rheum. 2019; 49: 337-350https://doi.org/10.1016/j.semarthrit.2019.04.008
- Non-surgical management of knee osteoarthritis: comparison of ESCEO and OARSI 2019 guidelines.Nat Rev Rheumatol. 2021; 17: 59-66https://doi.org/10.1038/s41584-020-00523-9
- Bias due to participant overlap in two-sample Mendelian randomization.Genet Epidemiol. 2016; 40: 597-608https://doi.org/10.1002/gepi.21998
Published online: March 06, 2023
Accepted: February 22, 2023
Received: November 6, 2022
Publication stageIn Press Journal Pre-Proof
© 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.