Summary
Objective
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.
Method
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.
Results
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.
Conclusion
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.
Keywords
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
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Article info
Publication history
Published online: March 06, 2023
Accepted:
February 22,
2023
Received:
November 6,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
