Causality of genetically determined metabolites and metabolic pathways on osteoarthritis: a two-sample mendelian randomization study

Abstract

Background: Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases and is the leading cause of pain and disability in the aged population. However, the underlying biological mechanism has not been fully understood. This study aims to reveal the causal effect of circulation metabolites on OA susceptibility.

Methods: A two-sample Mendelian Randomization (MR) analysis was performed to estimate the causality of GDMs on OA. A genome-wide association study (GWAS) of 486 metabolites was used as the exposure, whereas 8 different OA phenotypes, including any-site OA (All OA), knee and/or hip OA (knee/hip OA), knee OA, hip OA, spine OA, finger and/or thumb OA (hand OA), finger OA, thumb OA, were set the outcomes. Inverse-variance weighted (IVW) was used for calculating causal estimates. Methods including weight mode, weight median, MR-egger, and MR-PRESSO were used for the sensitive analysis. Furthermore, metabolic pathway analysis was performed via the web-based Metaconflict 4.0. All statistical analyses were performed in R software.

Results: In this MR analysis, a total of 235 causative associations between metabolites and different OA phenotypes were observed. After false discovery rate (FDR) correction and sensitive analysis, 9 robust causative associations between 7 metabolites (e.g., arginine, kynurenine, and isovalerylcarnitine) and 5 OA phenotypes were finally identified. Additionally, eleven significant metabolic pathways in 4 OA phenotypes were identified by metabolic pathway analysis.

Conclusion: The finding of our study suggested that identified metabolites and metabolic pathways can be considered useful circulating metabolic biomarkers for OA screening and prevention in clinical practice, and can also serve as candidate molecules for future mechanism exploration and drug target selection.

Keywords: Arginine; Genetically determined metabolites; Kynurenine; Mendelian randomization; Osteoarthritis.

Fig. 1

The overview of the research workflow

Fig. 2

Mendelian randomization associations of known metabolites on the risk of the 8 phenotypes of osteoarthritis. (derived from the fixed-effect IVW analysis). IVW inverse-variance weighted)

Fig. 3

Sensitivity analysis for significant metabolites on OA phenotypes passing Bonferroni correction

Fig. 4

Scatter plot showing the genetic associations of seven metabolites on the risk of 5 OA phenotypes. (A) ADpSGEGDFXAEGGGVR* on hip OA, (B) 4-acetaminophen sulfate on hip OA, (C) arginine on hip OA, (D) kynurenine on knee/hip OA, (E) isovalerylcarnitine on hand OA, (F) 1-linoleoylglycerophosphocholine on hand OA, (G) X-11423–O-sulfo-L-tyrosine on hand OA, (H) 1-linoleoylglycerophosphocholine on finger OA, (I) X-11423–O-sulfo-L-tyrosine on thumb OA, (J) taurocholate on thumb OA OA osteoarthritis

Fig. 5

The funnel plot represents IVs for each significant causal association between metabolites and OA phenotypes. A ADpSGEGDFXAEGGGVR* on hip OA, (B) 4-acetaminophen sulfate on hip OA, (C) arginine on hip OA, (D) kynurenine on knee/hip OA, (E) isovalerylcarnitine on hand OA, (F) 1-linoleoylglycerophosphocholine on hand OA, (G) X-11423–O-sulfo-L-tyrosine on hand OA, (H) 1-linoleoylglycerophosphocholine on finger OA, (I) X-11423–O-sulfo-L-tyrosine on thumb OA, (J) taurocholate on thumb OA OA osteoarthritis

Fig. 6

Enriched significant metabolic pathways of 4 OA phenotypes

Fig. 7

The illustration represents significant causal metabolites and metabolic pathways associated with different OA phenotypes