Genetic Variants Related to TGF-β Signaling Pathway Modulate Risk of Meniscus Injury: A Multiancestry Genome-wide Association Study.

BACKGROUND

Numerous clinical risk factors and moderate heritability have been reported for meniscus injury. However, the genetic etiology of meniscus injury remains understudied. This study was a multiancestry genome-wide association study (GWAS) of meniscus injury aimed at identifying genomic variants that influence risk and elucidating the mechanisms by which they may exert their effects.

QUESTIONS/PURPOSES: (1) Which single nucleotide polymorphisms (SNPs), genes, and molecular pathways are associated with meniscus injury? (2) How do independent SNPs with genome-wide significance alter the expression of genes within cells related to the meniscus? (3) Can a polygenic risk score (PRS) for meniscus injury discriminate between patients with meniscus injury and controls? (4) Does obesity increase the risk of meniscus injury using a Mendelian randomization framework?

METHODS

A meta-analysis of 38,062 patients with meniscus injury and 700,343 control participants was performed using GWAS summary statistics from the NIH's All of Us and FinnGen cohorts. All of Us provided an ancestrally diverse cohort for a multiancestry GWAS. Functional Mapping and Annotation of Genetic Variants (FUMA) and Meta-Analysis Gene-Set Mining of GWAS (MAGMA) platforms were used to identify genes of interest and perform expression quantitative trait loci and chromatin interaction mapping of SNPs with genome-wide significance. A PRS was developed for European individuals using the FinnGen GWAS and was validated on a European cohort from All of Us. Mendelian randomization assesses putative causal associations between an exposure and outcomes given random assortment of alleles during meiotic recombination and was used to analyze the risk of obesity and meniscus injury.

RESULTS

Twelve independent genome-wide significant loci (p < 5 × 10-8) were identified, and genes UQCC1, BMP6, EGR2, CAPZB, SMG6 were associated with meniscus injury after Bonferroni correction for all identified genes (p < 2.6 × 10-6). A subset of genes identified through MAGMA were enriched in the transforming growth factor-β (TGF-β) signaling pathway. Independent SNPs altered expression of genes related to the TGF-β pathway, including GDF5, BMP6, MMP24, and UQCC1. As an independent intronic SNP of UQCC1, rs2425055 was in chromosomal contact with GDF5OS in mesenchymal stem cells and decreased the expression of GDF5OS. A PRS for meniscus injury demonstrated differences in genetic risk between patients with meniscus injury and control participants (area under the curve 0.53 [95% confidence interval (CI) 0.51 to 0.54], OR per SD increase 1.10 [95% CI 1.05 to 1.15]; p = 3.34 × 10-5). Mendelian randomization demonstrated that genetic predisposition to obesity increased the risk of meniscus injury (OR 1.29 [95% CI 1.24 to 1.34]; p = 9.58 × 10-38).

CONCLUSION

The 12 independent genetic variants identified suggest a genetic contribution to meniscus injury risk across multiple ancestries. These SNPs may modulate meniscus injury risk by modifying genetic expression of key upstream regulators of the TGF-β signaling pathway (GDF5,BMP6,TGF-β2) and related genes (UQCC1,EGR2,MMP24). Although previous studies have implicated BMP6 and EGR2 in meniscus fibrochondrocyte differentiation and adaptive stress responses, our results demonstrate that genetic variation related to these genes modifies meniscus injury risk at a population level. In addition to demonstrating a putative causal relationship between obesity and meniscus injury through Mendelian randomization, we present a validated PRS that predicted risk of meniscal injury.

CLINICAL RELEVANCE

The genes related to meniscus injury identified in this GWAS are promising therapeutic targets for studies on meniscus regeneration. Our validated PRS presents an opportunity to develop screening and prevention strategies for individuals at high risk of meniscus injury.