CCS-Mediated Mechanistic Link Between Gestational Diabetes Mellitus and Carpal Tunnel Syndrome: A Multi-Omic MR Framework

Abstract

Background: Carpal tunnel syndrome (CTS) is a common condition in pregnancy, yet reliable tools for identifying women at high risk — particularly those with gestational diabetes mellitus (GDM) — remain lacking. Although GDM shares metabolic features with type 2 diabetes, a recognised CTS risk factor, whether GDM itself causally increases CTS risk and through which molecular pathways has not been established. Methods: We used linkage disequilibrium score regression and two-sample Mendelian randomisation across FinnGen and UK Biobank to evaluate the genetic correlation and causal effect of GDM on CTS. To identify molecular mediators, we integrated CTS GWAS with whole-blood cis-eQTLs and plasma protein QTLs using summary-data MR and Bayesian colocalisation. We then characterised trait specificity through phenome-wide MR and quantified mediation effects through two-step MR. Bulk RNA-seq of CTS tissue, single-cell RNA-seq of placental cell from women with and without GDM, murine histology and immunofluorescence, and molecular docking were used to delineate downstream mechanisms and therapeutic potential. Results: GDM and CTS showed significant genetic correlation (rg = 0.219). Genetic liability to GDM causally increased CTS risk across discovery, replication, and female-only models, independent of other metabolic or pregnancy-related traits. Multi-omic integration identified CCS as the only gene supported at both eQTL and pQTL levels and revealed its strongest and most specific causal association with CTS. Mediation MR demonstrated that circulating CCS accounts for a substantial proportion of the GDM-CTS effect. Transcriptomic, single-cell and animal analyses confirmed a CCS-high, inflamed and collagen-rich microenvironment in CTS, while docking analyses indicated that CCS-centred pathways are pharmacologically tractable. Conclusion: GDM exerts a causal effect on CTS, largely mediated through CCS-driven oxidative, immune and fibrotic pathways. CCS emerges as a promising biomarker for risk stratification and a potential therapeutic target. These findings provide a mechanistic foundation for early CTS surveillance and personalised management in women with GDM, addressing an important unmet clinical need in perinatal care.