gms | German Medical Science

Objectives/Interrogation: We recently performed the first ever genome-wide association study (GWAS) of Carpal Tunnel Syndrome (CTS), and discovered that several of the putative genes that predispose to CTS are important in skeletal growth. We also found that individuals with CTS are on average >2 cm shorter than controls. The aim of this study was to establish whether there is a causal relationship between shorter stature and increased risk of developing CTS.

Methods: Mendelian randomisation (MR) is an analytical method that provides evidence about causal relationships between a risk factor and a disease. It is less susceptible to reverse causation and confounding than conventional observational studies, because inherited genetic variation is randomly allocated at conception.

We performed a two-sample MR analysis using height as the exposure and CTS status as the outcome. We selected 601 single nucleotide polymorphisms (SNPs) for use as instrumental variables for height, taken from a large meta-analysis of adult height GWAS [1]. The genetic effect estimates for these SNPs with CTS risk were obtained from our own GWAS of CTS using data from UK Biobank. The analyses were performed using the MendelianRandomization package for R.

Results and Conclusions: Using the inverse variance-weighted (IVW) MR method on the 601 SNPs identified that a 1 standard deviation (equivalent to 9.24 cm) increase in height was associated with an odds ratio (OR) of 0.76 (95% CI: 0.70-0.82, p=2.24x10^-15) for development of CTS. The MR-Egger analysis gave an OR of 0.68 (95% CI: 0.52-0.83, p=2.87x10^-5) and no evidence to support the presence of confounding arising from the same genetic variants affecting both height and CTS status through different biological pathways (horizontal pleiotropy): intercept=0.0029; 95% CI: -0.0016, 0.0073, p=0.21. These associations persisted in various sensitivity analyses.

This study strongly supports the hypothesis that height is inversely causal in the aetiology of CTS, and, by extension, that altered anthropometric measures (of which height is a proxy) contributes to CTS predisposition. We therefore provide compelling genetic epidemiological evidence that is consistent with previously reported observations that altered hand anthropometric measurements and wrist dimensions correlate with CTS risk. We suggest that a significant proportion of the genetic contribution to CTS risk arises as a result of variants affecting genes that control skeletal growth.