The genetic architecture of carpal tunnel syndrome

Thesis

Carpal tunnel syndrome (CTS) is a debilitating disease of the hand caused by compression of the median nerve within an anatomical tunnel in the wrist. It is a common disease with an estimated population prevalence of 5–10%. Symptoms include pain, paraesthesia, and numbness of the hand, and thenar weakness that ultimately leads to functional impairment. Many patients require surgery to relieve the pressure on the median nerve; although surgery is successful in the majority of patients, a significant sub-group experiences persistent or recurrent symptoms.

Despite being such a common disease, the pathophysiology of CTS is poorly understood, and even less is known about the genetic contribution to the disease. The heritability of CTS is estimated at 0.46, and approximately one-third of patients report a family history. CTS is a complex disease, where genetic and non-genetic factors interact to affect overall phenotypic expression. The current best method for interrogating a complex disease is with a genome-wide association study (GWAS).

I present the findings from the first ever genome-wide association of CTS, undertaken in over 12,000 CTS cases and nearly 400,000 controls from UK Biobank. The GWAS uncovered 16 genomic loci significantly associated with CTS. In silico analyses of the GWAS data using an array of bioinformatic tools discovered genetic variants at the GWAS-associated loci with strong evidence of functionality, and implicated several biologically plausible genes in CTS pathogenesis, including EFEMP1, ADAMTS17 and ADAMTS10. These genes were strongly enriched for biological pathways and gene ontologies pertaining to the extracellular matrix.

These analyses were followed by epidemiological investigations in UK Biobank, including Mendelian randomisation to assess the causal role of various putative risk factors on CTS aetiology. These studies identified a causal role for shorter height, greater BMI, and younger age at menarche in the development of CTS.

In the final results chapter, a polygenic risk score was constructed to validate the genetic variants discovered in the GWAS in a small cohort of deeply phenotyped CTS patients. RNA- sequencing performed in tenosynovial tissues collected from these patients demonstrated high expression of the candidate genes that were identified in the GWAS. Several GWAS loci demonstrated genotype-specific expression of these genes, providing evidence of functionality.

This work represents the first use of big data and computational genetics to delineate the genetic basis of CTS. I have provided evidence for a robust genetic architecture underlying CTS and have identified several biologically plausible candidate genes that contribute to its pathophysiology. The insights into the aetiology of CTS have revealed testable functional hypotheses and potential therapeutic avenues for further research.

Authors: Wiberg, A

• DOI: 10.5287/ora-1av9bboye
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Subjects: Carpal tunnel syndrome