A Genetic Risk Score for Carpal Tunnel Syndrome

Introduction

Advances in our understanding of the human genome coupled with the rapidly falling cost of genome sequencing is ushering in an era of personalised medicine. Population-wide whole genome sequencing is becoming cheaper and more accessible¹, and this will profoundly affect the way in which diseases commonly encountered by plastic surgeons are diagnosed and treated. We recently performed the first ever genome-wide association study (GWAS) of Carpal Tunnel Syndrome (CTS), and identified 13 genome-wide susceptibility loci. The aim of this study was to demonstrate one potential application of our findings.

 

Methods

We developed a weighted genetic risk score² (wGRS) for CTS based on the genetic variants discovered in our GWAS. We obtained genotypic and diagnostic data from UK Biobank, a prospective cohort study of ~500,000 individuals from the UK who have had whole-genome genotyping undertaken, and have allowed linkage of these data with their medical records. We used ICD-10, OPCS and self-diagnosis codes to identify individuals with CTS and diseases known to be associated with CTS, and investigated whether individuals with certain phenotypes are genetically predisposed to CTS.

 

Results

There was a significant difference in wGRS between 12,106 CTS cases (0.326) vs 387,347 non-CTS controls (0.280) (p<0.0001), and also between 11,438 CTS patients who have undergone carpal tunnel surgery (0.328) and 668 CTS patients who have not (0.295) (p=0.00012). We did not observe an increased wGRS in patients with diabetes, rheumatoid arthritis, hypothyroidism and ulnar nerve entrapment. We found a highly statistically significant negative correlation between height and wGRS in both males (r=-0.044, p<0.0001) and females (r=-0.046, p<0.0001), and a weak positive correlation for BMI in males (r=0.0084, p=0.00032) but not in females (r=0.0038, p=0.075).

 

Conclusions

The significantly higher wGRS in operated CTS patients vs unoperated CTS patients suggests that our wGRS correlates with disease severity. The finding that wGRS is not higher in individuals with diseases known to be associated with CTS suggests that extraneous factors (such as oedema in hypothyroidism and synovitis in rheumatoid arthritis), rather than shared genetic factors, are likely to predispose to CTS in these groups. The negative correlation between wGRS and height explains the observation that CTS patients are on average >2cm shorter than non-CTS controls in the UK Biobank cohort. We are currently extending the wGRS to our own cohort of deeply phenotyped CTS patients, to correlate wGRS with symptoms and electrophysiological test severity, as well as surgical outcomes. We believe it is important for plastic surgeons to be mindful of the increasing role that genetics will play in our practice, and this study illustrates the proof of principle that a wGRS can potentially serve as useful tool in the future for the prognostication of CTS.

 

References

1. Jain M, Koren S, Miga KH, et al. Nanopore sequencing and assembly of a human genome with ultra-long reads. Nat Biotechnol. January 2018. http://dx.doi.org/10.1038/nbt.4060.

2. De Jager PL, Chibnik LB, Cui J, et al. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. Lancet Neurol. 2009;8(12):1111-1119.