Abstract
Carpal tunnel syndrome (CTS) is a common and disabling condition of the hand caused by entrapment of the median nerve at the level of the wrist. It is the commonest entrapment neuropathy, with estimates of prevalence ranging between 5–10%. Here, we undertake a genome-wide association study (GWAS) of an entrapment neuropathy, using 12,312 CTS cases and 389,344 controls identified in UK Biobank. We discover 16 susceptibility loci for CTS with p < 5 × 10−8. We identify likely causal genes in the pathogenesis of CTS, including ADAMTS17, ADAMTS10 and EFEMP1, and using RNA sequencing demonstrate expression of these genes in surgically resected tenosynovium from CTS patients. We perform Mendelian randomisation and demonstrate a causal relationship between short stature and higher risk of CTS. We suggest that variants within genes implicated in growth and extracellular matrix architecture contribute to the genetic predisposition to CTS by altering the environment through which the median nerve transits.
Highlights
ResultsAcross several of the loci there was strong evidence of functionality: 30 out of 422 genome-wide significant variants had a combined annotation-dependent depletion (CADD) score >12.37, the threshold suggested for deleterious SNPs26
Provided more than 50% of the total weight comes from SNPs without pleiotropic effects, the median MR estimate should remain unbiased to pleiotropy
URLs for online resources referenced in the manuscript can be found at UK Biobank, www.ukbiobank.ac.uk/; BOLT-LMM, https://data.broadinstitute.org/ alkesgroup/BOLT-LMM/; CADD, https://cadd.gs.washington.edu/; RegulomeDB, http://www.regulomedb.org/; ANNOVAR, http://annovar.openbioinformatics.org/ en/latest/; FUMA, http://fuma.ctglab.nl/; MAGMA, https://ctg.cncr.nl/software/ magma; GTEx Portal, http://gtexportal.org/home/; XGR, http://galahad.well.ox.ac. uk:3020/; LD Hub, http://ldsc.broadinstitute.org/ldhub/; SIFT, https://sift.bii.a-star. edu.sg/; PLINK, http://pngu.mgh.harvard.edu/~purcell/plink/; R, https://www.rproject.org; 1000 Genomes Project, http://www.1000genomes.org; flashpca, https:// github.com/gabraham/flashpca/; SHAPEIT3, https://jmarchini.org/shapeit3/; HRC, http://www.haplotype-reference-consortium.org/; and QCTOOL v2, http://www. well.ox.ac.uk/~gav/qctool_v2/#overview
Summary
Across several of the loci there was strong evidence of functionality: 30 out of 422 genome-wide significant variants had a combined annotation-dependent depletion (CADD) score >12.37, the threshold suggested for deleterious SNPs26 This included the two missense variants above and rs3791679, the fourth most significantly associated SNP (OR = 1.11, p = 2.0 × 10−12), which. A gene-based association analysis was implemented in MAGMA, and this identified 17 genes that were significantly associated with CTS (Supplementary Table 2; Supplementary Fig. 3), which included 7 of the 25 genes that mapped to our associated loci in FUMA. Gene-set analysis of the 25 FUMA-mapped genes revealed a strong enrichment for gene ontologies for cellular components associated with the extracellular matrix (adjusted p = 2.7 × 10−8) and GWAS catalogue-reported genes for waist circumference and height (Supplementary Table 3). Using the inverse variance-weighted (IVW) MR method on 601 SNPs, we identified that a 1 SD (equivalent to 9.24 cm) increase in genetically instrumented height was associated with an OR of 0.79
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