NEW YORK (GenomeWeb) – A team from the UK and Estonia has tracked down more than a dozen genetic loci that are linked to the risk of developing carpal tunnel syndrome, a so-called "entrapment neuropathy" condition that affects the wrist's median nerve.
As they reported online yesterday in Nature Communications, the researchers performed a genome-wide association study involving more than 12,300 individuals with carpal tunnel syndrome and more than 389,300 unaffected controls from the UK Biobank project. The search led to variants at 16 loci corresponding with carpal tunnel syndrome risk — SNPs the team used to search for causal genes and to guide expression analyses using RNA sequence data for carpal tunnel tenosynovium tissue from dozens of carpal tunnel syndrome patients treated with decompression surgery.
The team's Mendelian randomization analyses pointed to potential ties between genetic features involved in enhanced carpal tunnel syndrome and those contributing to short stature, while a gene-based analysis hinted at an overrepresentation of carpal tunnel syndrome-related variants in genes from growth and extracellular matrix pathways.
"Our findings strongly suggest that the genetic susceptibility to [carpal tunnel syndrome] arises from altered musculoskeletal growth and development and/or aberrant connective tissue architecture, and implicates an inverse causal role of height in the etiology of [carpal tunnel syndrome]," University of Oxford researchers Dominic Furniss and David Bennett, the study's co-senior and corresponding authors, and their colleagues wrote. "The insights into the etiology of [carpal tunnel syndrome] have revealed testable functional hypotheses and potential therapeutic avenues for further research."
Prior studies suggest both environmental and genetic factors play a significant role in the risk of developing carpal tunnel syndrome, the team noted. For example, in a study published in Arthritis and Rheumatology in 2002, UK researchers used data for thousands of identical twins, non-identical twins, and singleton individuals to come up with an estimated heritability of 46 percent for the carpal tunnel syndrome phenotypic variation. The condition also appears to be more common in women, and has shown potential overlap with other conditions ranging from obesity and diabetes to rheumatoid arthritis.
For the GWAS, the researchers considered 12,312 carpal tunnel syndrome cases and 389,344 unaffected controls from the UK Biobank that were genotyped at more than 800,000 sites in the genome with one of two Axiom arrays, using imputation with data from the 1000 Genomes Project, the UK10K project, and the Haplotype Reference Consortium reference panel to get a look at nearly 92.7 million autosomal SNPs, small insertions and deletions, and structural variants.
When the team compared variants in individuals with or without carpal tunnel syndrome, it uncovered 422 variants at 16 loci with genome-wide significant ties to carpal tunnel syndrome. Of those, the top carpal tunnel suspects turned up in the secreted extracellular proteolytic enzyme-coding genes ADAMTS17 and ADAMTS10, or in an enhancer for the extracellular matrix protein-coding gene EFEMP1.
In a series of follow-up analyses and experiments, the researchers mapped the carpal tunnel risk SNPs in relation to genes and gene functions, performed a gene-focused search for pathways contributing to the condition, searched for variants tied to specific forms of the condition, and explored expression profiles for related genes with RNA sequencing on tenosynovium and healthy skin samples from 41 individuals with carpal tunnel syndrome.
They also considered the heritability of the condition and potential risk scores for it and used Mendelian randomization to search for potential overlap with height, since several height-related SNPs turned up in the carpal tunnel GWAS.
"We found enrichment for musculoskeletal and connective tissues when we partitioned the heritability of [carpal tunnel syndrome] across different cell and tissue types," the authors reported, "and this was supported by the genetic correlation between [carpal tunnel syndrome] and anthropometric phenotypes."