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A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

ABSTRACT: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10^-24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

SUBMITTER: Skuladottir AT

PROVIDER: S-EPMC8948232 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

Skuladottir Astros Th AT Bjornsdottir Gyda G Ferkingstad Egil E Einarsson Gudmundur G Stefansdottir Lilja L Nawaz Muhammad Sulaman MS Oddsson Asmundur A Olafsdottir Thorunn A TA Saevarsdottir Saedis S Walters G Bragi GB Magnusson Sigurdur H SH Bjornsdottir Anna A Sveinsson Olafur A OA Vikingsson Arnor A Hansen Thomas Folkmann TF Jacobsen Rikke Louise RL Erikstrup Christian C Schwinn Michael M Brunak Søren S Banasik Karina K Ostrowski Sisse Rye SR Troelsen Anders A Henkel Cecilie C Pedersen Ole Birger OB Jonsdottir Ingileif I Gudbjartsson Daniel F DF Sulem Patrick P Thorgeirsson Thorgeir E TE Stefansson Hreinn H Stefansson Kari K

Nature communications 20220324 1

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10<sup>-24</sup>, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate ...[more]

PMID: 35332129

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Project description:BackgroundTrigger finger and carpal tunnel syndrome are the two most common non-traumatic connective tissue disorders of the hand. Both of these conditions frequently co-occur, often in patients with rheumatoid arthritis. However, this phenotypic association is poorly understood. Hypothesising that the co-occurrence of trigger finger and carpal tunnel syndrome might be explained by shared germline predisposition, we aimed to identify a specific genetic locus associated with both diseases.MethodsIn this genome-wide association study (GWAS), we identified 2908 patients with trigger finger and 436579 controls from the UK Biobank prospective cohort. We conducted a case-control GWAS for trigger finger, followed by co-localisation analyses with carpal tunnel syndrome summary statistics. To identify putative causal variants and establish their biological relevance, we did fine-mapping analyses and expression quantitative trait loci (eQTL) analyses, using fibroblasts from healthy donors (n=79) and tenosynovium samples from patients with carpal tunnel syndrome (n=77). We conducted a Cox regression for time to trigger finger and carpal tunnel syndrome diagnosis against plasma IGF-1 concentrations in the UK Biobank cohort.FindingsPhenome-wide analyses confirmed a marked association between carpal tunnel syndrome and trigger finger in the participants from UK Biobank (odds ratio [OR] 11·97, 95% CI 11·1-13·0; p<1 × 10-300). GWAS for trigger finger identified five independent loci, including one locus, DIRC3, that was co-localised with carpal tunnel syndrome and could be fine-mapped to rs62175241 (0·76, 0·68-0·84; p=5·03 × 10-13). eQTL analyses found a fibroblast-specific association between the protective T allele of rs62175241 and increased DIRC3 and IGFBP5 expression. Increased plasma IGF-1 concentrations were associated with both carpal tunnel syndrome and trigger finger in participants from UK Biobank (hazard ratio >1·04, p<0·02).InterpretationIn this GWAS, the DIRC3 locus on chromosome 2 was significantly associated with both carpal tunnel syndrome and trigger finger, possibly explaining their co-occurrence. The disease-protective allele of rs62175241 was associated with increased expression of long non-coding RNA DIRC3 and its transcriptional target, IGBP5, an antagonist of IGF-1 signalling. These findings suggest a model in which IGF-1 is a driver of both carpal tunnel syndrome and trigger finger, and in which the DIRC3-IGFBP5 axis directly antagonises fibroblastic IGF-1 signalling.FundingWellcome Trust, National Institute for Health Research, Medical Research Council.

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A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

Publications

A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

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