Shared Genetic Susceptibility Between Trigger Finger and Carpal Tunnel Syndrome: a Genome-wide Association Study

Overview

Journal Lancet Rheumatol

Specialty Rheumatology

Date 2022 Aug 31

PMID 36043126

Authors

Benjamin Patel

Sam O Kleeman

Drew Neavin

Joseph Powell

Georgios Baskozos

Michael Ng

Waheed-Ul-Rahman Ahmed

David L Bennett

Annina B Schmid

Dominic Furniss

Akira Wiberg

Affiliations

Soon will be listed here.

Abstract

Background: Trigger 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.

Methods: In 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.

Findings: Phenome-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). GWAS for trigger finger identified five independent loci, including one locus, , 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). eQTL analyses found a fibroblast-specific association between the protective T allele of rs62175241 and increased and 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).

Interpretation: In this GWAS, the 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 and its transcriptional target, , 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 axis directly antagonises fibroblastic IGF-1 signalling.

Funding: Wellcome Trust, National Institute for Health Research, Medical Research Council.

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