Shared genetic susceptibility between trigger finger and carpal tunnel syndrome: a genome-wide association study

Patel, B, Kleeman, SO, Neavin, D, Powell, J, Baskozos, G, Ng, M, Ahmed, WUR, Bennett, DL, Schmid, AB, Furniss, D, Wiberg, A (August 2022) Shared genetic susceptibility between trigger finger and carpal tunnel syndrome: a genome-wide association study. The Lancet Rheumatology, 4 (8). e556-e565. ISSN 2665-9913

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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 436 579 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 × 10−300). 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). Interpretation: In 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. Funding: Wellcome Trust, National Institute for Health Research, Medical Research Council.

Item Type:	Paper
Subjects:	Investigative techniques and equipment Investigative techniques and equipment > assays Investigative techniques and equipment > assays > genome wide association studies
CSHL Authors:	Kleeman, Sam
Communities:	CSHL labs > Janowitz lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	1 August 2022
Date Deposited:	22 Aug 2022 02:24
Last Modified:	29 Feb 2024 17:10
PMCID:	PMC7613465
Related URLs:	PubMed
URI:	https://repository.cshl.edu/id/eprint/40695

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