Integrative analysis of Dupuytren's disease identifies novel risk locus and reveals a shared genetic etiology with BMI

Abstract

Dupuytren's disease is a common inherited tissue‐specific fibrotic disorder, characterized by progressive and irreversible fibroblastic proliferation affecting the palmar fascia of the hand. Although genome‐wide association study (GWAS) have identified 24 genomic regions associated with Dupuytrens risk, the biological mechanisms driving signal at these regions remain elusive. We identify potential biological mechanisms for Dupuytren's disease by integrating the most recent, largest GWAS (3,871 cases and 4,686 controls) with eQTLs (47 tissue panels from five consortia, total n = 3,975) to perform a transcriptome‐wide association study. We identify 43 tissue‐specific gene associations with Dupuytren's risk, including one in a novel risk region. We also estimate the genome‐wide genetic correlation between Dupuytren's disease and 45 complex traits and find significant genetic correlations between Dupuytren's disease and body mass index (BMI), type II diabetes, triglycerides, and high‐density lipoprotein (HDL), suggesting a shared genetic etiology between these traits. We further examine local genetic correlation to identify 8 and 3 novel regions significantly correlated with BMI and HDL respectively. Our results are consistent with previous epidemiological findings showing that lower BMI increases risk for Dupuytren's disease. These 12 novel risk regions provide new insight into the biological mechanisms of Dupuytren's disease and serve as a starting point for functional validation.

The Genetic Architecture of Carbon Tetrachloride-Induced Liver Fibrosis in Mice

“… 39 , 40 Although the causative gene in this locus is not yet known, EPDR1 is a top candidate that has been functionally implicated in myofibroblasts. 41 , 42 This locus (at ELMO1 ) was also a human GWAS hit for primary biliary cholangitis. 43 ELMO1 (engulfment and cell motility 1) has been reported to confer susceptibility to human diabetic nephropathy, 44 which is a disease of excess ECM deposition, similar to fibrosis.…”

The relationship between body mass index and the risk of development of Dupuytren’s disease: a Mendelian randomization study

“…Several epidemiological studies have reported that a high body mass index (BMI) is associated with a lower risk of DD (Gudmundsson et al, 2000;Hacquebord et al, 2017). This association is supported by a recent transcriptome-wide association study, which revealed a negative genetic correlation between BMI and DD risk (Major et al, 2019). However, the causal relationship for this correlation has yet to be explored, and no biological mechanisms have been proposed to explain how high BMI could protect against the development of DD.…”

Dynamic Manugraphy as a Promising Tool to Assess the Outcome of Limited Aponeurectomy in Patients With Dupuytren's Contracture

“…Dupuytren's contracture is a benign, albeit irreversible progressive disease of the palmar aponeurosis that causes increasing flexion contractures, progressive flexion deformities and a decreased range of motion of the fingers (1,2). It is a common disorder of connective tissue, affecting 5-25% of individuals of European descent and genome-wide association study revealed several relevant loci (3)(4)(5)(6)(7). Furthermore, patients with diabetes mellitus, liver diseases or epilepsy as well as those with chronic exposure to strong hand-arm vibrations, high levels of alcohol consumption and smoking are at risk to develop such flexion deformities (1,2,(8)(9)(10)(11)(12).…”