A meta-analysis of genome-wide association studies in 614,243 individuals identifies 59 novel susceptibility loci underlying Dupuytren's contracture

Dupuytrens contracture or disease (DD) is a disabling, fibroproliferative disease of the hand that affects up to 25% of people of northwestern European descent. It typically manifests in adulthood and many affected individuals have a positive family history, yet the genetic architecture of DD is not completely understood. We conducted genome-wide association studies (GWAS) of DD in 8,846 cases and 347,659 population controls from the UK Biobank resource, and 4,616 cases and 253,122 population controls from the FinnGen study. We combined these datasets with a meta-analysis, which represents the largest GWAS conducted in DD to date including 13,462 cases. We identified 83 loci with genome-wide significance of p < 5 x 10-8. We replicated association at the 24 previously reported loci and discovered 59 novel loci, substantially increasing the number of risk loci for DD. Colocalization with expression quantitative trait loci and overlap with genes linked to phenotypically matched human Mendelian disorders or animal models support causal roles for at least 30 genes with high confidence. Among these, fifteen genes cause rare limb abnormalities when mutated, an observation that may potentially shed light on hand specificity of DD phenotype. Gene enrichment analysis revealed predominant role of connective tissue development and maintenance and extracellular matrix homeostasis but limited or no role of inflammatory processes in disease causality. These findings provide key insights into the biological mechanisms underlying DD and identify genetically informed therapeutic targets for DD and possibly for other fibrotic diseases.