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

Dupuytren’s 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 × 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. ### Competing Interest Statement Fedik Rahimov, Jacob F. Degner, John S. Lee, Xiuwen Zheng, Jozsef Karman, Howard J. Jacob, and Jeffrey F. Waring are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication ### Funding Statement This study was funded by AbbVie. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: North West Haydock Research Ethics Committee of the UK National Health Service gave approval for the UK Biobank study. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa gave approval for the FinnGen study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.