Network analysis and fine-mapping GWAS loci to identify genes and functional variants involved in the development of Dupuytren disease

The first genome-wide association study (GWAS) in Dupuytren disease (DD) has successfully identified nine genomic regions that harbor genetic variants contributing to the genetics of this disease. In GWASs common single nucleotide variants (SNVs) are investigated for association with a given trait or disease. These common SNVs are rarely the direct causative variants, but instead by chance, they capture the real causative variants in linkage disequilibrium (LD) at a given association locus. One of the major challenges in complex genetic diseases is the identification of these causal genetic variants that underlie the association signals. Integrative approaches that target the functional relevance of these causal variants on multiple levels are needed. The success of these approaches depends on the individual genetic architecture at each GWAS locus, which can be very complex, and the specific features of a given trait or disease. Targeted sequencing of the GWAS loci is one possible approach. Extensive analysis of GWAS data in conjunction with other possible data sources, e.g., expression data, is another approach to help to unravel the genetics of Dupuytren disease. We have been applying both approaches aiming to interrogate candidate gene variants and to characterize pathways of DD.