A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease

Abstract

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.

Fig. 1. Manhattan plot of the logistic regression for the meta-GWAS association analysis.

The horizontal red line represents a p-value threshold of 5 × 10⁻⁸ (e.g. the multiple comparison correction for genome-wide significance).

Fig. 2. Gene-based analysis as computed by MAGMA, using a multiple regression model.

Meta-GWAS summary statistics were mapped to 18,879 protein coding genes. Genome-wide significance (red dashed line in the plot) was defined by Bonferroni correction at p = 0.05/18,879 = 2.65 × 10⁻⁶.

Fig. 3. Cell population-relevant genes.

Heatmap showing specificity scores (between 0 [red] and 1 [blue] where a lower value indicates greater specificity to the cell type), produced by SNPsea, of meta-GWAS associated DD loci in cell populations derived from single cell RNA-seq of DD nodules (n = 6 patients). Dendrograms (clustering trees) can be observed for cell populations (y-axis) as well as genetic loci (x-axis).

Fig. 4. Variance explained through polygenic risk score analyses.

Density plot of the PRS distribution for cases and controls in (A) the Dutch CytoSNP cohort, (B) the Dutch GSA cohort, (C) UK Biobank cohort (D) the UK BSSH-GODD cohort, and (E) the Dutch FinnGen cohort.