Ubiquitous dysregulation of the Wnt pathway in immune thrombocytopenia genetic susceptibility Open Access

• ITP-associated Wnt pathway genes are dysregulated in multiple cell types, including lymphocytes and platelet/megakaryocyte lineage.

• Some of these genes are upregulated whereas others are downregulated in ITP, depending on the gene and the cell type.

The pathogenesis of immune thrombocytopenia (ITP) is complex and incompletely understood. Multiple cell types have been implicated, and their respective contribution is unclear. A recent genome-wide association study (GWAS) identified single nucleotide polymorphisms (SNPs) associated with pediatric ITP within or near five genes in the canonical Wnt signaling pathway. To investigate whether this pathway was dysregulated in ITP and identify which cell types were involved, we leveraged extensive functional genomics and single-cell RNA sequencing (scRNA-seq) data. By linking the SNPs identified to likely regulated genes, we showed an enrichment in the Wnt pathway and identified two additional genes in this pathway involved in ITP. The SNPs affect regulation of the genes of the Wnt pathway in multiples cell types. Indeed, scRNA-seq showed some of these genes were expressed in lymphocytes while others were expressed in platelets or megakaryocytes. By comparing the cell-specific expression of these genes between individuals with ITP and healthy controls, we demonstrate that several genes in the Wnt pathway were differentially expressed between these two groups. Some genes were upregulated while other were downregulated in ITP. In sum, the Wnt signaling pathway is broadly dysregulated in ITP with a complex pattern varying across genes and cell types.