Increased expression of genetically-regulated FLT3 implicated in Tourette’s Syndrome

Tourette’s Syndrome (TS) is a neurodevelopmental disorder that is characterized by motor and phonic tics. A recent TS genome-wide association study (GWAS) identified a genome-wide significant locus. However, determining the biological mechanism of GWAS signals remains difficult. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4,819 cases and 9,488 controls and found that increased expression of in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further showed that there is global dysregulation of across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizes with a posterior inclusion probability of 0.849. We validated the gene’s expression in 100 lymphoblastoid cell lines, establishing that TS cells had a 1.72 increased fold change compared to controls. A phenome-wide association study points towards having links with immune-related pathways such as monocyte count. We also identify several splicing events in and associated with TS, which are also implicated in immune function. This analysis of expression and splicing begins to explore the biology of TS GWAS signals.