Transcriptome-wide association study reveals increased neuronal FLT3 expression is associated with Tourette’s syndrome

Abstract

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. To characterize effects of expression quantitative trait loci (eQTLs) in TS and understand biological underpinnings of the disease. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4819 cases and 9488 controls. We demonstrate that increased expression of FLT3 in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further show that there is global dysregulation of FLT3 across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizes FLT3 with a posterior inclusion probability of 0.849. After, we proxy the expression with 100 lymphoblastoid cell lines, and demonstrate that TS cells has a 1.72 increased fold change compared to controls. A phenome-wide association study also points toward FLT3 having links with immune-related pathways such as monocyte count. We further identify several splicing events in MPHOSPH9, CSGALNACT2 and FIP1L1 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.

Molecular Landscape of Tourette’s Disorder

“…FLT3 shows regional specificity for TD, as it is highly expressed in the brain and in our TWAS, we found TD-associated eQTLs with a positive effect on FLT3 expression in multiple brain regions (top finding for the cortex; Z-score = 4.66 and p -value = 3.24 × 10 −6 ). In keeping with this, a recent study also found the most significant TD-associated TWAS signal for the cortex and, more specifically, the dorsolateral prefrontal cortex [ 226 ]. In the same study, the authors reported an increased expression of FLT3 in lymphoblastoid cell lines derived from TD patients compared to controls [ 226 ].…”

“…In keeping with this, a recent study also found the most significant TD-associated TWAS signal for the cortex and, more specifically, the dorsolateral prefrontal cortex [ 226 ]. In the same study, the authors reported an increased expression of FLT3 in lymphoblastoid cell lines derived from TD patients compared to controls [ 226 ]. As for its temporal specificity for TD, FLT3 is highly expressed in two brain regions for which we have found spatiotemporal enrichment of TD candidate gene expression (see above), i.e., in the cerebellum (in the neonatal period and infancy, early and middle-late childhood, adolescence, and young adulthood) and in the thalamus (in adolescence and young adulthood).…”

Tourette syndrome research highlights from 2022

“…Liao and colleagues performed a transcriptome-wide association study (TWAS) using previously published TS GWAS2 data ( Yu et al . 2019 ) (4819 TS cases and 9488 controls) and CommonMind Consortium and brain tissue panels from GTEx 53 v7 ( Liao et al . 2022a ).…”

The Identification of Significant Genes Related to Systemic Lupus Erythematosus through the Integration of the Results of a Transcriptome-Wide Association Study and an mRNA Expression Profile Analysis

“…Gene expression is a key step linking DNA sequence variation to phenotypes, GWAS have linked thousands of genomic loci to complex traits (16). However, GWAS are rarely ascertainable from identify causal genes that lead to trait changes (17). In 2018, a new omics analysis method, transcriptome-wide association studies (TWAS), emerged, which leverage expression reference panels (eQTL cohorts with expression and genotype data) to discover gene-trait associations in GWAS datasets, providing a powerful strategy that integrates GWAS results and gene expression references to identify signi cant expression-trait associations (18-20).…”

“…In recent years, TWASs have been widely used to identify risk genes in a variety of autoimmune diseases. For example, by using TWAS analysis, Díez-Obrero V et al provided insight into the tissue-speci c molecular processes underlying in ammatory bowel disease genetic susceptibility (17).…”