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Transcriptome-wide association study reveals increased neuronal FLT3 expression is associated with Tourette's
Calwing Liao1,2, Veikko Vuokila2, Hélène Catoire2
1Department of Human Genetics, McGill University, Montréal, QC, Canada.
Communications Biology
|March 31, 2022
Summary
Tourette's Syndrome (TS) involves motor and phonic tics. This study links increased FLT3 gene expression in the brain to TS, suggesting immune system involvement in the neurodevelopmental disorder.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Tourette's Syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics.
- Genome-wide association studies (GWAS) have identified genetic loci for TS, but underlying biological mechanisms remain unclear.
- Expression quantitative trait loci (eQTLs) can help elucidate the functional impact of GWAS findings.
Purpose of the Study:
- To investigate the role of gene expression and splicing in Tourette's Syndrome.
- To characterize the effects of eQTLs in TS and understand the disease's biological underpinnings.
- To explore the biological mechanisms of previously identified TS GWAS signals.
Main Methods:
- Conducted a transcriptome-wide association study (TWAS) in 4819 TS cases and 9488 controls.
- Performed probabilistic causal fine-mapping of TWAS signals.
- Analyzed gene expression in lymphoblastoid cell lines and conducted phenome-wide association studies (PheWAS).
- Identified splicing events associated with TS.
Main Results:
- Increased expression of FLT3 in the dorsolateral prefrontal cortex (DLPFC) was significantly associated with TS.
- Global dysregulation of FLT3 was observed across multiple brain regions.
- FLT3 was prioritized as a causal gene for the TWAS signal (posterior inclusion probability = 0.849).
- TS cells showed a 1.72-fold increased expression of FLT3 compared to controls in lymphoblastoid cell lines.
- PheWAS indicated FLT3's association with immune-related pathways, including monocyte count.
- Several TS-associated splicing events in MPHOSPH9, CSGALNACT2, and FIP1L1 implicated immune function.
Conclusions:
- Increased FLT3 expression in the DLPFC is a potential mechanism contributing to Tourette's Syndrome.
- FLT3 dysregulation and its links to immune pathways suggest a role for immune system involvement in TS.
- Splicing events in immune-related genes may also contribute to TS pathogenesis.
- This study provides insights into the biological mechanisms underlying TS GWAS signals.
