Department of Human Genetics, McGill University, Montréal, QC, Canada.
Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
Commun Biol. 2022 Mar 30;5(1):289. doi: 10.1038/s42003-022-03231-0.
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.
妥瑞氏症（TS）是一种神经发育障碍，其特征是运动性和发音性抽搐。最近的 TS 全基因组关联研究（GWAS）确定了一个全基因组显著的位置。然而，确定 GWAS 信号的生物学机制仍然很困难。为了描述 TS 中表达数量性状基因座（eQTL）的影响，并了解疾病的生物学基础。在这里，我们进行了一项包含 4819 例病例和 9488 例对照的 TS 转录组全基因组关联研究（TWAS）。我们证明，背外侧前额叶皮层（DLPFC）中 FLT3 的表达增加与 TS 有关。我们进一步表明，FLT3 在几个大脑区域存在全局失调，TWAS 信号的概率因果精细映射优先考虑 FLT3，后验纳入概率为 0.849。之后，我们用 100 个淋巴母细胞系来代表表达，并证明与对照相比，TS 细胞的 fold change 增加了 1.72。全表型关联研究也表明 FLT3 与免疫相关途径（如单核细胞计数）有关。我们进一步确定了与 TS 相关的几个剪接事件，包括 MPHOSPH9、CSGALNACT2 和 FIP1L1，这些事件也与免疫功能有关。这项表达和剪接分析开始探索 TS GWAS 信号的生物学。
