Abstract
Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.
Highlights
Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterized by several motor tics and at least one vocal tic that persist more than a year[1]
MAGMA analysis identified one significant gene set (Fig. 1), cell adhesion and trans-synaptic signaling (CATS), which achieved a nominal p-value of 6.2 × 10−5
Results were mainly driven by associations in the Cadherin 26 (CDH26), Cell Adhesion molecule 2 (CADM2), and Opioid binding protein/cell adhesion molecule like (OPCML) genes as indicated by MAGMA gene-based analysis (Table 1)
Summary
Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterized by several motor tics and at least one vocal tic that persist more than a year[1]. TS is highly polygenic in nature, it is highly heritable[4]. The genetic risk for TS that is derived from common variants is spread throughout the genome[4]. The two genome-wide association studies (GWAS) conducted to date[7,8] suggest that TS genetic variants may be associated, in aggregate, with tissues within the cortico-striatal and cortico-cerebellar circuits, and in particular, the dorsolateral prefrontal cortex. The GWAS results demonstrated significant ability to predict tic severity using TS polygenic risk scores[7,9]. A genome-wide CNV study identified rare structural variation contributing to TS on the NRXN1 and CNTN6 genes[10]. De novo mutation analysis studies in trios have highlighted two high confidence genes, CELSR and WWC1, and four probable genes, OPA1, NIPBL, FN1, and FBN2 to be associated with TS11,12
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