Candidate Genes and Pathways Associated with Gilles de la Tourette Syndrome—Where Are We?

Abstract

Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental and -psychiatric tic-disorder of complex etiology which is often comorbid with obsessive-compulsive disorder (OCD) and/or attention deficit hyperactivity disorder (ADHD). Twin and family studies of GTS individuals have shown a high level of heritability suggesting, that genetic risk factors play an important role in disease etiology. However, the identification of major GTS susceptibility genes has been challenging, presumably due to the complex interplay between several genetic factors and environmental influences, low penetrance of each individual factor, genetic diversity in populations, and the presence of comorbid disorders. To understand the genetic components of GTS etiopathology, we conducted an extensive review of the literature, compiling the candidate susceptibility genes identified through various genetic approaches. Even though several strong candidate genes have hitherto been identified, none of these have turned out to be major susceptibility genes yet.

Efficacy of deep brain stimulation of the anterior-medial globus pallidus internus in tic and non-tic related symptomatology in refractory Tourette syndrome

“…Several candidate genes for TS have been identified over the last years, but none have yet been confirmed as major susceptibility genes. Most studies in this regard are focusing on the candidate pathway approach that investigates genes related to neurotransmitters of the cortico- basal ganglia- thalamo- cortical loops [22] .…”

Oligogenic risk model for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders

“…Table 1 presents the distribution of basic and additional diagnoses. Although multiple genes have been proposed to be associated with GTS and TDs most of them are only backed up by limited evidence (Levy, Paschou, and Tümer 2021;Lin, Tsai, and Chou 2022) and the role of rare and non-coding variants in these genes is uncertain. To investigate the possible oligogenic model of GTS we constructed a list of genes (n=84) from diverse genetic studies on GTS (association studies, linkage analysis, GWAS, WES/WGS) offering a varied quality of evidence (Table 2).…”

Cytokine expression profiles in children and adolescents with tic disorders

“…Tic disorders in the DSM-5 include Tourette Syndrome (TS), persistent (chronic) motor/vocal tic disorder (CMVTD), and provisional tic disorder 1 , 2 . The consensus is that these disorders arise due to impaired function of the cortical-striatal-thalamic-cortical circuits, and aberrations of associated neurotransmitters may include dopamine, serotonin, gamma-aminobutyric acid (GABA), glutamate, acetylcholine, noradrenaline, and histamine 3 – 5 . The etiology of tic disorders is complex and involves multiple genetic, environmental, psychological, and immunological factors as well as their interactions 3 – 5 .…”

“…Candidate susceptibility genes included CNTNAP2, NLGN4, SLITRK1, HDC, IMMP2L, DRD2, DRD4, MAO-A, and GABAA receptors. These implicated potassium channels, membrane proteins, histidine metabolism, mitochondrial functioning, dopaminergic, GABAergic, and monoamine neurotransmitter function in etiology 3 – 6 . Genome wide association studies (GWAS) as well as studies evaluating single nucleotide polymorphisms (SNPs) suggest that tic disorders are polygenetic and the interaction between genetic predisposition and environmental factors increase the risk of their occurrence 3 – 5 , 7 .…”