Rare Copy Number Variants in Tourette Syndrome Disrupt Genes in Histaminergic Pathways and Overlap with Autism

Abstract

Background Studies of copy number variation (CNV) have successfully characterized loci and molecular pathways involved in a range of neuropsychiatric conditions. We conducted an analysis of rare CNVs in Tourette Syndrome (TS) to identify novel risk regions and relevant molecular pathways, evaluate the burden of structural variation in cases versus controls, and to assess the overlap of identified variations with those implicated in other neuropsychiatric syndromes. Methods We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370K to 1M probe arrays, and genome-wide genotyping data was used to match cases and controls for ancestry. Transmitted and de novo CNVs present in < 1% of the population were evaluated. Results While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (H1R and H2R) signaling pathways (p=5.8×10-4-1.6×10-2) as well as “axon guidance”, “cell adhesion”, “nervous system development” and “synaptic structure and function” processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders (ASD), but not intellectual disability or schizophrenia. Three large, likely-pathogenic, de novo events were identified, including one disrupting multiple gamma-Aminobutyric acid (GABA) receptor genes. Conclusions We identify further evidence supporting recent findings regarding the involvement of histaminergic and GABAergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and ASD.

Histaminergic modulation in Tourette syndrome

“…The presence of specific psychiatric comorbidities in some male members of this pedigree could also be explained by a dysfunction in the histaminergic system, as overriding inhibition of competing pathways within parallel cortico-striato-thalamo-cortical loops can hinder behavioral switching as seen in obsessivecompulsive disorder [89]. A more general association of histaminergic pathways with TS was identified by analysis of rare CNVs in a subsequent study [77]. The hypothesis of an involvement of the histaminergic system in the pathogenesis of TS was also supported by a more recent report on single nucleotide polymorphisms in the HDC region that are associated with TS [78].…”

“…In 2012, a case-control study of 460 patients with TS focused on copy number variants (CNVs) to identify risk regions or molecular pathways which may be associated with TS [77]. The authors found no statistically significant increase in CNVs when comparing patients with TS to controls, however there was some overlap between CNVs found in patients with TS and those previously identified in autism spectrum disorder.…”

A genetic model for neurodevelopmental disease

“…Studies of adults with schizophrenia and epilepsy demonstrate lower diagnostic yields of ~5% [11,12,18,23,24]. For other neurodevelopmental conditions there is either conflicting evidence for increased CNV burden, such as for bipolar disorder [25,26], or no evidence, as for Tourette's syndrome and dyslexia [19,20,27]. In all cases burden statistics are more significant when considering de novo events exclusively [15,18,21,22,26].…”

Decoding Neurodevelopment: Findings on Environmental Exposures and Synaptic Plasticity

“…Linkage studies have identified candidate autism susceptibility genes at multiple loci, most consistently on chromosomes 7q, 15q, and 16p (Autism Genome Project Consortium et al 2007;Sakurai et al 2011). Exome sequencing in sporadic cases of autism has detected new mutations (O'Roak et al 2011), and copy number variant studies have identified several hundred copy number variants putatively linked to autism (Fernandez et al 2012). The candidate genes most strongly implicated in NDD causation encode for proteins involved in synaptic architecture, neuro transmitter synthesis (e.g., g-amino butyric acid serotonin), oxytocin receptors, and cation trafficking (Sakurai et al 2011).…”