The Genetics of Gilles de la Tourette Syndrome: a Common Aetiological Basis with Comorbid Disorders?

Karagiannidis, Iordanis; Tsetsos, Fotis; Padmanabhuni, Shanmukha Sampath; Alexander, John J.; Georgitsi, Marianthi; Paschou, Peristera

doi:10.1007/s40473-016-0088-z

Cited by 10 publications

(10 citation statements)

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“…This is the first study to identify shared genetic factors underlying TS and ADHD, two closely related and often co-occurring neuropsychiatric disorders (Karagiannidis et al, 2016 ). We meta-analyzed 489 of the top hit SNPs in the first TS GWAS, that had also been tested in ADHD published GWASs and meta-analysis.…”

Section: Discussionmentioning

confidence: 99%

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Meta-Analysis of Tourette Syndrome and Attention Deficit Hyperactivity Disorder Provides Support for a Shared Genetic Basis

et al. 2016

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Gilles de la Tourette Sydrome (TS) is a childhood onset neurodevelopmental disorder, characterized phenotypically by the presence of multiple motor and vocal tics. It is often accompanied by multiple psychiatric comorbidities, with Attention Deficit/Hyperactivity Disorder (ADHD) among the most common. The extensive co-occurrence of the two disorders suggests a shared genetic background. A major step toward the elucidation of the genetic architecture of TS was undertaken by the first TS Genome-wide Association Study (GWAS) reporting 552 SNPs that were moderately associated with TS (p < 1E-3). Similarly, initial ADHD GWAS attempts and meta-analysis were not able to produce genome-wide significant findings, but have provided insight to the genetic basis of the disorder. Here, we examine the common genetic background of the two neuropsychiatric phenotypes, by meta-analyzing the 552 top hits in the TS GWAS with the results of ADHD first GWASs. We identify 19 significant SNPs, with the top four implicated genes being TBC1D7, GUCY1A3, RAP1GDS1, and CHST11. TBCD17 harbors the top scoring SNP, rs1866863 (p:3.23E-07), located in a regulatory region downstream of the gene, and the third best-scoring SNP, rs2458304 (p:2.54E-06), located within an intron of the gene. Both variants were in linkage disequilibrium with eQTL rs499818, indicating a role in the expression levels of the gene. TBC1D7 is the third subunit of the TSC1/TSC2 complex, an inhibitor of the mTOR signaling pathway, with a central role in cell growth and autophagy. The top genes implicated by our study indicate a complex and intricate interplay between them, warranting further investigation into a possibly shared etiological mechanism for TS and ADHD.

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Section: Discussionmentioning

confidence: 99%

“…The relationship of TS with ADHD is well established (Karagiannidis et al, 2016 ). Individuals with ADHD commonly present tics, and in individuals with TS and tics, ADHD is a significant commorbidity.…”

Section: Introductionmentioning

confidence: 99%

Meta-Analysis of Tourette Syndrome and Attention Deficit Hyperactivity Disorder Provides Support for a Shared Genetic Basis

et al. 2016

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“…Although each of these disorders defines a distinct DSM diagnostic category, they are highly comorbid. For instance, up to 55 % of TS patients also present with ADHD symptoms, 50% have OCD, and up to 20% present with ASD (5)(6)(7). The high comorbidity rates across these disorders lend support to the hypothesis of a common etiological thread that connects them across an impulsivity-compulsivity spectrum (8).…”

Section: Introductionmentioning

confidence: 94%

Cross-disorder GWAS meta-analysis for Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Obsessive Compulsive Disorder, and Tourette Syndrome

Yang¹,

Wu²,

Lee

et al. 2019

Preprint

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Attention Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Obsessive-Compulsive Disorder (OCD), and Tourette Syndrome (TS) are among the most prevalent neurodevelopmental psychiatric disorders of childhood and adolescence. High comorbidity rates across these four disorders point toward a common etiological thread that could be connecting them across the repetitive behaviors-impulsivity-compulsivity continuum. Aiming to uncover the shared genetic basis across ADHD, ASD, OCD, and TS, we undertake a systematic cross-disorder meta-analysis, integrating summary statistics from all currently available genome-wide association studies (GWAS) for these disorders, as made available by the Psychiatric Genomics Consortium (PGC) and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). We present analysis of a combined dataset of 93,294 individuals, across 6,788,510 markers and investigate associations on the single-nucleotide polymorphism (SNP), gene and pathway levels across all four disorders but also pairwise. In the ADHD-ASD-OCD-TS cross disorder GWAS meta-analysis, we uncover in total 297 genomewide significant variants from six LD (linkage disequilibrium) -independent genomic risk regions. Out of these genomewide significant association results, 199 SNPs, that map onto four genomic regions, show high posterior probability for association with at least three of the studied disorders (m-value>0.9). Gene-based GWAS metaanalysis across ADHD, ASD, OCD, and TS identified 21 genes significantly associated under Bonferroni correction. Out of those, 15 could not be identified as significantly associated based on the individual disorder GWAS dataset, indicating increased power in the cross-disorder comparisons. Cross-disorder tissue-specificity analysis implicates the Hypothalamus-Pituitary-Adrenal axis (stress response) as possibly underlying shared pathophysiology across ADHD, ASD, OCD, and TS. Our work highlights genetic variants and genes that may contribute to overlapping neurobiology across the four studied disorders and highlights the value of re-defining the framework for the study across this spectrum of highly comorbid disorders, by using transdiagnostic approaches.

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“…In fact, candidate gene studies, genome‐wide association studies, and copy number variation studies have consistently screened and identified reoccurring mutual mutations overlapping across TS and other neuropsychiatric disorders. The identified genes ( ASH1L, RIMS1, NRXN1, NLGN4X, SHANK3, LRRTMs, DISC1, SLC6A3, GRIN2b, SLITRK1, HDC, and CNTNAP2 ) (De Rubeis et al., 2014; Kim et al., 2009; Kosmicki et al., 2017; Peñagarikano et al., 2011; Pittenger, 2017; Abelson et al, 2005) encode proteins that converge onto certain conserved pathways, transcriptional control, and chromatin remodeling ( ASH1L ) (Taniguchi & Moore, 2014), synapse development and function ( NRXN1, RIMS1, NLGN4X, LRRTMs , and SHANK3 ) (Ebrahimi‐Fakhari & Sahin, 2015; Kelleher & Bear, 2008; Südhof, 2008), molecules involved in neuronal development ( DISC1 and CNTNAP2 ), or neurotransmitter receptors ( SLC6A3, GRIN2b, and HDC ), and thus, supporting the evidence of common biologic pathways underlying TS and other neuropsychiatric disorders (Karagiannidis et al, 2016; Georgitsi et al, 2016). However, results from genetic studies and reoccurrence trials in populations have been mixed so far, and no well‐defined TS‐associated risk gene with conclusive effect has been identified (Georgitsi et al, 2016; Paschou, 2013).…”

Section: Introductionmentioning

confidence: 87%

Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

Zhang

Zheng

et al. 2020

Developmental Neurobiology

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Ash1l potentially contributes to neurodevelopmental diseases. Although specific Ash1l mutations are rare, they have led to informative studies in animal models that may bring therapeutic advances. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome (TS), autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Functional convergence of Ash1l generated several significant signaling pathways: chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function. Here, we systematically review the literature on Ash1l, including its discovery, expression, function, regulation, implication in the nervous system, signaling pathway, mutations, and putative involvement in TS and other neurodevelopmental traits. Such findings highlight Ash1l pleiotropy and the necessity of transcending a single gene to complicated mechanisms of network convergence underlying these diseases. With the progress in functional genomic analysis (highlighted in this review), and although the importance and necessity of Ash1l becomes increasingly apparent in the medical field, further research is required to discover the precise function and molecular regulatory mechanisms related to Ash1l. Thus, a new perspective is proposed for basic scientific research and clinical interventions for cross‐disorder diseases.

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The Genetics of Gilles de la Tourette Syndrome: a Common Aetiological Basis with Comorbid Disorders?

Cited by 10 publications

References 132 publications

Meta-Analysis of Tourette Syndrome and Attention Deficit Hyperactivity Disorder Provides Support for a Shared Genetic Basis

Meta-Analysis of Tourette Syndrome and Attention Deficit Hyperactivity Disorder Provides Support for a Shared Genetic Basis

Cross-disorder GWAS meta-analysis for Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Obsessive Compulsive Disorder, and Tourette Syndrome

Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

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