Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism.
- Authors
- Fernandez, Thomas V; Sanders, Stephan J; Yurkiewicz, Ilana R; Ercan-Sencicek, A Gulhan; Kim, Young-Shin; Fishman, Daniel O; Raubeson, Melanie J; Song, Youeun; Yasuno, Katsuhito; Ho, Winson S C; Bilguvar, Kaya; Glessner, Joseph; Chu, Su Hee; Leckman, James F; King, Robert A; Gilbert, Donald L; Heiman, Gary A; Tischfield, Jay A; Hoekstra, Pieter J; Devlin, Bernie; Hakonarson, Hakon; Mane, Shrikant M; GΓΌnel, Murat; State, Matthew W
- Year
- 2012
- Journal
- Biological psychiatry
- PMID
- 22169095
- DOI
- 10.1016/j.biopsych.2011.09.034
- PMCID
- PMC3282144
BACKGROUND: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those 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 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. 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 (subtypes 1 and 2) signaling pathways (p = 5.8 Γ 10(-4) - 1.6 Γ 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 but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. CONCLUSIONS: We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.
Copy number variant (CNV) discovery, quality control, and annotation workflowTourette syndrome (TS) and control samples were genotyped on Illumina single nucleotide polymorphism (SNP) microarrays. Quality control was performed simultaneously in both cases and controls using SNP, LogR values, and CNV algorithm output. CNVs in remaining samples were annotated to determine rarity. Only CNVs meeting the definition of rare (occurring in <1% of all study samples and Database of Genomic Variants) were carried into further analysis for global burden, de novo burden, overlap with other neurodevelopmental disorders, and pathway analysis.
Rare copy number variant (CNV) burden in known autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SCZ) genes/regionsP-values were calculated using two-tailed Fisher exact test and are shown for each comparison between cases and controls. Comparisons were made for proportion of samples with CNV overlap with ASD implicated genes, ASD candidate genes, all (implicated + candidate) ASD genes, ID genes, and SCZ genes. Threshold for significance using a standard Bonferroni approach is p<0.013. TS subjects show significantly more overlap for ASD genes compared to controls, but no significant difference for ID or SCZ genes.
Large de novo copy number variants (CNV) in Tourette syndrome (TS) subjectsPlots of relative microarray probe Log R Ratios (LRR) and B Allele Frequencies (BAF) in unaffected father, TS proband, and unaffected mother. CNV regions are bounded by horizontal lines in LRR and BAF plots, outlined in red on chromosome ideograms, and represented by green (duplication) or red (deletion) below chromosome bands. Data is shown for (A) a 51.8 Mb heterozygous duplication on chromosome 5 (chr5: 127,500,000-179,295,570), containing 447 RefSeq transcripts; (B) a 1.2 Mb region on chromosome 20p13 (chr20: 2,758,098-3,942,609), containing 27 RefSeq transcripts; and (C) a 2.5 Mb region on chromosome 22q11.21 (chr22:17,269,490-19,792,353), containing 56 RefSeq transcripts. All de novo deletions were confirmed by qPCR.
Distribution of number of RefSeq genes overlapped by rare de novo copy number variants (CNV) in Tourette syndrome (TS) probands, autism probands, and sibling controlsDashed line represents two standard deviations from the mean number of genes overlapped by de novo CNVs in a large study of unaffected sibling control subjects (dark grey). Number of genes for TS cases (red) and autism probands (light grey) (38) are also plotted. Three of four TS de novo CNVs (this study) and 46% of autism proband de novo CNVs are beyond this threshold.
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| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Computational Identification of Blood-Brain Barrier-Permeant Microbiome Metabolites with Binding Affinity to Neurotransmitter Receptors in Neurodevelopmental Disorders. | Buendia-Corona RE et al. | β | 2026 | β |
| Characterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder. | Abdallah SB et al. | β | 2025 | β |
| Discovery of <sup>18</sup>F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor. | Song Z et al. | β | 2025 | β |
| Genetic advances and translational phenotypes in rodent models for Tourette disorder. | Kowalski TF et al. | β | 2025 | β |
| Genetics of Tourette Syndrome. | Fernandez TV | β | 2025 | β |
| Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders. | Ma Y et al. | β | 2024 | β |
| Addressing co-occurring conditions in behavioural therapy for tic disorders: a review and guideline. | Sanderson C et al. | β | 2024 | β |
| Identification of Novel Genes and Pathways of Ovarian Cancer Using a Comprehensive Bioinformatic Framework. | Rashid H et al. | β | 2024 | β |
| Microbiota profiling reveals alteration of gut microbial neurotransmitters in a mouse model of autism-associated 16p11.2 microduplication. | Fu Z et al. | β | 2024 | β |
| The use of high-resolution SNP arrays to detect congenital cardiac defects. | Linhuan H et al. | β | 2024 | β |
| A Targeted Combined Pharmacotherapy Approach for Aggressive Behavior in a Child with Autism Spectrum Disorder. | Zaydlin M et al. | β | 2023 | β |
| Emerging therapies and recent advances for Tourette syndrome. | Chou CY et al. | β | 2023 | β |
| Histamine originating from the BNST modulates corticostriatal synaptic transmission during early postnatal development | MΓ‘rquez-GΓ³mez R et al. | β | 2023 | β |
| Molecular Landscape of Tourette's Disorder. | Widomska J et al. | β | 2023 | β |
| The shared genetic risk factors between Tourette syndrome and obsessive-compulsive disorder. | Khoodoruth MAS et al. | β | 2023 | β |
| Current understanding of the genetics of tourette syndrome. | Lin WD et al. | β | 2022 | β |
| Genetic Dysruption of the Histaminergic Pathways: A Novel Deletion at the 15q21.2 <i>locus</i> Associated with Variable Expressivity of Neuropsychiatric Disorders. | Lintas C et al. | β | 2022 | β |
| Identity-by-descent analysis of a large Tourette's syndrome pedigree from Costa Rica implicates genes involved in neuronal development and signal transduction. | Ryan N et al. | β | 2022 | β |
| Role of histidine decarboxylase gene in the pathogenesis of Tourette syndrome. | Xu L et al. | β | 2022 | β |
| Tic Disorders, Anti-Tic Medications, and Risk of Atopy. | Hakimi M et al. | β | 2022 | β |
| Tourettic OCD: Current understanding and treatment challenges of a unique endophenotype. | Katz TC et al. | β | 2022 | β |
| White matter abnormalities in the <i>Hdc</i> knockout mouse, a model of tic and OCD pathophysiology. | Jindachomthong K et al. | β | 2022 | β |
| Animal Models for OCD Research. | Chamberlain BL et al. | β | 2021 | β |
| Candidate Genes and Pathways Associated with Gilles de la Tourette Syndrome-Where Are We? | Levy AM et al. | β | 2021 | β |
| Genetic architecture of Tourette syndrome: our current understanding. | DomΓ¨nech L et al. | β | 2021 | β |
| Histamine, Neuroinflammation and Neurodevelopment: A Review. | Carthy E et al. | β | 2021 | β |
| Leveraging large genomic datasets to illuminate the pathobiology of autism spectrum disorders. | Searles Quick VB et al. | β | 2021 | β |
| The Histaminergic System in Neuropsychiatric Disorders. | Cheng L et al. | β | 2021 | β |
| The Multi-Targeting Ligand ST-2223 with Histamine H<sub>3</sub> Receptor and Dopamine D<sub>2</sub>/D<sub>3</sub> Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice. | Eissa N et al. | β | 2021 | β |
| The tuberomamillary nucleus in neuropsychiatric disorders. | Shan L et al. | β | 2021 | β |
| The Ξ±6 GABA<sub>A</sub> Receptor Positive Allosteric Modulator DK-I-56-1 Reduces Tic-Related Behaviors in Mouse Models of Tourette Syndrome. | Cadeddu R et al. | β | 2021 | β |
| Brain histamine modulates recognition memory: possible implications in major cognitive disorders. | Provensi G et al. | β | 2020 | β |
| Role of Neuroinflammation in Autism Spectrum Disorder and the Emergence of Brain Histaminergic System. Lessons Also for BPSD? | Eissa N et al. | β | 2020 | β |
| The histidine decarboxylase model of tic pathophysiology: a new focus on the histamine H<sub>3</sub> receptor. | Pittenger C | β | 2020 | β |
| Tourette Syndrome Risk Genes Regulate Mitochondrial Dynamics, Structure, and Function. | Clarke RA et al. | β | 2020 | β |
| What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders? | Martino D et al. | β | 2020 | β |
| Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome. | Depienne C et al. | β | 2019 | β |
| Clinical and genetic analysis of children with a dual diagnosis of Tourette syndrome and autism spectrum disorder. | Carias KV et al. | β | 2019 | β |
| Genetic Studies of Tic Disorders and Tourette Syndrome. | Qi Y et al. | β | 2019 | β |
| De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis. | Wang S et al. | β | 2018 | β |
| Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach. | Abdulkadir M et al. | β | 2018 | β |
| Merging the Pathophysiology and Pharmacotherapy of Tics. | Augustine F et al. | β | 2018 | β |
| Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology. | Rapanelli M et al. | β | 2018 | β |
| Tics and Tourette syndrome. | Efron D et al. | β | 2018 | β |
| Tourette disorder and other tic disorders. | Fernandez TV et al. | β | 2018 | β |
| Altered expression of histamine signaling genes in autism spectrum disorder. | Wright C et al. | β | 2017 | β |
| Autism Spectrum Symptoms in a Tourette's Disorder Sample. | Darrow SM et al. | β | 2017 | β |
| Behavioral and stereological characterization of Hdc KO mice: Relation to Tourette syndrome. | Abdurakhmanova S et al. | β | 2017 | β |
| De Novo Coding Variants Are Strongly Associated with Tourette Disorder. | Willsey AJ et al. | β | 2017 | β |
| Genetic Approaches to Understanding Psychiatric Disease. | Michaelson JJ | β | 2017 | β |
| Genomic Disorders in Psychiatry-What Does the Clinician Need to Know? | Lowther C et al. | β | 2017 | β |
| Gilles de la Tourette syndrome. | Robertson MM et al. | β | 2017 | β |
| Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders. | Rapanelli M et al. | β | 2017 | β |
| Histamine modulation of the basal ganglia circuitry in the development of pathological grooming. | Rapanelli M et al. | β | 2017 | β |
| Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions. | Pittenger C | β | 2017 | β |
| Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing. | Eriguchi Y et al. | β | 2017 | β |
| Parental Psychopathology and Tourette Syndrome/Chronic Tic Disorder in Offspring: A Nationwide Case-Control Study. | Leivonen S et al. | β | 2017 | β |
| Progress in Genetic Studies of Tourette's Syndrome. | Qi Y et al. | β | 2017 | β |
| Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. | Huang AY et al. | β | 2017 | β |
| Tics and Tourette: a clinical, pathophysiological and etiological review. | Dale RC | β | 2017 | β |
| Tourette Syndrome and Chronic Tic Disorders: The Clinical Spectrum Beyond Tics. | Martino D et al. | β | 2017 | β |
| Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort. | Bertelsen B et al. | β | 2016 | β |
| Decreased Anterior Cingulate Cortex Ξ³-Aminobutyric Acid in Youth With Tourette's Disorder. | Freed RD et al. | β | 2016 | β |
| Functional Evaluations of Genes Disrupted in Patients with Tourette's Disorder. | Sun N et al. | β | 2016 | β |
| Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions. | Rapanelli M et al. | β | 2016 | β |
| Histamine and the striatum. | Bolam JP et al. | β | 2016 | β |
| Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation. | Frick L et al. | β | 2016 | β |
| Investigation of a Possible Role for the Histidine Decarboxylase Gene in Tourette Syndrome in the Chinese Han Population: A Family-Based Study. | Dong H et al. | β | 2016 | β |
| Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies. | Spinello C et al. | β | 2016 | β |
| Targeted Re-Sequencing Approach of Candidate Genes Implicates Rare Potentially Functional Variants in Tourette Syndrome Etiology. | Alexander J et al. | β | 2016 | β |
| The Genetic Etiology of Tourette Syndrome: Large-Scale Collaborative Efforts on the Precipice of Discovery. | Georgitsi M et al. | β | 2016 | β |
| The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons. | Rapanelli M et al. | β | 2016 | β |
| Transcriptome Analysis of the Human Striatum in Tourette Syndrome. | Lennington JB et al. | β | 2016 | β |
| TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of Gilles de la Tourette Syndrome. | Forde NJ et al. | β | 2016 | β |
| Using mice to model Obsessive Compulsive Disorder: From genes to circuits. | Ahmari SE | β | 2016 | β |
| What Makes You Tic? A New Lead in Tourette Syndrome Genetics. | Fernandez TV | β | 2016 | β |
| Advances in Tourette syndrome: diagnoses and treatment. | Serajee FJ et al. | β | 2015 | β |
| A personal 35 year perspective on Gilles de la Tourette syndrome: assessment, investigations, and management. | Robertson MM | β | 2015 | β |
| Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear. | Xu M et al. | β | 2015 | β |
| International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. | Panula P et al. | β | 2015 | β |
| Multifactorial Origin of Neurodevelopmental Disorders: Approaches to Understanding Complex Etiologies. | De Felice A et al. | β | 2015 | β |
| No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins. | Murdoch JD et al. | β | 2015 | β |
| Reduced GABAergic inhibition and abnormal sensory symptoms in children with Tourette syndrome. | Puts NA et al. | β | 2015 | β |
| The role of immune mechanisms in Tourette syndrome. | Martino D et al. | β | 2015 | β |
| The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods. | Dietrich A et al. | β | 2015 | β |
| Tourette's syndrome and translational clinical science. | Fernandez TV et al. | β | 2015 | β |
| Tourette Syndrome: Bridging the Gap between Genetics and Biology. | Richer P et al. | β | 2015 | β |
| Urinary amino acid alterations in 3-year-old children with neurodevelopmental effects due to perinatal dioxin exposure in Vietnam: a nested case-control study for neurobiomarker discovery. | Nishijo M et al. | β | 2015 | β |
| A national profile of Tourette syndrome, 2011-2012. | Bitsko RH et al. | β | 2014 | β |
| Animal models of tic disorders: a translational perspective. | Godar SC et al. | β | 2014 | β |
| An inherited small microdeletion at 15q13.3 in a patient with early-onset obsessive-compulsive disorder. | Cappi C et al. | β | 2014 | β |
| Balance within the Neurexin Trans-Synaptic Connexus Stabilizes Behavioral Control. | Clarke RA et al. | β | 2014 | β |
| Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study. | McGrath LM et al. | β | 2014 | β |
| Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. | Lionel AC et al. | β | 2014 | β |
| DPP6 gene disruption in a family with Gilles de la Tourette syndrome. | Prontera P et al. | β | 2014 | β |
| Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome. | Rapanelli M et al. | β | 2014 | β |
| Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders. | Cukier HN et al. | β | 2014 | β |
| Genetics of obsessive-compulsive disorder and related disorders. | Browne HA et al. | β | 2014 | β |
| Histaminergic system in brain disorders: lessons from the translational approach and future perspectives. | Baronio D et al. | β | 2014 | β |
| Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. | Baldan LC et al. | β | 2014 | β |
| Modulation of behavior by the histaminergic system: lessons from HDC-, H3R- and H4R-deficient mice. | Schneider EH et al. | β | 2014 | β |
| Mouse models of neurodevelopmental disease of the basal ganglia and associated circuits. | Pappas SS et al. | β | 2014 | β |
| Neurobehavioral aspects, pathophysiology, and management of Tourette syndrome. | Shprecher DR et al. | β | 2014 | β |
| The Inheritance of Tourette Disorder: A review. | Pauls DL et al. | β | 2014 | β |
| The Semiology of Tics, Tourette's, and Their Associations. | Ganos C et al. | β | 2014 | β |
| An introduction to the clinical phenomenology of Tourette syndrome. | Martino D et al. | β | 2013 | β |
| Attention deficit hyperactivity disorder, tic disorder, and allergy: is there a link? A nationwide population-based study. | Chen MH et al. | β | 2013 | β |
| Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria. | Sajan SA et al. | β | 2013 | β |
| Brain mechanisms for prepulse inhibition in adults with Tourette syndrome: initial findings. | Zebardast N et al. | β | 2013 | β |
| Chromosomal rearrangements in Tourette syndrome: implications for identification of candidate susceptibility genes and review of the literature. | Bertelsen B et al. | β | 2013 | β |
| CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1. | Nag A et al. | β | 2013 | β |
| Conceptual issues in neurodevelopmental disorders: lives out of synch. | Clegg J et al. | β | 2013 | β |
| Genetic susceptibility and neurotransmitters in Tourette syndrome. | Paschou P et al. | β | 2013 | β |
| Genome-wide association study of autistic-like traits in a general population study of young adults. | Jones RM et al. | β | 2013 | β |
| Genome-wide association study of Tourette's syndrome. | Scharf JM et al. | β | 2013 | β |
| Histamine is required for Hβ receptor-mediated alcohol reward inhibition, but not for alcohol consumption or stimulation. | Vanhanen J et al. | β | 2013 | β |
| Impacts of variation in the human genome on gene regulation. | Haraksingh RR et al. | β | 2013 | β |
| Microduplication of 15q13.3 and Xq21.31 in a family with Tourette syndrome and comorbidities. | Melchior L et al. | β | 2013 | β |
| Molecular mechanism of histamine clearance by primary human astrocytes. | Yoshikawa T et al. | β | 2013 | β |
| Nondopaminergic neurotransmission in the pathophysiology of Tourette syndrome. | Udvardi PT et al. | β | 2013 | β |
| Pharmacological treatment of Gilles de la Tourette syndrome. | Hartmann A et al. | β | 2013 | β |
| Polymorphisms and genetic linkage of histamine receptors. | Micallef S et al. | β | 2013 | β |
| Sequence analysis of SLITRK1 for var321 in Danish patients with Tourette syndrome and review of the literature. | Yasmeen S et al. | β | 2013 | β |
| Support of the histaminergic hypothesis in Tourette syndrome: association of the histamine decarboxylase gene in a large sample of families. | Karagiannidis I et al. | β | 2013 | β |
| Systematic review: pharmacological treatment of tic disorders--efficacy of antipsychotic and alpha-2 adrenergic agonist agents. | Weisman H et al. | β | 2013 | β |
| The genetic basis of Gilles de la Tourette Syndrome. | Paschou P | β | 2013 | β |
| The histaminergic network in the brain: basic organization and role in disease. | Panula P et al. | β | 2013 | β |
| Tic disorders. | Martino D et al. | β | 2013 | β |
| What's next for developmental psychiatry? | Leckman JF | β | 2013 | β |
| A genetic model for neurodevelopmental disease. | Coe BP et al. | β | 2012 | β |
| A research strategy to discover the environmental causes of autism and neurodevelopmental disabilities. | Landrigan PJ et al. | β | 2012 | β |
| Genomic tics in tourette syndrome. | Mulle JG et al. | β | 2012 | β |
| The genetic variability and commonality of neurodevelopmental disease. | Coe BP et al. | β | 2012 | β |