De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

Wang, Sheng; Mandell, Jeffrey D.; Kumar, Yogesh; Sun, Nawei; Morris, Montana T.; Arbelaez, Juan David; Nasello, Cara; Dong, Shan; Duhn, Clif; Zhao, Xin; Yang, Zhiyu; Padmanabhuni, Shanmukha Sampath; Yu, Dongmei; King, Robert A.; Dietrich, Andrea; Khalifa, Najah; Dahl, Niklas; Huang, Alden; Neale, Benjamin M.; Coppola, Giovanni; Mathews, Carol A.; Scharf, Jeremiah M.; Fernandez, Thomas; Buxbaum, Joseph D.; Rubeis, Silvia De; Grice, Dorothy E.; Xing, Jinchuan; Heiman, Gary A.; Tischfield, Jay A.; Paschou, Peristera; Willsey, A. Jeremy; State, Matthew W.

doi:10.1016/j.celrep.2018.08.082

Cited by 95 publications

(79 citation statements)

References 71 publications

(163 reference statements)

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“…68 Two individuals also had variants in CELSR3 , a gene that was recently recognized as a candidate gene for TS. 22 The possible contribution of these genes to TS etiology needs to be confirmed in further studies, as are the nature and number of the variants acting in concert necessary to lead to TS.…”

Section: Discussionmentioning

confidence: 99%

“…8–10 Main genes possibly involved in TS so far include NRXN1 , CNTN6 , CELSR3 , SLITRK1 , and HDC . 11–22 SLITRK1 encodes a transmembrane protein modulating neurite outgrowth belonging to a family comprising six paralogues ( SLITRK1 to SLITRK6 ) in mammals. 23,24 HDC encodes histidine decarboxylase, the enzyme catalyzing the synthesis of histamine through decarboxylation of histidine.…”

Section: Introductionmentioning

confidence: 99%

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Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Depienne

Ciura

Trouillard

et al. 2019

Tremor and Other Hyperkinetic Movements

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Depienne

Ciura

Trouillard

et al. 2019

Tremor and Other Hyperkinetic Movements

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“…MQ≥30), allele frequency in general population (usually <1% or 0.1% as a more stringent cutoff), etc. [5,22]. Nonetheless, all DNMs (or randomly selected subsets) are re-sequenced by other methods, usually Sanger sequencing, to check the accuracy of the findings.…”

Section: Dnv Curationmentioning

confidence: 99%

PsyMuKB: A De Novo Variant Knowledge Base Integrating Transcriptional and Translational Information to Identify Isoform-specific Mutations in Developmental Disorders

Lin

Guo

Xian

et al. 2019

Preprint

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AbstractDe novo variants (DNVs) are one of the most significant contributors to severe early-onset genetic disorders such as autism spectrum disorder, intellectual disability, and other developmental and neuropsychiatric (DNP) disorders. Currently, a plethora of DNVs have being identified through the use of next-generation sequencing and much effort has been made to understand their impact at the gene level; however, there has been little exploration of the impact at the isoform level. The brain contains a high level of alternative splicing and regulation, and exhibits a more divergent splicing program than other tissues; therefore, it is crucial to explore variants at the transcriptional regulation level to better interpret the mechanisms underlying DNP disorders. To facilitate better usage and improve the isoform-level interpretation of variants, we developed the PsyMuKB (NeuroPsychiatric Mutation Knowledge Base), a knowledge base containing a comprehensive, carefully curated list of DNVs with transcriptional and translational annotations to enable identification of isoform-specific mutations. PsyMuKB allows a flexible search of genes or variants and provides both table-based descriptions and associated visualizations, such as expression, transcript genomic structures, protein interactions, and the mutation sites mapped on the protein structures. It also provides an easy-to-use web interface, allowing users to rapidly visualize the locations and characteristics of mutations and the expression patterns of the impacted genes and isoforms. PsyMuKB thus constitutes a valuable resource for identifying tissue-specific de novo mutations for further functional studies of related disorders. PsyMuKB is freely accessible at http://psymukb.net.

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“…TS has been shown to have a large genetic component, in which the first-degree relatives of TS patients have a 10-to 100-fold higher rate of TS compared to the general population 2,3 . Past genetic studies of TS have identified several implicated genes such as CELSR3, a gene where recurrent do novo variants are found in probands 4 . Furthermore, a recent genome-wide association study (GWAS) identified a genome-wide significant hit on chromosome 13, rs2504235, which is within the FLT3 (Fms Related Tyrosine Kinase 3) gene 5 .…”

Section: Introductionmentioning

confidence: 99%

Increased expression of genetically-regulatedFLT3implicated in Tourette’s Syndrome

Liao

Vuokila

Catoire

et al. 2019

Preprint

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Tourette's Syndrome (TS) is a neurodevelopmental disorder that is characterized by motor and phonic tics. A recent TS genome-wide association study (GWAS) identified a genome-wide significant locus. However, determining the biological mechanism of GWAS signals remains difficult. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4,819 cases and 9,488 controls and found that increased expression of FLT3 in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further showed that there is global dysregulation of FLT3 across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizes FLT3 with a posterior inclusion probability of 0.849. We validated the gene's expression in 100 lymphoblastoid cell lines, establishing that TS cells had a 1.72 increased fold change compared to controls. A phenome-wide association study points towards FLT3 having links with immune-related pathways such as monocyte count. We also identify several splicing events in MPHOSPH9, CSGALNACT2 and FIP1L1 associated with TS, which are also implicated in immune function. This analysis of expression and splicing begins to explore the biology of TS GWAS signals.

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De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

Cited by 95 publications

References 71 publications

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

PsyMuKB: A De Novo Variant Knowledge Base Integrating Transcriptional and Translational Information to Identify Isoform-specific Mutations in Developmental Disorders

Increased expression of genetically-regulatedFLT3implicated in Tourette’s Syndrome

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