Integrating Common and Rare Variation to Discover Genes Associated with Tourette Syndrome

整合常见和罕见变异来发现与抽动秽语综合征相关的基因

• 批准号: 10359202
• 负责人: Carol A Mathews
• 金额: $ 95.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359202
• 关键词: Academic Medical Centers; Accounting; Adult; Affect; Americas; Biological; Biology; California; Child; Childhood; Chromosomal Rearrangement; Clinical; Clinical Data; Clinical Markers; Code; Collaborations; Complex; Computational Biology; Copy Number Polymorphism; Corpus striatum structure; DNA; DNA sequencing; Data; Data Set; Development; Disease; Disease Outcome; Disease Pathway; Family; Florida; Funding; Future; Gene Dosage; General Hospitals; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genotype; Gilles de la Tourette syndrome; Goals; Heritability; Individual; International; Lead; Libraries; Los Angeles; Massachusetts; Measures; Modeling; Molecular; Morbidity - disease rate; National Institute of Neurological Disorders and Stroke; Neurodevelopmental Disorder; Onset of illness; Outcome; Parents; Pathogenesis; Pathogenicity; Phenotype; Prevention; Recurrence; Research; Research Personnel; Risk; SNP array; SNP genotyping; Severities; Severity of illness; Susceptibility Gene; Symptoms; Techniques; Testing; Universities; Variant; Work; base; cohort; data integration; de novo mutation; disability; exome sequencing; functional disability; gene discovery; genetic architecture; genetic variant; genome wide association study; genome-wide; genome-wide analysis; high risk; insight; loss of function; neuropsychiatric disorder; next generation; next generation sequencing; novel; phenotypic data; polygenic risk score; precision medicine; predictive modeling; proband; psychiatric comorbidity; side effect; whole genome

Integrating Common and Rare Variation to Discover Genes Associated with Tourette Syndrome Tourette Syndrome (TS) is a childhood-onset, neuropsychiatric disorder that is highly heritable, though discovery of definitive TS susceptibility genes has been challenging. This multi-PD/PI application, which aims to identify new susceptibility genes for TS and to examine their relationship to clinical disease outcomes, continues the work of the Tourette Association of America International Consortium for Genetics (TAAICG), the longest standing research collaborative group dedicated to understanding the genetic causes underlying TS. The research plan consists of: 1) Whole exome sequencing of 1,400 TS parent-proband trios to identify rare, potentially deleterious genetic variants of relevance to TS; 2) Genome-wide analyses of de novo copy-number variation (CNVs) in these 1,400 TS trios to identify high impact, rare structural variation associated with TS; 3) Use of information about TS-relevant common variation from existing genome-wide association study (GWAS) data on 4,819 TS cases and 9,488 controls to prioritize a subset of 800 of the 1,400 TS trios for cryptic structural variation sequencing studies to capture de novo gene-disrupting chromosomal rearrangements not detectable by standard techniques; and 4) Integration of identified rare and common variation to develop prediction models of disease outcome, including tic severity, functional impairment, tic persistence into adulthood, and psychiatric comorbidity. The proposed study will be conducted at Massachusetts General Hospital, University of Florida, University of California at Los Angeles, and Vanderbilt University Medical Center, each who have complementary expertise in computational biology, analysis of next-generation sequencing data, and integration of disease-associated DNA variation with clinical data. This proposal provides a unique and exciting opportunity to rapidly advance the goal of identifying the biological basis of this complex and important model neuropsychiatric disorder which in the future could lead to prediction of disease severity and to targeted treatments and/or prevention.

整合常见和罕见变异以发现与Tourette综合征相关的基因 图雷特综合征（TS）是一种儿童期发病的神经精神疾病，具有高度遗传性， 确定性TS易感基因的发现一直具有挑战性。这种多PD/PI应用程序，其目的是 为了鉴定TS的新易感基因并检查它们与临床疾病结果的关系， 继续美国妥瑞症协会国际遗传学联盟（TAAICG）的工作， 成立时间最长的研究合作小组，致力于了解TS的遗传原因。 研究计划包括：1）对1,400例TS父母-先证者三人组进行全外显子组测序，以识别罕见的， 与TS相关的潜在有害遗传变异; 2）从头拷贝数的全基因组分析 在这1，400个TS三重奏中进行CNVs分析，以确定与TS相关的高影响、罕见的结构变异; 3)利用来自现有全基因组关联研究的关于TS相关常见变异的信息 （GWAS）4，819例TS病例和9，488例对照的数据，以优先考虑1，400例TS三重奏中的800例子集， 隐藏的结构变异测序研究，以捕获从头基因破坏染色体 通过标准技术检测不到的重排;和4）整合鉴定的罕见和常见的重排。 变异，以开发疾病结果的预测模型，包括抽搐严重程度、功能障碍、抽搐 持续到成年和精神共病。 拟定研究将在马萨诸塞州总医院、佛罗里达大学、 加州在洛杉矶，和范德比尔特大学医学中心，每个人都有互补的专业知识 在计算生物学中，分析下一代测序数据，整合疾病相关的 DNA变异与临床数据。这一提议提供了一个独特而令人兴奋的机会， 目的是确定这种复杂而重要的神经精神障碍模型的生物学基础， 在未来可能导致疾病严重程度的预测和有针对性的治疗和/或预防。

项目成果

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

人群分离株的扩展谱系中常见和罕见变异对双相情感障碍易感性的贡献。

• DOI: 10.1038/s41398-020-0758-1
• 发表时间: 2020
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Sul,JaeHoon;Service,SusanK;Huang,AldenY;Ramensky,Vasily;Hwang,Sun-Goo;Teshiba,TerriM;Park,YoungJun;Ori,AnilPS;Zhang,Zhongyang;Mullins,Niamh;OldeLoohuis,LoesM;Fears,ScottC;Araya,Carmen;Araya,Xinia;Spesny,Mitzi;Bejaran
• 通讯作者: Bejaran

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

从头序列和拷贝数变体与图雷氏障碍障碍密切相关，并暗示细胞极性在发病机理中。

• DOI: 10.1016/j.celrep.2018.08.082
• 发表时间: 2018-09-25
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Wang S;Mandell JD;Kumar Y;Sun N;Morris MT;Arbelaez J;Nasello C;Dong S;Duhn C;Zhao X;Yang Z;Padmanabhuni SS;Yu D;King RA;Dietrich A;Khalifa N;Dahl N;Huang AY;Neale BM;Coppola G;Mathews CA;Scharf JM;Tourette International Collaborative Genetics Study (TIC Genetics);Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE);Tourette Association of America International Consortium for Genetics (TAAICG);Fernandez TV;Buxbaum JD;De Rubeis S;Grice DE;Xing J;Heiman GA;Tischfield JA;Paschou P;Willsey AJ;State MW
• 通讯作者: State MW

xGAP: a python based efficient, modular, extensible and fault tolerant genomic analysis pipeline for variant discovery.

xGAP：一个基于 python 的高效、模块化、可扩展和容错的基因组分析管道，用于变异发现。

• DOI: 10.1093/bioinformatics/btaa1097
• 发表时间: 2021
• 期刊: Bioinformatics (Oxford, England)
• 作者: Gorla,Aditya;Jew,Brandon;Zhang,Luke;Sul,JaeHoon
• 通讯作者: Sul,JaeHoon

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.

NRXN1和CNTN6中的罕见拷贝数变体增加了Tourette综合征的风险。

• DOI: 10.1016/j.neuron.2017.06.010
• 发表时间: 2017-06-21
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Huang AY;Yu D;Davis LK;Sul JH;Tsetsos F;Ramensky V;Zelaya I;Ramos EM;Osiecki L;Chen JA;McGrath LM;Illmann C;Sandor P;Barr CL;Grados M;Singer HS;Nöthen MM;Hebebrand J;King RA;Dion Y;Rouleau G;Budman CL;Depienne C;Worbe Y;Hartmann A;Müller-Vahl KR;Stuhrmann M;Aschauer H;Stamenkovic M;Schloegelhofer M;Konstantinidis A;Lyon GJ;McMahon WM;Barta C;Tarnok Z;Nagy P;Batterson JR;Rizzo R;Cath DC;Wolanczyk T;Berlin C;Malaty IA;Okun MS;Woods DW;Rees E;Pato CN;Pato MT;Knowles JA;Posthuma D;Pauls DL;Cox NJ;Neale BM;Freimer NB;Paschou P;Mathews CA;Scharf JM;Coppola G;Tourette Syndrome Association International Consortium for Genetics (TSAICG);Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI)
• 通讯作者: Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI)

Epidemiology of Functional Seizures Among Adults Treated at a University Hospital.

• DOI: 10.1001/jamanetworkopen.2020.27920
• 发表时间: 2020-12-01
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Goleva SB;Lake AM;Torstenson ES;Haas KF;Davis LK
• 通讯作者: Davis LK