Quantifying the impact of rare mutations on ADHD

量化罕见突变对多动症的影响

• 批准号: 8871524
• 负责人: Benjamin Michael Neale
• 金额: $ 39.4万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871524
• 关键词: Adult; Attention; Attention deficit hyperactivity disorder; Autistic Disorder; Bioinformatics; Biological; Biological Assay; Biological Process; California; Child; Childhood; Code; Collaborations; Collection; Communities; Comorbidity; Copy Number Polymorphism; DNA; DSM-IV; Data; Data Analyses; Databases; Deposition; Diagnosis; Disease; Enrollment; Ensure; Etiology; European; Failure; Family; Family Study; Functional disorder; Funding; Gene Frequency; General Hospitals; Genes; Genetic; Genetic study; Genotype; Health Care Costs; Heritability; Human; Human Genome; Inherited; Institutes; International; Joints; Letters; Light; Los Angeles; Massachusetts; Medical; Meta-Analysis; Molecular; Molecular Genetics; Mutation; Nature; Occupational; Outcome; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Preventive; Protocols documentation; Regulation; Research; Research Personnel; Risk; Risk Factors; Role; Sample Size; Sampling; Schizophrenia; Schools; Secure; Single Nucleotide Polymorphism; Societies; Subgroup; Substance abuse problem; Susceptibility Gene; Technology; Testing; Time; Traffic accidents; Twin Studies; United States National Institutes of Health; Universities; Variant; Work; base; case control; chromatin immunoprecipitation; cohort; cost; cost effective; database of Genotypes and Phenotypes; disability; exome; exome sequencing; family genetics; follow-up; genetic linkage analysis; genetic variant; genome sequencing; genome wide association study; genome-wide; genome-wide linkage; health care service utilization; health economics; improved; innovation; insight; meetings; prevent; proband; psychosocial; rare variant; research study; sample collection; tool

DESCRIPTION (provided by applicant): The technological revolution in genetics is beginning to yield results for ADHD. Rare copy number variants have been identified that confer risk to ADHD providing the first molecular evidence for risk to the disease. In contrast, genome-wide association studies of single nucleotide polymorphisms (SNPs), to date, have yet to unequivocally identify risk factors that predisposes to ADHD with the most recent meta-analysis totaling 2,064 trios, 896 cases and 2,455 controls. This lack of progress stands in stark contrast to the strong evidence for heritability of ADHD, attention and activity levels from twin and family studies. Among the several possible explanations for this disconnect is that rare SNPs confer risk to ADHD. Given that rare CNVs clearly play a role in the pathophysiology of ADHD, it is not unreasonable to expect that rare SNPs of large effect may also exist. We are proposing the first study to comprehensively define the role of rare SNPs drawn from the coding region of genes in the etiology of the disorder. We will do so by using the newly developed exome chip, an innovative, cost-effective technology that will allow us to assay approximately 200,000 rare SNPs found in the coding region of the human genome. This exome chip assay should capture nearly all SNPs at an allele frequency threshold of 0.1% in European populations and captures an estimated 80% of the variants with an allele frequency of 0.02%. Our specific aims are: Aim 1: Assay Rare Variation in 1,800 ADHD Trios. We will generate exome chip data on a total of 1,800 ADHD trio families to identify rare functional inherited variation that predisposes to ADHD. We will assay approximately 200,000 rare SNP mutations in the exome. Aim 2: Comprehensively Analyze the Identified Rare Variation. Upon completion of the genotyping assays, we will perform single-locus and regional association analysis of the exome chip data. We will then extend these primary analyses by interrogating genes and pathways by leveraging bioinformatics tools to improve the power to detect genes and to more clearly interpret our primary results. Aim 3: Share All Data with the Scientific Community. We are committed to ensuring that all data generated by this application will be deposited in dbGaP and any other database required by NIH regulations. Upon completing this project, we expect to provide the field with a treasure trove of rare DNA variants that can be followed up with functional, biologica assays. This work is significant because ADHD is a common disorder of childhood associated with school failure, psychiatric comorbidity and psychosocial disability in childhood. Most cases persist into adulthood when the disorder is additionally associated with occupational failure, criminality, traffic accidents, substance abuse and increased medical health care utilization. Health economic studies suggest that, in adulthood, the cost of ADHD to society is between $77.5 and $115.9 billion each year. Current treatments are only partially effective, and no preventive treatments exist. New treatment targets are needed to develop better medications for treating ill patients and, perhaps, for preventing the disorder in susceptible people.

描述（由申请人提供）：遗传学的技术革命开始产生ADHD的结果。罕见的拷贝数变异已被确定与ADHD风险相关，为该疾病风险提供了第一个分子证据。相比之下，迄今为止，单核苷酸多态性（snp）的全基因组关联研究尚未明确确定易患ADHD的风险因素，最近的荟萃分析共涉及2064个三人组，896个病例和2455个对照。这一进展的缺乏与双胞胎和家庭中ADHD、注意力和活动水平的遗传性的有力证据形成鲜明对比

项目成果

An Integrated Analysis of Neural Network Correlates of Categorical and Dimensional Models of Attention-Deficit/Hyperactivity Disorder.

• DOI: 10.1016/j.bpsc.2018.11.014
• 发表时间: 2019-05
• 期刊: Biological psychiatry. Cognitive neuroscience and neuroimaging
• 作者: R. Pruim;C. Beckmann;M. Oldehinkel;J. Oosterlaan;D. Heslenfeld;C. Hartman;P. Hoekstra;S. Faraone;B. Franke;J. Buitelaar;M. Mennes

Role of conduct problems in the relation between Attention-Deficit Hyperactivity disorder, substance use, and gaming.

行为问题在注意力缺陷多动障碍、药物滥用和游戏之间的关系中的作用。

• DOI: 10.1016/j.euroneuro.2018.06.003
• 发表时间: 2020
• 期刊: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
• 作者: Schoenmacker,GH;Groenman,AP;Sokolova,E;Oosterlaan,J;Rommelse,N;Roeyers,H;Oades,RD;Faraone,SV;Franke,B;Heskes,T;AriasVasquez,A;Claassen,T;Buitelaar,JK
• 通讯作者: Buitelaar,JK

Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

人类攻击性的遗传结构：OMIM 中基因-表型关系的研究。

• DOI: 10.1002/ajmg.b.32363
• 发表时间: 2016
• 期刊: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
• 作者: Zhang-James,Yanli;Faraone,StephenV
• 通讯作者: Faraone,StephenV

Endosomal system genetics and autism spectrum disorders: A literature review.

• DOI: 10.1016/j.neubiorev.2016.03.022
• 发表时间: 2016-06
• 期刊: Neuroscience and biobehavioral reviews
• 影响因子: 8.2
• 作者: Patak J;Zhang-James Y;Faraone SV
• 通讯作者: Faraone SV

Attention-deficit/hyperactivity disorder and lifetime cannabis use: genetic overlap and causality.

• DOI: 10.1038/s41380-018-0339-3
• 发表时间: 2020-10
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Soler Artigas M;Sánchez-Mora C;Rovira P;Richarte V;Garcia-Martínez I;Pagerols M;Demontis D;Stringer S;ADHD Group of the Psychiatric Genomics Consortium, International Cannabis Consortium;Vink JM;Børglum AD;Neale BM;Franke B;Faraone SV;Casas M;Ramos-Quiroga JA;Ribasés M
• 通讯作者: Ribasés M