Next Generation Gene Discovery in Familial Autism

家族自闭症的下一代基因发现

• 批准号: 8789789
• 负责人: Zoran Brkanac
• 金额: $ 64.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-03 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789789
• 关键词: Affect; Autistic Disorder; Benign; Bioinformatics; Biological; Candidate Disease Gene; Case-Control Studies; Collection; Copy Number Polymorphism; Data; Data Analyses; Databases; Deposition; Diagnosis; Early Intervention; Epidemiologic Studies; Etiology; Evaluation; Exons; Extended Family; Family; Family member; Genes; Genetic; Genome; Genomics; Genotype; Goals; Hereditary Disease; Human Genome; Individual; Massive Parallel Sequencing; Methods; Mutation; National Institute of Mental Health; Neurodevelopmental Disorder; Nuclear; Open Reading Frames; Other Genetics; Parents; Pathway interactions; Phenotype; Play; Population; Research Personnel; Resolution; Role; Technology; Twin Multiple Birth; United States National Institutes of Health; Universities; Validation; Variant; Washington; base; case control; comparative genomic hybridization; data sharing; disease transmission; exome; gene discovery; genetic variant; genome wide association study; genome-wide; identity by descent; in vitro Model; next generation; novel; novel strategies; proband; segregation; targeted sequencing; transmission process

Autism is one of most heritable neurodevelopmental disorders with genetic basis well established through family and twin epidemiological studies. Genome-wide association studies have not found strong evidence for the contribution of common variants, and linkage studies indicate the presence of multiple loci, each of which contributes negligibly to the genetic variants on a population level. The goal of this proposal is to apply novel analytic approach to identify families from existing UW-ACE and NIH collections where inheritance is most parsimonious with single gene transmission, and to apply novel genomic technologies to identify the genes that are responsible. To identify families where the likelihood of dominant and recessive inheritance is increased we will apply identity-by-descent an extent-of-homozygosity analyses to the existing genotype data. Next, we will capitalize on newly available methods for a whole genome evaluation of protein coding regions for sequence and copy number variants that might be causal. Lastly, the candidate genes identified will be evaluated for association with autism in a large case control study and functional analyses of candidate genes with the highest evidence for causality will be initiated. To facilitate validation of our findings we will deposit genotype information in NIMH data-base. The understanding of genetics of autism will facilitate early interventions by enabling presymptomatic diagnosis, implicate additional biological pathways involved in autism and increase the number of targets for causative treatments.

自闭症是具有遗传基础的最遗传神经发育障碍之一 家庭和双流行病学研究。全基因组的关联研究尚未找到有力的证据 常见变体和连锁研究的贡献表明存在多个基因座，每个基因座 在人群水平上造成了遗传变异的巨大贡献。该提议的目的是应用小说 分析方法可以从现有的UW-ACE和NIH收藏中识别家庭最多的家庭 与单个基因传播相比，并应用新颖的基因组技术来识别这些基因 负责。确定占主导地位和隐性继承可能性增加的家庭，我们 将对现有的基因型数据进行逐个同生的身份分析。接下来，我们会的 利用新的可用方法，用于序列的蛋白质编码区域的整个基因组评估 和可能是因果的复制号变体。最后，将评估所鉴定的候选基因 在大型案例对照研究中与自闭症相关的候选基因的功能分析 将启动有关因果关系的最高证据。为了促进我们发现的验证，我们将沉积基因型 NIMH数据库中的信息。对自闭症遗传学的理解将有助于通过 实现预症状诊断，暗示与自闭症有关的其他生物学途径，并增加因果治疗的靶标数量。

项目成果

Next Generation Sequencing Mitochondrial DNA Analysis in Autism Spectrum Disorder.

• DOI: 10.1002/aur.1792
• 发表时间: 2017-08
• 期刊: Autism research : official journal of the International Society for Autism Research
• 作者: Patowary A;Nesbitt R;Archer M;Bernier R;Brkanac Z
• 通讯作者: Brkanac Z

Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes.

• DOI: 10.1007/s00439-015-1585-y
• 发表时间: 2015-10
• 期刊: Human genetics
• 影响因子: 5.3
• 作者: Chapman NH;Nato AQ Jr;Bernier R;Ankenman K;Sohi H;Munson J;Patowary A;Archer M;Blue EM;Webb SJ;Coon H;Raskind WH;Brkanac Z;Wijsman EM
• 通讯作者: Wijsman EM