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.

孤独症是一种遗传性最强的神经发育障碍，其遗传基础已通过 家庭和双胞胎流行病学研究。全基因组关联研究尚未发现强有力的证据， 常见变异的贡献和连锁研究表明存在多个位点，每个位点 在种群水平上对遗传变异的贡献可以忽略不计。该提案的目的是应用新的 分析方法，以确定家庭从现有的UW-ACE和NIH收集的遗传是最 吝啬与单基因传播，并应用新的基因组技术，以确定基因， 都有责任为了确定显性和隐性遗传可能性增加的家庭，我们 将对现有的基因型数据应用血统同一性和纯合性程度分析。接下来我们就 利用新的可用方法对蛋白质编码区进行全基因组评估， 和可能是因果关系的拷贝数变异。最后，将对所确定的候选基因进行评估， 在一项大型病例对照研究中， 将启动因果关系的最高证据。为了便于验证我们的发现，我们将存款基因型 NIMH数据库中信息。了解自闭症的遗传学将有助于早期干预， 使症状前诊断，牵连其他生物途径参与自闭症和增加的目标数量的病因治疗。

项目成果

Next Generation Sequencing Mitochondrial DNA Analysis in Autism Spectrum Disorder.

下一代测序在自闭症谱系障碍中线粒体DNA分析。

• 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