Next Generation Gene Discovery in Familial Autism

家族自闭症的下一代基因发现

• 批准号: 8021889
• 负责人: Zoran Brkanac
• 金额: $ 69.97万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8021889
• 关键词: Abbreviations; Affect; Autistic Disorder; Benign; Bioinformatics; Biological; Candidate Disease Gene; Case-Control Studies; Code; Collection; Data; Data Analyses; Databases; Deposition; Diagnosis; Diagnostic; Early treatment; Epidemiologic Studies; Etiology; Evaluation; Exons; Extended Family; Family; Family member; Gene Frequency; Genes; Genetic; Genome; Genomics; Genotype; Goals; Hereditary Disease; Human Genome; Hybridization Array; Individual; Interview; Methods; Minor; Mutation; National Institute of Mental Health; Neurodevelopmental Disorder; Nuclear; Open Reading Frames; Other Genetics; Parents; Pathway interactions; Phenotype; Play; Population; Proteins; Research Personnel; Resolution; Resources; Role; Schedule; Science; Symptoms; Technology; Twin Multiple Birth; United States National Institutes of Health; Universities; Validation; Variant; Washington; autism spectrum disorder; base; case control; comparative genomic hybridization; data sharing; disease transmission; exome; gene discovery; genetic variant; genome wide association study; genome-wide; in vitro Model; next generation; novel; novel strategies; proband; programs; segregation; 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.

自闭症是最具有遗传性的神经发育障碍之一，其遗传基础通过 家庭和双胞胎流行病学研究。全基因组关联研究尚未找到强有力的证据 常见变异的贡献和连锁研究表明存在多个基因座，每个基因座 对群体水平上的遗传变异的贡献可以忽略不计。该提案的目标是应用新颖的 分析方法从现有的 UW-ACE 和 NIH 收藏中识别遗传最多的家族 节约单基因传播，并应用新颖的基因组技术来识别基因 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，我们将 利用新的可用方法对蛋白质编码区进行全基因组序列评估 以及可能有因果关系的拷贝数变异。最后，将评估确定的候选基因 大型病例对照研究中与自闭症的关联以及候选基因的功能分析 将启动因果关系的最高证据。为了便于验证我们的发现，我们将保存基因型 NIMH 数据库中的信息。对自闭症遗传学的了解将有助于早期干预 实现症状前诊断，揭示与自闭症有关的其他生物学途径，并增加病因治疗的目标数量。