Next Generation Gene Discovery in Familial Autism

自闭症是一种最易遗传的神经发育障碍，其遗传学基础已被证实。 家庭和双胞胎流行病学研究。全基因组关联研究没有发现强有力的证据表明 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 在种群水平上对遗传变异的贡献可以忽略不计。这项提议的目标是将小说 从现有的UW-ACE和NIH集合中识别遗传最多的家族的分析方法 节俭的单基因传播，并应用新的基因组技术来识别 是有责任的。为了确定显性和隐性遗传的可能性增加的家系，我们 将对现有的基因数据进行血统同一性和纯合子程度分析。接下来，我们将 利用最新可用的方法对序列的蛋白质编码区进行全基因组评估 以及可能有因果关系的拷贝数变异。最后，将对确定的候选基因进行评估 一项大型病例对照研究中孤独症的相关性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，我们将存储基因 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 能够进行症状前诊断，牵涉到自闭症涉及的其他生物学途径，并增加了致病治疗的靶点数量。

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.