Autism genetics: homozygosity mapping and functional validation

自闭症遗传学：纯合性作图和功能验证

• 批准号: 8531350
• 负责人: Christopher A. Walsh
• 金额: $ 73.51万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531350
• 关键词: Accounting; Affect; Alleles; American; Autistic Disorder; Behavior; Biochemical Pathway; Biological Assay; Biological Models; Brain; Candidate Disease Gene; Categories; Cell Line; Cells; Child; Complex; DNA Resequencing; Data; Databases; Defect; Dendrites; Dendritic Spines; Diagnosis; Disease; Emotional; Enrollment; Environment; Etiology; Face; Family; Family member; Financial cost; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Models; Genetic Variation; Genome; Genomics; Genotype; Heritability; Heterogeneity; Impairment; In Vitro; Individual; Intellectual functioning disability; Intervention; Laboratories; Language Delays; Maps; Metabolic; Methods; Middle East; Morphologic artifacts; Morphology; Mutation; National Institute of Mental Health; Nature; Neurologic; Neuronal Differentiation; Neurons; Parents; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Play; Population; Publishing; RNA Interference; Recurrence; Regulation; Role; Sampling; Sequence Analysis; Social Behavior; Social Interaction; Societies; Somatic Cell; Stereotyping; Synapses; Testing; Time; Validation; Variant; Work; Yeast Model System; Yeasts; autism spectrum disorder; cohort; cost; exome; exome sequencing; follow-up; gene discovery; genetic linkage; genetic pedigree; genome sequencing; in vivo; interest; mouse model; novel; psychologic; recessive genetic trait; sample collection; synaptogenesis; therapy development; unpublished works; validation studies

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) affect 1% or more of American children. ASDs are characterized by defects in social behavior, including language delay, abnormal social interactions, and repetitive or stereotyped interests or behaviors. ASDs show a large genetic component, with estimates of heritability as high as 60- 90%. However, the extreme heterogeneity of ASD is a persistent hurdle to gene discovery, and known genetic causes account for less than 15% of diagnoses. Although high throughput sequencing (HTS) methods allow systematic analysis of genetic variation across the entire exome, or even the entire genome, the interpretation of this data faces analytical challenges that have by no means been solved. The use of consanguineous pedigrees, in which parents share ancestry, allows the identification of candidate genes that can then be analyzed more broadly in nonconsanguineous families. Consanguineous families 1] reduce the heterogeneity of ASD, 2] simplify HTS analysis and validation, and 3] provide genetic linkage evidence to support the validity of specific mutations in a single family. Preliminary data confirms that HTS in such pedigrees can efficiently identify, in an unbiased fashion, recessive genetic causes of ASD relevant to both consanguineous and nonconsanguineous cohorts of patients. This study will seek to enroll consanguineous families diagnosed with ASD, perform homozygosity mapping to locate regions of the genome likely to harbor the mutation that causes their ASD, and perform whole genome sequencing (WGS) on the affected individuals to identify candidate variants. Further, linkage and whole exome sequencing data that was generated on consanguineous families from previous studies will continue to be analyzed. This study will expand on the previous work by 1] Generating WGS data on normal controls to identify common alleles within Middle Eastern populations thus allowing swifter, more sensitive and ultimately cheaper analysis in this and many other Middle Eastern WGS studies; 2] Generating relatively high throughput methods of functionally validating strong candidate genes discovered through WGS using yeast models, transformed somatic cell lines, and other model systems; and 3] Using RNAi to generate mouse models of candidate genes discovered in this study, and an ongoing neuronal activity-dependent gene study, to examine the effects of removing the genes on dendrite and dendritic spine morphology and synaptic activity. Recent studies suggest that, despite the high level of heterogeneity, there are common biochemical pathways associated with ASD. The findings from this study will be instrumental in the identification of the genes that make up these pathways, and provide potential pharmaceutical targets for the treatment of ASD.

描述（由申请人提供）： 自闭症谱系障碍（ASDS）会影响1％或更多的美国儿童。 ASD的特征是社会行为的缺陷，包括语言延迟，异常的社会互动以及重复或刻板印象的利益或行为。 ASDS显示出较大的遗传成分，估计遗传力高达60-90％。然而，ASD的极端异质性是基因发现的持续障碍，已知的遗传导致不到诊断的15％。 尽管高吞吐量测序（HTS）方法允许对整个外显子组甚至整个基因组的遗传变异进行系统的分析，但该数据的解释却面临着无法解决的分析挑战。父母共同祖先的血统血统书的使用允许识别候选基因，然后可以在非语言家庭中对这些基因进行更广泛的分析。血统家族1]减少ASD的异质性，2]简化HTS分析和验证，以及3]提供遗传连锁证据，以支持单个家族中特定突变的有效性。初步数据证实，此类血统中的HTS可以有效地以公正的方式识别与血管和非副语言患者群体相关的ASD遗传遗传原因。 这项研究将寻求招募被诊断为ASD的血统家庭，进行纯合性映射，以定位可能携带导致其ASD突变的基因组区域，并对受影响的个体进行整个基因组测序（WGS）以识别候选变异。此外，将继续分析对先前研究的亲属家族产生的联系和整个外显子组测序数据。这项研究将通过1]对正常控制的WGS数据进行扩展，以识别中东人群中的常见等位基因，从而在此和许多其他中东WGS研究中允许Swifter，更敏感且最终更便宜的分析； 2]生成相对较高的吞吐量方法，在功能上验证了使用酵母模型，转换的体细胞系和其他模型系统发现的强大候选基因； 3]使用RNAi生成本研究中发现的候选基因的小鼠模型，以及持续的神经元素依赖性基因研究，以检查去除基因对树突和树突状脊柱形态和突触活动的影响。 最近的研究表明，尽管异质性高度，但仍有与ASD相关的常见生化途径。这项研究的发现将有助于鉴定构成这些途径的基因，并为治疗ASD的治疗提供潜在的药物靶标。