Genetic analysis of 15q11-q13 in Autism

自闭症 15q11-q13 基因分析

• 批准号: 6892075
• 负责人: JAMES S SUTCLIFFE
• 金额: $ 46.74万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892075
• 关键词: artificial chromosomes; autism; behavior test; behavioral genetics; chromosome aberrations; clinical research; cytogenetics; family genetics; fluorescent in situ hybridization; gene expression; genetic mapping; genetic markers; genetic polymorphism; genetic susceptibility; genomic imprinting; human genetic material tag; human subject; linkage disequilibriums; linkage mapping; microarray technology; molecular biology information system; parents; patient oriented research; phlebotomy; psychometrics; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Autism is a neuropsychiatric disorder exhibiting a complex genetic etiology with significant clinical and locus heterogeneity. Duplications affecting chromosome 15q11-q13 are the most common cytogenetic abnormality in autism, and linkage and association studies indicate that this region is involved in inherited susceptibility for autism in chromosomally normal families. We propose dissecting the genetic basis for inherited risk associated with 15q11-q13 in autism by (1) employing a thoroughly phenotyped dataset of 365 parent-child trios and 330 multiplex families; (2) characterization of duplicon-mediated rearrangements and potential epigenetic effects; (3) identifying genetically more homogeneous subgroups with which to detect and characterize genetic effects; and (4) performing high-resolution linkage disequilibrium mapping using single nucleotide polymorphisms (SNPs) to define haplotypes for use in analysis of allelic effects in these families. Our goal will be accomplished through five specific aims. (1) Recruitment and detailed clinical assessment of singleton families using a standardized panel of diagnostic instruments and algorithms. (2) Characterization of chromosomal rearrangements involving 15q and examination of potential epigenetic dysregulation of imprinted expression. (3) Construction of a complete haplotype map for the 15q11-q13 candidate region and identification of a reduced set of SNPs for discrimination of all common (>5%) haplotypes. (4) Application of individual markers and multi-marker haplotypes to characterize allelic and epistatic effects in these autism families. (5) Identification of 15q11-q13 allelic variants in autism and preliminary characterization of the functional effect of those variations. Associated haplotype blocks and/or functionally-significant regions within candidate genes will be screened to identify likely functional variants. We will evaluate the significance of any genetic findings by examination of independent datasets through collaboration with other groups. The result of these efforts will be an understanding of how 15q11-q13 contributes to inherited susceptibility in autism and the broader autism spectrum.

描述（由申请人提供）：自闭症是一种神经精神疾病，表现出复杂的遗传病因，具有显着的临床和基因座异质性。影响15q11-Q13染色体的重复是自闭症中最常见的细胞遗传学异常，连锁和关联研究表明，该区域与染色体正常家庭中自闭症的遗传敏感性有关。我们建议通过（1）采用365个亲子三重奏和330个多重多重家族的彻底表型数据集来解剖与自闭症15q11-Q13相关的遗传基础； （2）二重奏介导的重排和潜在的表观遗传效应的表征； （3）鉴定遗传上更均匀的亚组，以检测和表征遗传效应； （4）使用单核苷酸多态性（SNP）进行高分辨率连杆不平衡映射，以定义单倍型以用于分析这些家族的等位基因效应。我们的目标将通过五个具体目标来实现。 （1）使用标准化的诊断仪器和算法小组对单身家族的招募和详细临床评估。 （2）表征涉及15q的染色体重排以及对烙印表达的潜在表观遗传失调的检查。 （3）为15q11-Q13候选区域的完整单倍型图的构建，并鉴定了减少的SNP集，以辨别所有常见（> 5％）单倍型。 （4）应用单个标记和多标记单倍型在这些自闭症家庭中表征等位基因和上皮效应。 （5）自闭症中15q11-Q13等位基因变体的鉴定以及这些变化的功能效应的初步表征。将筛选候选基因中相关的单倍型块和/或功能上重要的区域，以识别可能的功能变体。我们将通过与其他群体的协作检查独立数据集来评估任何遗传发现的重要性。这些努力的结果将是对15q11-Q13如何促进自闭症和更广泛的自闭症谱系的遗传易感性的理解。