Computational tools to analyze SNP data from patients with mental illness

分析精神疾病患者 SNP 数据的计算工具

• 批准号: 7670133
• 负责人: Thomas Downey
• 金额: $ 24.3万
• 依托单位: PARTEK, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-17 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670133
• 关键词: 16p11.2; Affect; Alleles; Aneuploidy; Autistic Disorder; Base Pairing; Bipolar Disorder; Child; Chromosomal Duplication; Chromosome abnormality; Chromosomes; Complex; Computer software; DNA; DNA Sequence; Data; Data Analyses; Data Set; Deposition; Dimensions; Disease; Event; Family; Fathers; Gene Mutation; Generations; Genes; Genetic; Genome; Genomics; Genotype; Goals; Gold; Human Genetics; Imagery; Individual; Inheritance Patterns; Inherited; Lead; Loss of Heterozygosity; Measurement; Measures; Meiosis; Meiotic Recombination; Mental Retardation; Mental disorders; Metric; Microarray Analysis; Missouri; Mothers; Mutation; National Institute of Mental Health; Online Systems; Output; Parents; Patients; Performance; Phase; Public Health; Relative (related person); Reporting; Research; Research Personnel; Resolution; Role; Sampling; Schizophrenia; Series; Siblings; Single Nucleotide Polymorphism; Small Business Innovation Research Grant; Software Tools; Statistical Methods; Syndrome; Technology; Testing; Trisomy; Uniparental Disomy; Variant; Work; autism spectrum disorder; base; computerized tools; density; design; disorder risk; father role; genetic analysis; genetic pedigree; genetic resource; genome wide association study; grandchild; grandparent; human disease; insight; member; programs; prototype; public health relevance; software development; statistics; tool

DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed research is to develop a software product that can be used to facilitate the analysis of genetic changes in order to elucidate chromosomal abnormalities that underlie diseases such as autism spectrum disorder, bipolar disorder, and schizophrenia. Recent technological advances allow samples of DNA from patients to be analyzed on single nucleotide polymorphism (SNP) arrays, generating up to millions of data points from each sample. These data must be analyzed to identify chromosomal abnormalities (e.g. DNA mutations, hemizygous or homozygous deletions, or translocations) that confer risk for these diseases. Two main approaches to data analysis include copy number estimates (based on the intensity of hybridization of samples to SNP arrays) and genotype analysis (revealing heterozygosity and homozygosity). Software such as Partek Genomics Suite (GS) exists to perform data analysis and visualization. A goal of this proposal is to add another dimension to the analysis of high density SNP data by incorporating information about the genetic relatedness of individuals into the data analysis repertoire of Partek GS. The specific aims are as follows. (1) Incorporate SNPtrio into a new Partek GS module. This program analyzes genotype and copy number data from trios consisting of father, mother, and child and produces graphical and tabular descriptions of uniparental inheritance (e.g. uniparental isodisomy in which two copies of a chromosome or chromosomal segment are inherited from one parent; such a mechanism is known to cause a variety of mental retardation and other syndromes). (2) Incorporate SNPduo into PartekGS; this program performs pairwise analyses of SNP data sets, allowing the description of relatedness between individuals (by identity-by-state measurements). This is useful for a variety of purposes including identifying outliers, replicate samples, non-paternity, and confirming the genetic relatedness of members of a pedigree. (3) Incorporate a set of analytic tools that measure meiotic recombination in pedigrees consisting of one, two, or three generations. Such tools may be useful to exclude loci in association studies or to characterize mechanisms by which deletions or duplications occur. The software tools described in aims (1) to (3) will be assembled into a new prototype version of Partek GS. In aim (4), this prototype will be used to analyze a set of 500,000 SNPs measured in 2,883 individuals from 700 families having two or more individuals affected with autism. This analysis will demonstrate the functionality of the Partek GS prototype, demonstrating the usefulness of incorporating new tools for genetic analysis to discover chromosomal abnormalities that may have roles in autism. PUBLIC HEALTH RELEVANCE: Newly available technologies allow the measurement of millions of variations in DNA sequence between samples from individuals with diseases (such as autism and schizophrenia) relative to unaffected individuals (controls). The proposed research is designed to create software analysis tools that will facilitate the discovery of chromosomal abnormalities in diseases. This may lead to treatments for these disorders, serving a large public health need.

描述(由申请人提供)：拟议研究的广泛、长期目标是开发一种软件产品，可用于促进基因变化的分析，以阐明导致自闭症谱系障碍、双相情感障碍和精神分裂症等疾病的染色体异常。最近的技术进步使患者的DNA样本能够在单核苷酸多态性(SNP)阵列上进行分析，从每个样本中产生多达数百万个数据点。必须对这些数据进行分析，以确定染色体异常(例如DNA突变、半合子或纯合子缺失或易位)，从而增加这些疾病的风险。数据分析的两种主要方法包括拷贝数估计(基于样本与SNP阵列杂交的强度)和基因分析(揭示杂合性和纯合性)。Partek基因组学套件(GS)等软件是用来执行数据分析和可视化的。这项建议的一个目标是通过将有关个体遗传相关性的信息纳入Partek GS的数据分析库中，为高密度SNP数据的分析增加另一个维度。具体目标如下。(1)将SNPtrio并入新的Partek GS模块。这个程序分析由父亲、母亲和孩子组成的三人组的基因型和拷贝数数据，并产生单亲遗传的图形和表格描述(例如，单亲等二体，其中一个染色体或染色体片段的两个副本从父母中继承；这种机制已知会导致各种智力低下和其他症状)。(2)将SNPduo纳入PartekGS；该程序对SNP数据集执行配对分析，允许描述个人之间的关联性(通过逐个州的测量)。这对于各种目的是有用的，包括识别异常值、重复样本、非亲子关系以及确认家系成员的遗传关系。(3)结合一套分析工具来测量由一代、二代或三代组成的家系中的减数分裂重组。这类工具可用于排除关联研究中的基因座，或描述发生缺失或重复的机制。AIMS(1)至(3)所述的软件工具将组装成Partek GS的新原型版本。在AIM(4)中，这个原型将被用来分析一组500,000个SNPs，这些SNPs来自700个家庭的2883个个体，其中有两个或更多自闭症患者。这项分析将展示Partek GS原型的功能，展示纳入新的遗传分析工具以发现可能在自闭症中起作用的染色体异常的有用性。 与公共卫生相关：新可用的技术允许测量患有疾病(如自闭症和精神分裂症)的个人样本与未受影响的个人(对照)之间的数百万DNA序列变异。这项拟议的研究旨在创建软件分析工具，以促进发现疾病中的染色体异常。这可能会导致对这些疾病的治疗，满足大量的公共卫生需求。