A Genome-Wide Association Study of Schizophrenia

精神分裂症的全基因组关联研究

• 批准号: 7498560
• 负责人: Pablo V. Gejman
• 金额: $ 183.09万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498560
• 关键词: African; African American; Bioinformatics; Biological; Biological Assay; Brain; Candidate Disease Gene; Chromosomes; Clinical; Clinical Data; Code; Complex; Conserved Sequence; DNA Resequencing; Data; Data Analyses; Data Set; Databases; Depth; Development; Disease; Elements; European; Exons; Family; Frequencies; Functional disorder; Funding; Gene Expression; Genes; Genetic Variation; Genome; Genomics; Genotype; Goals; Grant; Haplotypes; Individual; Information Networks; Maps; Mental disorders; Methodological Studies; Methods; Morbidity - disease rate; Mutation; NIH Program Announcements; Numbers; Online Systems; Pathway interactions; Policies; Population; Predisposition; Rate; Reporting; Research Design; Research Personnel; Risk; Role; Sampling; Schizophrenia; Site; Statistical Methods; Statistical Study; Testing; Variant; base; case control; cost; gene interaction; genetic association; genome wide association study; improved; positional cloning; programs; repository; research study; size

DESCRIPTION (provided by applicant): This is a revised application for 3 years of funding for two sites and 5 consortium sites (PA 05-106, "Deep Sequencing and Haplotype Profiling of Mental Disorders"). The goal is to identify and characterize genetic variation that contributes to schizophrenia (SZ) susceptibility, by carrying out a genome-wide association GWA) study followed by resequencing, genotyping and biological experiments. Two samples will be studied: 3,000 SZ and 3,000 control subjects of European ancestry (EA), and 1,200 cases and 1,200 controls of African-American (AA) ancestry. The GWA datasets will include 550,000 SNPs in the EA sample (the revised Affymetrix 500K array and 50K Gene-Focused chip that includes 20K nsSNPs), and the new Affymetrix 1M array in the AA sample (the 500K array and 500K additional SNPs with increased coverage of African variation). The new 500K array also provides genomewide assays of additional copy number variants (CNVs). The Genetic Association Information Network (GAIN) will genotype 1450/1450 EA cases/controls (500K) and the entire AA sample (1M). The Affymetrix consortium site will genotype the remaining 1550/1550 EA cases/controls with the 500K array, and all EA subjects with the 50K chip. Preliminary statistical studies are proposed, to select an optimal data analysis strategy that tests every HapMap SNP using single- and multi-marker tests, evaluates evidence for association on European- and African-ancestry chromosomes (after inferring local ancestry in admixed individuals) and in the combined data, controls for subtle population substructure, and evaluates empirical p-values through permutation. A set of" 15 candidate intervals will be selected based on p-value threshold, Rank Truncated Product analysis, replication experiments, and bioinformatic and biological information. Deep resequencing experiments will detect any significant case-control difference in rare functional mutations, and will discover new rare and common SNPs. Further genotyping of each region will include rare/functional SNPs and additional common SNPs for optimal tagging of common variants. Based on evidence for association and available information about each gene, the associated genomic interval, and the associated variants, biological studies will be undertaken to begin to evaluate the functional effects of these variants and the implications for hypothesis about mechanisms underlying susceptibility to SZ.

描述（由申请人提供）：这是为两个站点和 5 个联盟站点提供 3 年资助的修订申请（PA 05-106，“精神障碍的深度测序和单倍型分析”）。目标是通过进行全基因组关联 GWA）研究，然后进行重测序、基因分型和生物实验，来识别和表征导致精神分裂症 (SZ) 易感性的遗传变异。将研究两个样本：3,000 名欧洲血统 (EA) 的 SZ 受试者和 3,000 名对照受试者，以及 1,200 名非裔美国人 (AA) 血统的病例和 1,200 名对照受试者。 GWA 数据集将包括 EA 样本中的 550,000 个 SNP（修订版 Affymetrix 500K 阵列和 50K 基因聚焦芯片，​​其中包括 20K nsSNP），以及 AA 样本中的新 Affymetrix 1M 阵列（500K 阵列和覆盖范围更大的 500K 附加 SNP）非洲变异）。新的 500K 阵列还提供额外拷贝数变异 (CNV) 的全基因组检测。遗传关联信息网络 (GAIN) 将对 1450/1450 个 EA 病例/对照 (500K) 和整个 AA 样本 (1M) 进行基因分型。 Affymetrix 联盟网站将使用 500K 阵列对剩余的 1550/1550 EA 病例/对照进行基因分型，并使用 50K 芯片对所有 EA 受试者进行基因分型。提出了初步统计研究，以选择最佳数据分析策略，使用单标记和多标记测试来测试每个 HapMap SNP，评估欧洲和非洲血统染色体关联的证据（在推断混合个体的本地血统之后），并在组合数据，控制微妙的总体子结构，并通过排列评估经验 p 值。将根据 p 值阈值、Rank Truncated Product 分析、复制实验以及生物信息学和生物信息来选择一组“15 个候选区间。深度重测序实验将检测罕见功能突变中任何显着的病例对照差异，并发现每个区域的新的罕见和常见 SNP 的进一步基因分型将包括罕见/功能性 SNP 和其他常见 SNP，以根据每个基因的关联证据和可用信息、相关基因组区间和相关变体，将进行生物学研究，以开始评估这些变体的功能效应以及对 SZ 易感性机制假设的影响。