Genome-wide Association Study of Schizophrenia

描述（由申请人提供）：这是一份3年资助的修订申请，涉及2个站点和5个联盟站点（PA 05-106，“精神障碍的深度测序和单倍型分析”）。目标是通过开展全基因组关联（GWA）研究，然后进行重测序、基因分型和生物学实验，确定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：欧洲血统（EA）的3000名SZ和3000名对照受试者，以及非洲裔美国人（AA）血统的1200名病例和1200名对照受试者。GWA数据集将包括EA样本中的55万个snp（修订后的Affymetrix 500K阵列和50K基因聚焦芯片，其中包括20K非snp），以及AA样本中的新Affymetrix 1M阵列（500K阵列和500K额外snp，增加了非洲变异的覆盖范围）。新的500K阵列还提供额外拷贝数变异（cnv）的全基因组分析。遗传关联信息网络（GAIN）将对1450/1450例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例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。我们提出了初步的统计研究，以选择一种最佳的数据分析策略，使用单标记和多标记测试测试每个HapMap SNP，评估欧洲和非洲血统染色体（在推断混合个体的本地血统后）和组合数据中关联的证据，控制微妙的群体子结构，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学信息选择一组15个候选区间。深度重测序实验将发现罕见功能突变中任何显著的病例对照差异，并将发现新的罕见和常见的snp。每个区域的进一步基因分型将包括罕见/功能性snp和额外的常见snp，以便对常见变异进行最佳标记。基于相关证据和关于每个基因、相关基因组间隔和相关变异的现有信息，将开展生物学研究，开始评估这些变异的功能影响以及对SZ易感性机制的假设的影响。

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.