A Genome-Wide Association Study of Schizophrenia

描述（由申请人提供）：这是一个修改后的申请，为两个网站和5个财团网站提供3年的资金（PA 05-106，“精神疾病的深度测序和单倍型分析”）。目的是通过全基因组关联研究，随后进行重测序、基因分型和生物学实验，鉴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：3,000名SZ和3,000名欧洲血统（EA）的对照受试者，以及1,200名非裔美国人（AA）血统的病例和1,200名对照。GWA数据集将包括EA样本中的550，000个SNP（修订后的Affyoung 500 K阵列和50 K Gene-Focused芯片，其中包括20 K nsSNP），以及AA样本中的新Affyoung 1 M阵列（500 K阵列和500 K额外的SNP，增加了非洲变异的覆盖率）。新的500 K阵列还提供了额外拷贝数变异（CNV）的全基因组检测。遗传关联信息网络（GAIN）将对1450/1450例EA病例/对照（500 K）和整个AA样本（1 M）进行基因分型。Affyandum联盟研究中心将使用500 K阵列对剩余的1550/1550例EA病例/对照进行基因分型，并使用50 K芯片对所有EA受试者进行基因分型。初步的统计研究，提出了选择一个最佳的数据分析策略，测试每个HapMap单核苷酸多态性使用单标记和多标记测试，评估欧洲和非洲血统的染色体（在混合个体推断当地血统后）和组合数据的关联证据，控制微妙的人口亚结构，并通过排列评估经验p值。将根据p值阈值、秩截尾乘积分析、重复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。深度重测序实验将检测罕见功能突变的任何显著病例对照差异，并将发现新的罕见和常见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，用于常见变体的最佳标记。基于关联证据和关于每个基因、相关基因组间隔和相关变体的可用信息，将进行生物学研究以开始评估这些变体的功能效应和对SZ易感性潜在机制的假设的影响。

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.