Genomic Association Study of Bipolar Disorder

描述（由申请人提供）：双相情感障碍是一种主要的精神疾病，影响世界人口的1- 2%，并消耗了相当大一部分的精神卫生保健美元。许多双胞胎和家庭的研究已经证明了大量的遗传成分，和家庭为基础的连锁研究已经确定了几个易感基因座。近年来，作为人类基因组单核苷酸多态性（SNPs）研究的一部分，HapMap计划和高通量芯片基因分型技术的发展使得全基因组高密度关联分析成为可能。这种方法具有更大的能力来检测较小影响的基因，以及基因水平分辨率的优点。自1989年以来，我们的联盟一直由NIMH资助，用于双相情感障碍的遗传研究。我们一起收集了600多个双相情感障碍的家庭，并进行了迄今为止最大的连锁研究之一，确定了几个可能的易感基因座。我们目前由NIMH资助，收集了5,500名双相I型受试者的样本，用于大型病例对照研究。我们还获得了4,000名系统确定的对照受试者的样本，这些样本是作为精神分裂症单独研究的一部分收集的。我们建议使用基于寡核苷酸微阵列的方法，即Affytek 500 K芯片，检查分布在基因组中平均6 kb密度的500，000个SNP标记。将选择家族性早发性双相I型病例用于研究的所有阶段，以最大化遗传负荷。在第一阶段，将对1，000例双相I型白人病例和1，000例种族匹配的对照进行基因分型。这些数据将使用多种基于单倍型的方法并采用几种替代的临床定义的亚表型进行分析。将基于相关SNP的统计学显著性和聚类选择阳性基因和区域，并在2期复制样本中进行基因分型。该II期样本将包括一组单独匹配的2,000例白人家族性早发双相I型受试者和1,000例白人种族匹配对照;一组400例白人父母的TDT分析病例子集;以及一组400例双相I型病例和400例对照的非裔美国人样本。阳性区域将使用10，000个SNP，使用Affyssin分子倒置探针技术以高密度进行基因分型，并辅以三种额外的基因分型方法。在独立的大样本中进行基因分型的第二阶段将提供关键的复制和检查基因-基因相互作用和临床亚表型相关性的机会。将使用新的生物信息学方法检查已识别的基因，以确定可能的疾病途径。

DESCRIPTION (provided by applicant): Bipolar disorder is a major psychiatric disorder that affects 1-2 percent of the world's population and consumes a substantial portion of mental healthcare dollars. Numerous twin and family studies have demonstrated a substantial heritable component, and family-based linkage studies have identified several susceptibility loci. Recently, the identification of large numbers of single nucleotide polymorphisms (SNPs) in the genome as part of the HapMap project and advances in high throughput array-based genotyping have made possible whole genome high density association analyses. Such an approach has the advantages of much greater power to detect genes of smaller effect, and gene-level resolution. Our consortium has been funded by NIMH for genetic studies of bipolar disorder since 1989. Together we have collected over 600 families with bipolar disorder and conducted one of the largest linkage studies to date that identified several possible susceptibility loci. We are presently funded by NIMH to collect a sample of 5,500 bipolar I subjects for large case-control studies. We also have access to a sample of 4,000 systematically ascertained control subjects collected as part of a separate study of schizophrenia. We propose to examine 500,000 SNP markers distributed at an average 6 kb density across the genome using an oligonucleotide microarray-based method, the Affymetrix 500K chip. Familial, early onset bipolar I cases will be selected for all phases of the study in order to maximize the genetic loading. In the first phase, 1,000 bipolar I Caucasian cases and 1,000 ethnically matched controls will be genotyped. These data will be analyzed using a variety of haplotype- based methods and employing several alternative clinically defined subphenotypes. Positive genes and regions will be selected based on statistical significance and clustering of associated SNPs, and genotyped in a phase 2 replication sample. This phase 2 sample will include a separate matched set of 2,000 Caucasian familial, early onset, bipolar I subjects and 1,000 Caucasian ethnically matched controls; a set of 400 Caucasian parents of a subset of the cases for TDT analysis; and an African-American sample of 400 bipolar I cases and 400 controls. Positive regions will be genotyped at high density using 10,000 SNPs using Affymetrix Molecular Inversion Probe technology and supplemented by three additional genotyping methods. This second phase of genotyping in an independent large sample will provide critical replication and the opportunity to examine gene-gene interactions and association in clinical subphenotypes. Identified genes will be examined using novel bioinformatics methods to identify possible disease pathways.