Genomic Association Study of Bipolar Disorder

描述(由申请者提供)：双相情感障碍是一种主要的精神障碍，影响着世界1%-2%的人口，并消耗了相当大一部分精神卫生保健资金。大量的双胞胎和家族研究已经证明了一个重要的可遗传成分，基于家族的连锁研究已经确定了几个易感基因座。最近，作为HapMap计划的一部分，基因组中大量单核苷酸多态(SNPs)的识别以及基于高通量阵列的基因分型的进展使全基因组高密度关联分析成为可能。这种方法的优点是检测效果较小的基因的能力要大得多，并且具有基因水平的分辨率。我们的联盟自1989年以来一直由NIMH资助进行双相情感障碍的基因研究。我们总共收集了600多个双相情感障碍家庭，并进行了迄今为止规模最大的连锁研究之一，确定了几个可能的易感基因。我们目前由NIMH资助，为大型病例对照研究收集了5500名双相I型受试者的样本。我们还可以获得作为精神分裂症单独研究的一部分收集的4000名系统确定的对照受试者的样本。我们建议使用一种基于寡核苷酸微阵列的方法Affymetrix 500K芯片来检测500,000个分布在整个基因组中的平均6kb密度的SNP标记。家族性、早发性双相I型病例将被选入研究的所有阶段，以最大限度地增加遗传负荷。在第一阶段，将对1000例双相I型高加索患者和1000名种族匹配的对照进行基因分型。这些数据将使用各种基于单倍型的方法进行分析，并采用几种可供选择的临床定义的亚型。阳性基因和区域将根据统计意义和相关SNPs的聚集性进行选择，并在第二阶段复制样本中进行基因分型。这一第二阶段的样本将包括一组独立的配对样本，包括2000名高加索家族性、早发性、双相I型患者和1000名高加索人种匹配的对照；一组400名高加索父母的子集病例用于TDT分析；以及一组非裔美国人样本，400名双相I型病例和400名对照。阳性区域将使用Affymetrix分子反转探针技术使用10,000个SNP以高密度进行基因分型，并辅之以三种额外的基因分型方法。在一个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机会，以检查临床亚型中的基因-基因相互作用和关联。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.