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障碍，影响着世界上1- 2%的人口，消耗了很大一部分精神卫生保健资金。许多双胞胎和家庭研究已经证明了大量的遗传成分，基于家庭的连锁研究已经确定了几个易感位点。近年来，基因组中大量单核苷酸多态性（snp）的鉴定作为HapMap计划的一部分，以及基于高通量阵列的基因分型技术的进步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影响较小的基因和基因水平分辨率的优点。自1989年以来，我们的联盟一直由NIMH资助进行双相情感障碍的遗传研究。我们一起收集了600多个双相情感障碍家庭，并进行了迄今为止最大的联系研究之一，确定了几个可能的易感位点。我们目前由NIMH资助，收集了5500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4000个系统确定的对照对象的样本，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Affymetrix 500K芯片，以平均6kb的密度检测分布在基因组中的500,000个SNP标记。家族性、早发性双相I型病例将被选择用于研究的所有阶段，以最大限度地增加基因负荷。在第一阶段，将对1000例双相I型高加索病例和1000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进行分析，并采用几种替代的临床定义的亚表型。阳性基因和区域将根据相关snp的统计显著性和聚类进行选择，并在二期复制样本中进行基因分型。该2期样本将包括一组单独的匹配组，包括2000名高加索家族性、早发性、双相情感障碍I型受试者和1000名高加索种族匹配对照；一组用于TDT分析的病例子集的400名白人父母；以及400名非裔美国人I型躁郁症患者和400名对照。阳性区域将使用Affymetrix分子倒置探针技术，使用10,000个snp进行高密度基因分型，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机会，以检查临床亚表型中的基因相互作用和关联。已鉴定的基因将使用新的生物信息学方法来鉴定可能的疾病途径。

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.