Genomic studies of bipolar disorder and chromosome 22

双相情感障碍和 22 号染色体的基因组研究

基本信息

批准号：
7036536
负责人：
John R. Kelsoe
金额：
$ 62.49万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7036536
关键词：
behavioral genetics biotechnology bipolar depression caucasian American cell line chromosomes clinical research family genetics gel mobility shift assay gene expression genetic mapping genetic regulatory element genetic susceptibility human data human genetic material tag human tissue neuroblastoma single nucleotide polymorphism

项目摘要

DESCRIPTION (provided by applicant): Bipolar disorder is a major psychiatric disorder affecting approximately 1-2% of the population. Numerous family studies and twin studies support a substantial genetic component. We have conducted a genome scan that indicated the presence of a susceptibility locus on 22q with a maximum tod score of 3.8 at the marker D22S278. The evidence for linkage on the chromosome extended over nearly 15 Mb and suggested a possible second peak 10 Mb telomeric at the gene for G protein receptor kinase 3 (GRK3). Both of these two regions on 22q have also been reported to be linked or associated to both bipolar disorder and schizophrenia. This suggests that one or more genes may exist on this chromosome that predisposes to both disorders. Our results are consistent with recent meta-analyses of genome scans of bipolar disorder which found 22q to be one of the most robust linkage findings in the genome. Though the strongest Iod score results in our study initially were to the D22S278 locus, another linkage study in a second sample, as well as, animal microarray studies have supported the role of the GRK3 locus. We have also identified several possible functional SNPs in the promoter of this gene and shown them to be associated to bipolar disorder in two independent samples. It is our hypothesis, that there are two distinct loci for bipolar disorder on this chromosome. We propose to 1) confirm the role of GRK3 as a susceptibility gene by additional association studies and functional studies of gene expression; and 2) identify the susceptibility locus near D22S278. 250 kb surrounding the GRK3 gene will be sequenced in bipolar subjects from families linked to the GRK3 locus. 200 SNPs will be genotyped across a 1 Mb interval including the GRK3 locus in a sample of 800 Caucasian bipolars and 800 Caucasian controls. We hypothesize a defect in transcriptional regulation of the GRK3 gene that results in a failure of receptor desensitization. The regulation of gene expression of GRK3 will be tested in lymphoblastoid cell lines from bipolar patients and in a transfection reporter promoter assay in a neuroblastoma cell line. In order to identify candidate genes near D22S278, 500 SNPs will be genotyped at a 10 kb density across 5 Mb in this region. Positional candidate genes will then be sequenced and genotyped at higher density in order to identify those associated with illness.

描述（由申请人提供）：双相情感障碍是一种主要的精神疾病，影响大约 1-2% 的人口。许多家庭研究和双胞胎研究都支持重要的遗传成分。我们进行了基因组扫描，结果表明 22q 上存在易感位点，标记 D22S278 处的最大 tod 得分为 3.8。染色体上连锁的证据延伸了近 15 Mb，并表明 G 蛋白受体激酶 3 (GRK3) 基因上可能存在第二个峰值 10 Mb 端粒。据报道，22q 上的这两个区域都与双相情感障碍和精神分裂症有关。这表明该染色体上可能存在一个或多个基因，导致这两种疾病的发生。我们的结果与最近对双相情感障碍基因组扫描的荟萃分析一致，该分析发现 22q 是基因组中最强大的连锁发现之一。尽管我们研究中最强的 Iod 评分结果最初是针对 D22S278 基因座，但第二个样本中的另一项连锁研究以及动物微阵列研究支持了 GRK3 基因座的作用。我们还在该基因的启动子中鉴定了几个可能的功能性 SNP，并在两个独立样本中证明它们与躁郁症相关。我们的假设是，这条染色体上有两个不同的双相情感障碍基因座。我们建议1）通过额外的关联研究和基因表达的功能研究来确认GRK3作为易感基因的作用； 2) 确定 D22S278 附近的易感位点。 GRK3 基因周围的 250 kb 将在来自与 GRK3 基因座相关的家族的双相情感障碍受试者中进行测序。将在 1 Mb 间隔内对 200 个 SNP 进行基因分型，其中包括 800 个白人双相情感障碍样本和 800 个白人对照样本中的 GRK3 位点。我们假设 GRK3 基因的转录调控存在缺陷，导致受体脱敏失败。 GRK3 基因表达的调节将在双相情感障碍患者的淋巴母细胞系中进行测试，并在神经母细胞瘤细胞系中进行转染报告基因启动子测定。为了识别 D22S278 附近的候选基因，将以 10 kb 的密度在该区域的 5 Mb 范围内对 500 个 SNP 进行基因分型。然后将以更高的密度对位置候选基因进行测序和基因分型，以识别与疾病相关的基因。