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

• 批准号: 7183489
• 负责人: John R. Kelsoe
• 金额: $ 62.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/7183489
• 关键词: 22q; 22q12.1; Affect; Agonist; Alleles; Animals; Binding; Biological Assay; Bipolar Disorder; Candidate Disease Gene; Caucasians; Caucasoid Race; Cell Line; Chromosomes; Chromosomes, Human, Pair 22; Collection; DNA Resequencing; Data; Databases; Defect; Detection; Disease; Dopamine; Electrophoretic Mobility Shift Assay; European; Failure; Family; Family Study; G Protein Gene; GTP-Binding Proteins; Gene Expression; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genome; Genome Scan; Genomics; Genotype; Goals; Haplotypes; Human Genome Project; Individual; Link; Linkage Disequilibrium; Literature; Luciferases; Maps; Mediating; Mental disorders; Meta-Analysis; Methods; Microsatellite Repeats; Molecular; Molecular Analysis; Mutation; Neuroblastoma; Neurotransmitters; Patients; Phosphotransferases; Population; Predisposition; Psychotic Disorders; Reporter; Reporting; Rice; Role; Sampling; Schizophrenia; Score; Screening procedure; Shipping; Ships; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Susceptibility Gene; Testing; Transcriptional Regulation; Transfection; Twin Studies; Untranslated Regions; Variant; base; case control; density; desensitization; human study; lymphoblastoid cell line; proband; promoter; receptor; response; tool; transcription factor

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障碍，影响大约1%-2%的人口。众多的家庭研究和双胞胎研究支持大量的遗传成分。我们已经进行了基因组扫描，发现在22q上存在一个易感基因，标记D22S278的TOD最高值为3.8。染色体上连锁的证据超过了15Mb，并提示G蛋白受体激酶3(GRK3)基因可能有第二个10Mb的端粒。22q上的这两个区域也都被报道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易患这两种疾病的基因。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。虽然我们研究中最强的IoD评分结果最初与D22S278基因座有关，但在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确定了几个可能的功能SNPs，并在两个独立的样本中表明它们与双相情感障碍有关。这是我们的假设，在这条染色体上有两个不同的双相情感障碍基因。我们建议1)通过进一步的关联研究和基因表达的功能研究来确定GRK3作为易感基因的作用；2)确定D22S278附近的易感基因。GRK3基因周围250kb的序列将在双相受试者中进行，这些受试者来自与GRK3基因连锁的家系。在800名高加索人和800名高加索人对照样本中，200个SNPs将在1Mb的间隔内进行基因分型，包括GRK3基因座。我们假设GRK3基因转录调控存在缺陷，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报告启动子实验。为了确定D22S278附近的候选基因，将在该区域以10kb的密度对500个SNPs进行基因分型。然后，位置候选基因将被测序，并以更高的密度进行基因分型，以便识别与疾病相关的基因。