Genomic studies of bipolar disorder and chromosome 22

描述（由申请人提供）： 双相情感障碍是一种主要的精神疾病，影响约1-2%的人口。许多家庭研究和双胞胎研究支持大量的遗传成分。我们进行了基因组扫描，表明在22 q上存在一个易感基因座，在标记D22 S278处的最大tod得分为3.8。染色体上连锁的证据延伸到近15 Mb，并建议在G蛋白受体激酶3（GRK 3）基因的端粒处可能存在第二个峰10 Mb。据报道，22 q上的这两个区域与双相情感障碍和精神分裂症都有联系或相关。这表明，在这条染色体上可能存在一个或多个基因，这些基因易患这两种疾病。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22 q是基因组中最强大的连锁发现之一。虽然在我们的研究中最强的IOD评分结果最初是D22 S278位点，但在第二个样品中的另一个连锁研究以及动物微阵列研究支持GRK 3位点的作用。我们还确定了该基因启动子中的几个可能的功能性SNP，并在两个独立的样本中显示它们与双相情感障碍相关。我们的假设是，在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GRK 3作为易感基因的作用; 2）确定D22 S278附近的易感基因座。将在来自与GRK 3基因座连锁的家族的双相情感障碍受试者中对GRK 3基因周围的250 kb进行测序。在800名高加索双极患者和800名高加索对照的样本中，将在1 Mb间隔内对200个SNP进行基因分型，包括GRK 3基因座。我们假设GRK 3基因的转录调控缺陷导致受体脱敏失败。GRK 3基因表达的调节将在来自双相患者的淋巴母细胞样细胞系中以及在神经母细胞瘤细胞系中的转染报告基因启动子测定中进行测试。为了鉴定D22 S278附近的候选基因，将在该区域的5 Mb上以10 kb密度对500个SNP进行基因分型。然后将对位置候选基因进行测序，并以更高的密度进行基因分型，以确定与疾病相关的基因。

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.