Fine mapping 8q24 in Familial Bipolar Disorder

描述(申请人提供)：这是一项修订后的提案，旨在确定位于染色体8q24上的与双相情感障碍相关的易感基因或基因组区域。它使用基于关联的方法来识别家庭样本中的关联，并在病例/对照设计中复制关联。有很好的证据表明8q24上存在易感基因。我们报告了65个多重双相家系中位于8q24的D8S256处的参数2点LOD为3.32，这在全基因组范围内具有重要意义。我们正在与安特卫普大学的研究人员合作，他们也有全基因组证据表明与8q24有关。我们的复制样本将来自NIMH双相情感障碍遗传学倡议(NiMH-GI BP)的家系。我们将使用最近发表的方法，从NIMH-GI BP家族中选择有证据表明D8S256基因座周围的等位基因共享增加的病例，这些方法在遗传分析程序Merlin中实现，从而丰富了我们对8q24遗传病例的复制样本。初步分析发现有284个家系在NIMH-GI BP的8q24上等位基因共享增加。我们将使用在NIMH-GI主持下确定的类似数量的控制措施。安特卫普大学的调查人员也在积极调查这一地区，他们已经同意在他们的样本中测试我们的阳性关联发现。这是有吸引力的，因为安特卫普的样本主要来自北欧，类似于霍普金斯和尼姆赫斯的样本。根据实际家系结构和我们的病例/对照设计进行的初步功率分析发现，样本足以满足我们的阈值，在基于家族的分析中需要显著性p&lt；0.001，在NIMH-GI病例/对照样本中需要p&lt；0.01.我们在安特卫普样本中增加了第三个显著性阈值水平p&lt；0.01。满足这些标准将为这附近存在易感基因提供令人信服的论据。我们建议在工业规模上进行SNP基因分型，使用目前在霍普金斯大学可用的基于Illumina阵列的技术，在14Mb的区域放置1,536个SNP，SNP之间的平均间隔为10kb。我们将首先对Hopkins/Dana样本进行基因分型，并追踪来自连锁NIMH-GI BP家系的病例/对照样本中的阳性区域。这些分析的重大关联随后将在安特卫普样本中进行测试(不为安特卫普申请资金)。如果该区域被复制，我们将从携带风险等位基因或单倍型的霍普金斯和NIMH样本中受影响的受试者的峰值附近开始测序，目标是识别与复制结果紧邻的所有SNP变异。测序中确定的变异将在更大的样本中进行分型，到本提案结束时，这些样本将包括目前NIMH-GI 5000BP病例确定的对象。随着BP和8q24关联的鉴定、复制和表征，我们将处于有利地位，可以进行进一步的基因和功能研究。

DESCRIPTION (provided by applicant): This is a revised proposal that aims to identify the susceptibilitygene or genomic region located on chromosome 8q24 associated with bipolar disorder. It uses association-based methods to identify an association in a family sample and replicate the association in a case/control design. There is good evidence for a susceptibility gene on 8q24. We reported a parametric 2-pt LOD of 3.32 at D8S256 on 8q24 in 65 multiplex bipolar families, which is significant, genome-wide. We are collaborating with investigators at the U. Antwerp who also have genome-wide evidence of linkage to 8q24. Our replication sample will be derived from the pedigrees of NIMH Genetics Initiative for Bipolar disorder (NiMH-GI BP). We will select cases from NIMH-GI BP families with evidence of increased allele sharing around the D8S256 locus, using recently published methods, implemented in the genetic analytic program, Merlin, thereby enriching our replication sample for 8q24 genetic cases. Preliminary analysis finds 284 pedigrees with increased allele sharing on 8q24 in NIMH-GI BP. We will use a similar number of controls ascertained under the auspices of the NIMH-GI. Investigators at the U Antwerp are also actively pursuing this region and they have agreed to test our positive association findings in their sample. This is attractive because the Antwerp sample is predominantly of N. European origin, similar to the Hopkins and NIMH samples. Preliminary power analyses based on the actual pedigree structure and our case/control design find that the sample is sufficientto meet our thresholds, requiring significance p<0.001 in the family based analysis and p< 0.01 in the NIMH-GI case/control sample. We have added a third significance threshold level of p<0.01 in the Antwerp sample. Meeting these standards would make a compelling argument for the presence of a susceptibility gene in this vicinity. We propose SNP genotyping on an industrial scale, using Illumina array-based technology now available at Hopkins, placing 1,536 SNPs in a 14 Mb region, with an average of 10 kb interval between SNPs. We will begin with genotyping the Hopkins/Dana sample, and follow-up the positive regions in the case/control sample derived from the linked NIMH-GI BP pedigrees. Significant associations from these analyses would subsequently be tested in the Antwerp sample (no funding requested for Antwerp). If the region is replicated we would begin sequencing around the peak in affected subjects from the Hopkins and NIMH samples that carry the risk allele or haplotype, the goal being to identify all SNP variants immediately adjacent to the replicated result. The variants identified in sequencing would then be typed in larger samples, which by the conclusion of this proposal will include the subjects from the current NIMH-GI 5,000 BP case ascertainment. With the identification, replication and characterization of the association for BP and 8q24 we will be in a strong positionto pursue further gene and functional studies.