Fine mapping 8q24 in Familial Bipolar Disorder

描述（由申请人提供）：这是一个修订后的提案，旨在确定位于染色体8 q24上与双相情感障碍相关的易感基因或基因组区域。它使用关联为基础的方法来确定一个家庭样本中的关联，并复制的情况下/控制设计的关联。有很好的证据表明8 q24上存在易感基因。我们报道了65个多重双极家族中8 q24上D8 S256处的参数2-pt LOD为3.32，这在全基因组范围内是显著的。我们正在与美国的调查人员合作。安特卫普的人也有全基因组证据表明与8 q24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，在遗传分析程序Merlin中实施，从NIMH-GI BP家族中选择具有D8 S256位点周围等位基因共享增加的证据的病例，从而丰富我们的8 q24遗传病例的复制样本。初步分析发现284个家系在NIMH-GI BP的8 q24上具有增加的等位基因共享。我们将使用在NIMH-GI主持下确定的类似数量的控制。安特卫普大学的研究人员也在积极研究这一地区，他们同意在他们的样本中测试我们的正相关发现。这是有吸引力的，因为安特卫普样品主要是N。欧洲来源，与霍普金斯和NIMH样本相似。基于实际谱系结构和我们的病例/对照设计的初步功效分析发现，样本符合我们的阈值，在基于家族的分析中需要显著性p<0.001，在NIMH-GI病例/对照样本中需要显著性p< 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<0.01。满足这些标准将为易感基因在这附近的存在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，使用霍普金斯现有的基于Illumina阵列的技术，在14 Mb区域中放置1,536个SNP，SNP之间的平均间隔为10 kb。我们将开始对霍普金斯/达纳样本进行基因分型，并对来自连锁NIMH-GI BP家系的病例/对照样本中的阳性区域进行随访。随后将在安特卫普样本中检验这些分析得出的重要关联（安特卫普没有申请资金）。如果该区域被复制，我们将开始围绕来自携带风险等位基因或单倍型的霍普金斯和NIMH样本的受影响受试者的峰进行测序，目标是鉴定紧邻复制结果的所有SNP变体。然后，在测序中识别的变体将在更大的样本中进行分型，根据本提案的结论，将包括来自当前NIMH-GI 5，000 BP病例确定的受试者。随着BP和8 q24关联的鉴定、复制和表征，我们将处于有利地位，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.