Fine mapping 8q24 in Familial Bipolar Disorder

家族性双相情感障碍中 8q24 的精细定位

• 批准号: 6869005
• 负责人: MELVIN G MCINNIS
• 金额: $ 34.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-20 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869005
• 关键词: behavioral genetics; bipolar depression; clinical research; family genetics; genetic susceptibility; genotype; human genetic material tag; linkage mapping; microarray technology; nucleic acid sequence; patient oriented research; psychobiology; single nucleotide polymorphism

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.

描述（由申请人提供）：这是一项修订后的提案，旨在鉴定位于染色体 8q24 上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/对照设计中复制该关联。有充分证据表明 8q24 上存在易感基因。我们报告了 65 个多重双极家族中 8q24 上的 D8S256 的参数 2 点 LOD 为 3.32，这在全基因组范围内都很重要。我们正在与安特卫普大学的研究人员合作，他们也拥有与 8q24 连锁的全基因组证据。我们的复制样本将来自 NIMH 双相情感障碍遗传学计划 (NiMH-GI BP) 的谱系。我们将使用最近发表的方法，从 NIMH-GI BP 家族中选择具有 D8S256 位点周围等位基因共享增加的证据的病例，并在遗传分析程序 Merlin 中实施，从而丰富我们的 8q24 遗传病例的复制样本。初步分析发现 NIMH-GI BP 中 284 个家系的 8q24 等位基因共享增加。我们将使用在 NIMH-GI 的支持下确定的类似数量的控制措施。安特卫普大学的研究人员也在积极探索该地区，他们已同意在他们的样本中测试我们的积极关联发现。这很有吸引力，因为安特卫普样本主要来自北欧，与霍普金斯和 NIMH 样本类似。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，样本足以满足我们的阈值，要求在基于家族的分析中显着性p<0.001，在NIMH-GI病例/对照样本中要求显着性p<0.01。我们在安特卫普样本中添加了第三个显着性阈值水平 p<0.01。满足这些标准将为该附近存在易感基因提供令人信服的论据。我们建议采用霍普金斯大学现有的基于 Illumina 阵列的技术进行工业规模的 SNP 基因分型，将 1,536 个 SNP 放置在 14 Mb 的区域中，SNP 之间的平均间隔为 10 kb。我们将从 Hopkins/Dana 样本的基因分型开始，并跟踪源自关联 NIMH-GI BP 谱系的病例/对照样本中的阳性区域。随后将在安特卫普样本中测试这些分析的显着关联（安特卫普无需资助）。如果该区域被复制，我们将开始对霍普金斯和 NIMH 样本中带有风险等位基因或单倍型的受影响受试者的峰值周围进行测序，目标是识别紧邻复制结果的所有 SNP 变体。然后，测序中识别出的变异将在更大的样本中进行分类，根据本提案的结论，这些样本将包括来自当前 NIMH-GI 5,000 BP 病例确定的受试者。通过对 BP 和 8q24 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。