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）：这是一项修订建议，旨在识别位于与双相情感障碍相关的8q24染色体上的易感性或基因组区域。它使用基于关联的方法来识别家庭样本中的关联并在案例/控制设计中复制关联。有很好的证据证明了8q24上的敏感性基因。我们报道了65个多重双极家族中的D8S256的参数2-PT LOD在D8S256上为3.32，全基因组很重要。我们正在与美国安特卫普的调查员合作，他们也有与第8季度联系的基因组的证据。我们的复制样本将源自NIMH遗传学的躁郁症（NIMH-GI BP）的谱系。我们将从NIMH-GI BP家族中选择案例，这些病例是使用最近发表的方法在遗传分析计划（Merlin）中实施的D8S256基因座增加等位基因共享的证据，从而丰富了8q24遗传病例的复制样本。初步分析发现284个血统，在NIMH-GI BP中的第8季度共享等位基因共享增加。我们将使用在NIMH-GI的主持下确定的类似数量的控件。 U Antwerp的调查人员也在积极追求该地区，他们同意在样本中测试我们的积极关联发现。这很有吸引力，因为Antwerp样品主要是欧洲猪笼草。基于实际的谱系结构和我们的案例/控制设计的初步功率分析发现，样品足以满足我们的阈值，在家庭分析中需要显着性p <0.001，而在NIMH-GI案例/对照样本中需要P <0.01。我们在安特卫普样品中添加了p <0.01的第三个显着性阈值水平。符合这些标准将对在这个附近存在易感基因的存在引起令人信服的论点。我们使用基于Illumina Array的技术在霍普金斯（Hopkins）提供的基于Illumina Array的技术提出了SNP基因分型，在14 MB区域将1,536个SNP放置在14 MB区域，SNP之间平均为10 kb的间隔。我们将从基因分型霍普金斯/DANA样本开始，然后跟踪从链接的NIMH-GI BP谱系中得出的病例/对照样本中的正区域。这些分析的显着关联将随后在安特卫普样本中进行测试（不要求安特卫普的资金）。如果复制该区域，我们将开始在霍普金斯和NIMH样品中围绕具有风险等位基因或单倍型的NIMH样本的受试者的峰进行排序，其目标是识别与复制结果相邻的所有SNP变体。然后将在测序中鉴定出的变体在较大的样本中键入，通过该提案的结论将包括当前NIMH-GI 5,000 bp案例确定的受试者。通过鉴定，复制和表征BP和8Q24的关联，我们将处于强大的位置，以追求进一步的基因和功能研究。