2/2-Rare Bipolar Loci Identification Through Synaptome Sequencing.

通过突触组测序鉴定 2/2-罕见双极基因座。

• 批准号: 8116675
• 负责人: William Richard McCombie
• 金额: $ 103.95万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-23 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116675
• 关键词: Alleles; Area; Biology; Bipolar Disorder; Brain; Chronic; Code; Complement; Cytoskeletal Proteins; DNA Resequencing; Diabetes Mellitus; Disease; Disease Pathway; Etiology; Exons; Extended Family; Family; Functional disorder; Gene Cluster; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Heritability; Lead; Linkage Disequilibrium; Mental disorders; Meta-Analysis; Molecular; Molecular Genetics; Neurobiology; Neurotransmitters; Pathway Analysis; Patients; Pharmaceutical Preparations; Predisposition; Proteins; Recurrence; Scaffolding Protein; Signal Transduction; Specialist; Synapses; Synaptic Transmission; Talents; Technology; Testing; Therapeutic; Variant; Work; adhesion receptor; cost; disability; exome; genetic variant; genome wide association study; genome-wide; next generation; novel strategies; proband; promoter; public health relevance; research study; segregation; success

DESCRIPTION (provided by applicant): PROJECT SUMMARY This is a proposal to take a novel approach to the genetics of bipolar disorder (BP) through sequencing of all known synaptic genes (the synaptome). The project will take advantage of the talents of a next-generation sequencing leader, a BP genetics expert, and a synapse neurobiology specialist. Together we hope to discover rare BP susceptibility variants. BP, the sixth-leading cause of disability worldwide, is highly heritable. Molecular genetics work in BP is currently focused on uncovering common disease variants. The first four genome-wide association (GWA) scans have, however, been disappointing yielding no genome-wide significant signals, although one signal surpassed that threshold in a combined analysis. Interestingly, the two strongest genes in that analysis encode synaptic proteins, and in a pathway analysis of two of these GWA studies, the most significantly enriched gene set was for synaptic transmission. We propose to determine the genetic variation in genes encoding components of the synapse including neurotransmitters and their receptors, adhesion/cytoskeletal proteins and scaffold proteins. Advances in sequencing technology and the ability to target specific genomic areas will allow us, in Aim 1, to resequence exons and promoters of 1,500 synaptome genes in 800 BP probands and 400 controls, and to similarly screen the whole exome in 80 probands from our largest BP families and from 40 controls. In Aim 2 we will bioinformatically assess the likely functional impact of variants, and compare variation in cases to variation in 800 controls (our sequenced controls plus 400 sequenced by the 1000 Genomes Project) to determine whether genes and/or clusters are enriched for rare deleterious variants. We will similarly compare whole-exome variation in 80 cases and 80 controls. In Aim 3 we will genotype extended families of Aim 1 probands carrying likely susceptibility variants to assess for linkage, and genotype 1,600 cases and 1,600 controls to replicate gene and cluster enrichment of functional variants in BP. We will also resequence in a subset of genes to replicate enrichment in BP of functional variants. Our study holds out the possibility of finding, not merely variants in linkage disequilibrium with BP susceptibility variants, but the functional disease variants themselves. Further, it is important to emphasize that the great majority of psychiatric drugs modulate synaptic mechanisms. We therefore consider that discovery of BP genes encoding synaptic proteins has very high translational potential as these potentially represent the most "druggable" targets in BP. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE This is a proposal to take a novel approach to the genetics of bipolar disorder through sequencing of all known genes that code for proteins in the brain's synapses. Our study holds out the possibility of finding, not merely gene variants that lie near those that confer susceptibility to bipolar disorder, but the actual disease variants themselves. Further, it is important to emphasize that the great majority of psychiatric drugs modulate brain synapse mechanisms. We therefore consider that discovery of bipolar disorder genes encoding synaptic proteins has very high translational potential as these potentially represent the most "druggable" targets in bipolar disorder. )

描述（由申请人提供）： 这是一项通过对所有已知的突触基因（突触体）进行测序来研究双相情感障碍（BP）遗传学的新方法的提议。该项目将利用下一代测序领导者、BP遗传学专家和突触神经生物学专家的才能。我们希望共同发现罕见的BP易感性变体。BP是全球第六大残疾原因，具有高度遗传性。BP的分子遗传学工作目前专注于发现常见疾病的变异。然而，前四次全基因组关联（GWA）扫描令人失望，没有产生全基因组显著信号，尽管在联合分析中有一个信号超过了该阈值。有趣的是，在该分析中，两个最强的基因编码突触蛋白，并且在其中两项GWA研究的通路分析中，最显着富集的基因集是突触传递。我们建议确定基因编码的突触组件，包括神经递质及其受体，粘附/细胞骨架蛋白和支架蛋白的遗传变异。测序技术的进步和靶向特定基因组区域的能力将使我们能够在目标1中对800个BP先证者和400个对照中的1，500个突触组基因的外显子和启动子进行重测序，并类似地筛选来自我们最大的BP家族的80个先证者和40个对照中的整个外显子组。在目标2中，我们将从生物信息学的角度评估变异的可能功能影响，并将病例中的变异与800个对照中的变异进行比较（我们测序的对照加上1000个基因组计划测序的400个对照），以确定基因和/或簇是否富含罕见的有害变异。我们将类似地比较80例病例和80例对照的全外显子组变异。在目标3中，我们将对携带可能的易感性变体的目标1先证者的大家族进行基因分型以评估连锁，并对1，600例病例和1，600例对照进行基因分型以复制BP中功能变体的基因和簇富集。我们还将在一个基因子集中重新测序，以复制功能变体的BP富集。我们的研究提供了发现的可能性，不仅是与BP易感性变体连锁不平衡的变体，而且是功能性疾病变体本身。此外，重要的是要强调，绝大多数精神药物调节突触机制。因此，我们认为，BP基因编码突触蛋白的发现具有非常高的翻译潜力，因为这些潜在的代表最“可药”的目标BP。 公共卫生相关性： 这是一个通过对大脑突触中编码蛋白质的所有已知基因进行测序来对双相情感障碍的遗传学采取新方法的提议。我们的研究提供了发现的可能性，不仅是那些与双相情感障碍易感性相关的基因变异，而且是实际的疾病变异本身。此外，重要的是要强调，绝大多数精神药物调节脑突触机制。因此，我们认为，双相情感障碍基因编码突触蛋白的发现具有非常高的翻译潜力，因为这些潜在的代表了最“可药”的目标，在双相情感障碍。)