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: 8006117
• 负责人: William Richard McCombie
• 金额: $ 113.53万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006117
• 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）： 项目摘要这是一项提议，是通过对所有已知突触基因（突触器）的测序来采用新颖的躁郁症遗传学方法（BP）。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敏感性变体。 BP是全球残疾的第六个领先原因，是高度遗传的。 BP中的分子遗传学工作目前侧重于发现常见的疾病变异。然而，尽管在组合分析中，一个信号超过了该阈值，但前四个全基因组关联（GWA）扫描仍令人失望，但没有产生全基因组的重要信号。有趣的是，该分析中的两个最强基因编码突触蛋白，以及对其中两项GWA研究的途径分析，最显着富集的基因集用于突触传播。我们建议确定编码突触成分的基因的遗传变异，包括神经递质及其受体，粘附/细胞骨架蛋白和支架蛋白。测序技术的进步和靶向特定基因组区域的能力将使我们以AIM 1的形式重新设置800 bp概率和400个对照的1,500个突触器基因的外显子和启动子，并类似地将整个外显子筛选为80个概率， BP家庭和40个控件。在AIM 2中，我们将生物信息评估变体的可能功能影响，并将病例的变化与800个控件的变异（我们的测序对照组以及由1000个基因组项目测序的400个）的变化，以确定基因和/或簇是否富含稀有有害的基因和/或簇变体。我们将类似地比较80例和80个对照中的全外观变化。在AIM 3中，我们将基因型的AIM 1概率的扩展家族携带可能的敏感性变体来评估连锁，以及基因型1,600例和1,600个对照，以复制BP中功能变体的基因和群集富集。我们还将在基因的一部分中重新复制功能变体BP的富集。我们的研究提出了发现的可能性，不仅是与BP易感性变异的连锁不平衡的变体，而且是功能性疾病变异本身。此外，重要的是要强调，绝大多数精神药物都会调节突触机制。因此，我们认为编码突触蛋白的BP基因具有很高的转化潜力，因为这些潜在代表了BP中最“可药的”靶标。 公共卫生相关性： 项目叙述这是一项建议，通过对所有已知基因进行测序，以对大脑突触中的蛋白质进行编码，以采用新颖的方法来解决躁郁症的遗传学。我们的研究提出了发现的可能性，不仅是赋予对双相情感障碍易感性的基因变异，而且是实际疾病变体本身。此外，重要的是要强调，绝大多数精神药物调节脑突触机制。因此，我们认为，编码突触蛋白的双相情感障碍基因的发现具有很高的转化潜力，因为这些潜在代表了躁郁症中最“可药的”靶标。 ）