1/2 Rare Bipolar Loci identification through Synaptome Sequencing

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。该项目将利用下一代测序负责人、BP遗传学专家和Synapse神经生物学专家的人才。我们希望共同发现罕见的BP易感变异。BP是全球第六大致残原因，具有高度的遗传性。BP的分子遗传学工作目前专注于发现常见的疾病变异。然而，前四次全基因组关联(GWA)扫描令人失望，没有产生全基因组的显著信号，尽管在联合分析中有一个信号超过了这个阈值。有趣的是，该分析中最强的两个基因编码突触蛋白，在对其中两项GWA研究的路径分析中，最显著丰富的基因集是突触传递。我们建议确定编码突触组成部分的基因的遗传变异，包括神经递质及其受体、黏附/细胞骨架蛋白和支架蛋白。测序技术的进步和针对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个对照的1,500个突触体基因的外显子和启动子进行重新排序，并类似地筛选来自我们最大的BP家族和40个对照的80个先证者的整个外显子。在目标2中，我们将从生物信息学上评估变异对功能的可能影响，并将病例中的变异与800个对照中的变异(我们的测序对照加上1000基因组计划测序的400个)进行比较，以确定基因和/或簇是否对罕见的有害变异进行了浓缩。我们将类似地比较80例患者和80名对照的全外显子变异。在目标3中，我们将对携带可能易感变异的AIM 1先证者的大家族进行基因分型，以评估是否存在连锁，并对1,600例患者和1,600名对照进行基因分型，以复制BP功能变异的基因和聚集性浓缩。我们还将对基因的一个子集进行重新排序，以复制功能变异的BP富集区。我们的研究提供了发现的可能性，不仅是与BP易感变异连锁不平衡的变异，还有功能性疾病变异本身。此外，重要的是要强调的是，绝大多数精神药物调节突触机制。因此，我们认为编码突触蛋白的BP基因的发现具有非常高的翻译潜力，因为这些基因可能代表BP中最“可用药”的靶标。 公共卫生相关性： 项目叙述这是一项提议，通过对大脑突触中编码蛋白质的所有已知基因进行测序，采用一种新的方法来研究双相情感障碍的遗传学。我们的研究提供了发现的可能性，不仅是位于那些赋予双相情感障碍易感性的基因变异附近，而且是实际的疾病变异本身。此外，重要的是要强调的是，绝大多数精神药物调节大脑突触机制。因此，我们认为，发现编码突触蛋白的双相情感障碍基因具有非常高的翻译潜力，因为这些基因可能代表了双相情感障碍中最易“下药”的靶点。)

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. )