1/2 Rare Bipolar Loci identification through Synaptome Sequencing

通过突触组测序鉴定 1/2 罕见双极基因座

基本信息

批准号：
8626447
负责人：
James B. Potash
金额：
$ 43.75万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-23 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8626447
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 sequencing novel strategies proband promoter public health relevance rare variant research study segregation success

项目摘要

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.

描述（由申请人提供）：项目摘要这是一项通过对所有已知的突触基因（突触组）进行测序来研究双相情感障碍 (BP) 遗传学的新方法的提案。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血压易感性变异。 BP 是全球第六大致残原因，具有高度遗传性。 BP 的分子遗传学工作目前侧重于发现常见疾病变异。然而，前四次全基因组关联（GWA）扫描令人失望，没有产生全基因组显着信号，尽管在组合分析中一个信号超过了该阈值。有趣的是，该分析中最强的两个基因编码突触蛋白，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基因。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 个对照中的 1,500 个突触组基因的外显子和启动子进行重新测序，并类似地筛选来自我们最大的 80 个先证者的整个外显子组。 BP 家族和 40 名对照者。在目标 2 中，我们将以生物信息学方式评估变异可能的功能影响，并将病例变异与 800 个对照（我们的测序对照加上 1000 个基因组计划测序的 400 个）的变异进行比较，以确定基因和/或簇是否富含罕见有害物质。变种。我们将类似地比较 80 个病例和 80 个对照的全外显子组变异。在目标 3 中，我们将对目标 1 先证者的大家族携带可能的易感性变异进行基因分型，以评估连锁，并对 1,600 个病例和 1,600 个对照进行基因分型，以复制 BP 中功能变异的基因和聚类富集。我们还将对一部分基因进行重新测序，以复制功能变异的 BP 富集。我们的研究不仅有可能发现与血压易感性变异连锁不平衡的变异，而且有可能发现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转化潜力，因为它们可能代表 BP 中最“可成药”的靶标。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A hybrid likelihood model for sequence-based disease association studies.

用于基于序列的疾病关联研究的混合可能性模型。

DOI：
发表时间：
2013
期刊：
影响因子：
4.5
作者：
Chen, Yun;Carter, Hannah;Parla, Jennifer;Kramer, Melissa;Goes, Fernando S;Pirooznia, Mehdi;Zandi, Peter P;McCombie, W Richard;Potash, James B;Karchin, Rachel
通讯作者：
Karchin, Rachel

Validation and assessment of variant calling pipelines for next-generation sequencing.

验证和评估用于下一代测序的变体调用管道。

DOI：
发表时间：
2014-07-30
期刊：
影响因子：
4.5
作者：
Pirooznia, Mehdi;Kramer, Melissa;Parla, Jennifer;Goes, Fernando S;Potash, James B;McCombie, W Richard;Zandi, Peter P
通讯作者：
Zandi, Peter P

A probabilistic model to predict clinical phenotypic traits from genome sequencing.

通过基因组测序预测临床表型特征的概率模型。

DOI：
发表时间：
2014-09
期刊：
影响因子：
4.3
作者：
Chen, Yun;Douville, Christopher;Wang, Cheng;Niknafs, Noushin;Yeo, Grace;Beleva;Carter, Hannah;Stenson, Peter D;Cooper, David N;Li, Biao;Mooney, Sean;Karchin, Rachel
通讯作者：
Karchin, Rachel

New developments in the genetics of bipolar disorder.

双相情感障碍遗传学的新进展。