Genetic Linkage and Association in Bipolar Disorder

双相情感障碍的遗传连锁和关联

• 批准号: 8745720
• 负责人: Francis J McMahon
• 金额: $ 71.42万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745720
• 关键词: 3' Untranslated Regions; Action Potentials; Alleles; Area; Autopsy; Bioinformatics; Biological; Biological Models; Biology; Bipolar Disorder; Blood; Brain; Brain imaging; Cause of Death; Cell Line; Cell model; Cells; Cessation of life; Chromosomes; Circadian Rhythms; Clinical; Collaborations; Communities; Corpus Callosum; DNA; Data; Data Analyses; Databases; Development; Disease; Family; Fibroblasts; Gene Chips; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Heterogeneity; Genetic Identity; Genetic Variation; Genome; Goals; Heritability; Hippocampus (Brain); Image; Individual; Institutional Review Boards; Laboratories; Life; Light; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Mental disorders; Methods; Modeling; Molecular Profiling; Mood Disorders; Morphology; National Heart, Lung, and Blood Institute; National Institute of Mental Health; Neuroglia; Neuronal Plasticity; Neurons; Nuclear Family; Occupational; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Point Mutation; Positron-Emission Tomography; Public Health; Regenerative Medicine; Research Support; Resources; Risk; Risk Factors; Role; Sampling; Schizophrenia; Scientist; Second Messenger Systems; Siblings; Skin; Source; Suicide; Symptoms; Testing; Tissues; Toxin; Transcript; United States National Institutes of Health; Use of New Techniques; Variant; Work; age group; base; brain cell; brain tissue; disability; early onset; endophenotype; exome sequencing; functional genomics; genetic association; genetic linkage; genetic variant; genome wide association study; genome-wide; healthy volunteer; high end computer; induced pluripotent stem cell; insertion/deletion mutation; neuroimaging; novel; phenome; proband; programs; research study; response; risk variant; severe mental illness; social; stem cell technology; tool; transcriptome sequencing; volunteer

IRB 80-M-0083 NCT00001174 This collaboration has developed a bipolar disorder family resource that has proven to be uniquely valuable in testing clinically-based hypotheses about the genetic heterogeneity of the illness. We have ascertained and assessed about 150 nuclear families with a bipolar I proband and two or more siblings with a major affective disorder. One important goal is to derive and test genetically meaningful clinical subtypes. We previously generated a database of clinical variables, The Bipolar Disorder Phenome Database, based in part on this sample. The database contains several hundred clinical variables, harmonized with those collected by the NIMH Genetics Initiative, describing the course, symptoms, and clinical picture of bipolar disorder. We have made the database available to the scientific community to support research into the genetics of bipolar disorder and related conditions. In collaboration with scientists at Cold Spring Harbor Laboratory and UCSD, we have used cutting-edge genetic tools to search for relatively small structural variations in chromosomes, known as copy number variants (CNVs), that may play a role in bipolar disorder. Using a set of trios we collected with collaborators, we found evidence that some CNVs strongly over-represented among people with schizophrenia may also play a role in bipolar disorder, especially in an early-onset form. In the coming year, we plan to perform exome sequencing on the same set of trios in order to detect damaging insertions, deletions, and point mutations that arise de novo and may contribute to the risk for bipolar disorder or modify its clinical presentation. In order to better interpret the impact of genetic variation on the brain biology of bipolar disorder, we are pursuing a variety of functional genomics studies, including brain imaging, microarray gene expression and RNA-seq in post-mortem brain tissue, and cellular phenotyping of neurons derived from induced pluripotent stem cells. Neuroimaging genetics work over the past year has focused on structural imaging as well as positron emission tomography (PET). We contributed data to the ENIGMA brain imaging consortium, which detected SNPs associated with hippocampal volume. This important endophenotype may shed light on the mechanisms whereby common genetic variants influence risk for psychiatric disorders. We also used magnetic resonance imaging (MRI) data from volunteers with major depressive or bipolar disorder, along with healthy volunteers, to assess the heritability of corpus callosum(CC) size and the genetic correlations among anatomical sub regions of the CC among individuals with and without mood disorders. Significant heritability was found for several sub-regions, with strong and significant genetic correlations among most sub-regions. Distinct genetic factors seem to be involved in caudal and rostral regions, consistent with the divergent functional specialization of the brain areas. In the coming year we plan to use genome-wide SNP data to assess heritability and genetic correlations of brain imaging phenotypes, exploiting new developments in genetic identity-by-state methods. We have also carried out the first study to use the new technique of RNA-seq to characterize the transcribed portion of the genome (transcriptome) in bipolar disorder. The resulting data were analyzed using several bioinformatics tools on high-performance computers at NIH. This study highlighted several genes and transcripts that were involved in dysregulation of neuroplasticity, circadian rhythms and second-messenger systems in bipolar disorder. In the coming year we will analyze the data for allele-specific expression, extended brain-specific 3 untranslated regions, (UTRs) novel, brain-expressed genes that may be involved in bipolar disorder. Over the past year we have also begun experiments aimed at modeling functional genomics of disease-related genes in cells derived from induced pluripotent stem cell (iPSC) lines. This project, led by Staff Scientist Sevilla-Detera-Wadleigh, aims to explore the ways in which we can use iPSC technology to study the biological impact of genes and genetic mutations that we identify in our other ongoing studies. Working with the NIH Center for Regenerative Medicine and the iPSC core of NHLBI we have so far successfully reprogrammed fibroblasts from 5 different individuals; we are also studying lines reprogrammed in collaborating labs. We are differentiating the cells into neurons and glia, and characterizing their morphology, action potential, gene expression profiles, and response to drugs and toxins. Careful analysis of these phenotypes could reveal differences between control and patient-derived cells, but we are also exploring ways to measure the functional impact of genetic mutations at the cellular level and to use genome editing tools such as TALENs to assess rescue phenotypes.

IRB 80-M-0083 NCT00001174 此次合作开发了双相情感障碍家庭资源，该资源已被证明在测试有关疾病遗传异质性的临床假设方面具有独特的价值。 我们已经确定并评估了大约 150 个核心家庭，其中有 I 型双相情感障碍先证者和两个或更多患有严重情感障碍的兄弟姐妹。一个重要的目标是衍生和测试具有遗传意义的临床亚型。 我们之前部分基于该样本生成了一个临床变量数据库，即双相情感障碍表型数据库。该数据库包含数百个临床变量，与 NIMH 遗传学倡议收集的变量一致，描述了双相情感障碍的病程、症状和临床情况。我们已向科学界提供该数据库，以支持双相情感障碍和相关疾病的遗传学研究。 我们与冷泉港实验室和加州大学圣地亚哥分校的科学家合作，使用尖端的遗传工具来寻找染色体中相对较小的结构变异，称为拷贝数变异（CNV），它可能在双相情感障碍中发挥作用。使用我们与合作者收集的一组三重奏，我们发现证据表明，在精神分裂症患者中比例过高的一些 CNV 也可能在双相情感障碍中发挥作用，尤其是在早发性双相情感障碍中。来年，我们计划对同一组三人组进行外显子组测序，以检测从头出现的破坏性插入、缺失和点突变，这些突变可能会增加双相情感障碍的风险或改变其临床表现。 为了更好地解释遗传变异对双相情感障碍脑生物学的影响，我们正在进行各种功能基因组学研究，包括脑成像、死后脑组织中的微阵列基因表达和RNA-seq，以及细胞表型分析。源自诱导多能干细胞的神经元。 过去一年的神经影像遗传学工作主要集中在结构成像和正电子发射断层扫描（PET）上。我们向 ENIGMA 脑成像联盟贡献了数据，该联盟检测到了与海马体积相关的 SNP。这种重要的内表型可能揭示常见遗传变异影响精神疾病风险的机制。我们还使用来自患有重度抑郁症或双相情感障碍的志愿者以及健康志愿者的磁共振成像 (MRI) 数据来评估胼胝体 (CC) 大小的遗传力以及患有和无情绪障碍。多个子区域具有显着的遗传力，大多数子区域之间具有很强且显着的遗传相关性。尾部和喙部区域似乎涉及不同的遗传因素，这与大脑区域不同的功能专业化一致。来年，我们计划利用全基因组 SNP 数据来评估大脑成像表型的遗传力和遗传相关性，利用遗传身份状态方法的新发展。 我们还开展了第一项研究，利用RNA-seq新技术来表征双相情感障碍基因组的转录部分（转录组）。使用 NIH 高性能计算机上的多种生物信息学工具对所得数据进行了分析。这项研究强调了与双相情感障碍的神经可塑性、昼夜节律和第二信使系统失调有关的几个基因和转录本。来年，我们将分析等位基因特异性表达、扩展的大脑特异性 3 个非翻译区 (UTR)、可能与双相情感障碍有关的新的大脑表达基因的数据。 在过去的一年里，我们还开始了旨在对诱导多能干细胞（iPSC）系细胞中疾病相关基因的功能基因组进行建模的实验。 该项目由科学家 Sevilla-Detera-Wadleigh 领导，旨在探索如何使用 iPSC 技术来研究我们在其他正在进行的研究中发现的基因和基因突变的生物学影响。 迄今为止，我们与 NIH 再生医学中心和 NHLBI 的 iPSC 核心合作，已成功对 5 个不同个体的成纤维细胞进行了重编程；我们还在合作实验室研究重新编程的生产线。我们正在将细胞分化为神经元和神经胶质细胞，并表征它们的形态、动作电位、基因表达谱以及对药物和毒素的反应。对这些表型的仔细分析可以揭示对照细胞和患者来源的细胞之间的差异，但我们也在探索在细胞水平上测量基因突变的功能影响的方法，并使用 TALEN 等基因组编辑工具来评估救援表型。