Identification of Genes Involved in Major Mood Disorders

鉴定与主要情绪障碍相关的基因

• 批准号: 8939979
• 负责人: Francis J McMahon
• 金额: $ 128.71万
• 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/8939979
• 关键词: 3p21; 5' Untranslated Regions; Adoption; Affect; Alleles; Amish; Attention deficit hyperactivity disorder; Biopsy; Bipolar Disorder; Blood specimen; Case-Control Studies; Cause of Death; Cells; Cessation of life; Child; Chromosomes; Chromosomes, Human, Pair 21; Clinical Data; Code; Cognitive; Collaborations; Collection; Communities; DNA; DNA Repository; DNA analysis; Data Set; Diagnosis; Diagnostic; Disease; Distant; Emotional; Family; Fibroblasts; Functional RNA; Functional disorder; Gene Cluster; Gene Expression Regulation; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Goals; Individual; Inherited; Institutes; Institutional Review Boards; International; Interview; Life; Lithium; Major Depressive Disorder; Mennonite; Mental disorders; Meta-Analysis; Methods; Modeling; Mood Disorders; Mutation; National Institute of Mental Health; Nuclear Family; Occupational; Parents; Parkinson Disease; Participant; Pathway interactions; Patients; Play; Population; Predictive Value; Prevention; Process; Protocols documentation; Recording of previous events; Recruitment Activity; Relative (related person); Resources; Risk; Risk Factors; Role; Sampling; Schizophrenia; Signal Transduction; Site; Skin; Source; Suicide; Symptoms; Systems Biology; Technology; Testing; Therapeutic Effect; Twin Multiple Birth; United States; Universities; Untranslated RNA; Variant; Work; X Chromosome; age group; base; case control; clinical risk; cohort; disability; exome; exome sequencing; functional genomics; genetic linkage; genetic pedigree; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genome-wide; high risk; induced pluripotent stem cell; insertion/deletion mutation; instrument; kindred; lymphoblastoid cell line; member; nervous system disorder; neuronal excitability; novel; offspring; promoter; rare variant; response; risk variant; severe mental illness; social; treatment response

IRB Protocol 80-M-0083 NCT00001174 Starting in 1993, in collaboration with 10 academic centers across the United States, we recruited a large sample of over 3,000 individuals with bipolar or related mood disorders. All participants did a diagnostic interview and provided a blood sample for DNA analysis. DNA and clinical data are available through the NIMH Center for Genetics. Genetic linkage studies suggested several chromosomal regions may contain genes that contribute to mood disorders in this sample. To identify individual causal genes, we conducted the first genome-wide association study of bipolar disorder in 2007. The results implicated several genes, each of small effect, suggesting that bipolar disorder is a polygenic disease. Our 2011 meta-analysis of independent case-control studies of bipolar disorder supported association with a cluster of genes on chromosome 3p21, markers near TRANK1, LMAN2L, and PTGFR, and 2 independent regions of ANK3 implicated in previous studies. Many of these findings have now been replicated in independent samples. Ongoing work, supported by NARSAD, is using genome-wide association methods in large samples of cases and controls to detect additional risk genes on the X-chromosome, which has so far been little studied in bipolar disorder by GWAS methods. We have shown that models based on large numbers of markers can distinguish between cases and controls in independent datasets with high significance, but only modest predictive value. These studies also suggest that common alleles predisposing to bipolar disorder also predispose to major depression and schizophrenia, but not to neurological diseases such as Parkinson Disease. Collaborative work we did with the Cross-Disorder Group of the Psychiatric Genomics Consortium has confirmed that there are substantial genetic correlations between schizophrenia and bipolar disorder, schizophrenia and major depressive disorder, bipolar and major depressive disorder, and between ADHD and major depressive disorder. These results point to shared genetic risk factors among major psychiatric disorders that may reflect shared pathophysiologies. To identify genetic variants that may have a larger impact on individual risk for major mood disorders, we have undertaken genome sequencing studies in selected populations with reduced genetic diversity and large families. Large families increase the opportunities for ascertaining distant relatives with a mood disorder, and individuals belonging to different nuclear families are often related, forming an extended kindred ideal for genome sequencing studies. So far we have collected close to 1400 individuals from Amish and Mennonite communities whose unique genetic history makes them especially good candidates for this kind of study. All blood samples are processed by the Rutgers Cell and DNA Repository who also establish lymphoblastoid cell lines and distribute DNA as a resource for the general scientific community. We will also continue to collect families as they are identified. Our goal is to collect at least 100 additional cases, along with their parents and offspring. Offspring are studied in collaboration with Dr Leibenluft's group at NIMH IRP, which performs additional cognitive and emotional testing on these high-risk children. Genome sequencing began in 2012 using technology that captured only the exome, or the expressed portions of the genome. So far we have completed about 80 exome sequences in individuals of Amish or Mennonite ancestry. Although no rare, damaging mutations have been found that are shared by the majority of cases in our study, we have identified over 1000 promising variants shared by distantly-related cases. These have been submitted to the Bipolar Sequencing Consortium (BSC) where they will become part of a large meta-analysis of sequenced cases, controls, and families. Skin biopsies are obtained on sequenced individuals and converted to fibroblasts. Several fibroblast lines have been reprogrammed into induced pluripotent stem cells (iPSc) for functional genomic studies. Last year, with support and collaboration from the Institute of Systems Biology (ISB), we completed whole genome sequence on 105 individuals from the collection. Ongoing analyses are aimed at detecting genetic variants that influence BD risk by virtue of their impact on gene regulation. We are also examining small deletions and insertions that can be readily detected in whole genome sequence. Those that overlap known genes and tend to segregate with mood disorders in families may be particularly important. Also in collaboration with ISB, and the Bipolar Disorder Genome Study (BiGS), we have analyzed whole-genome sequences performed on 200 members of 41 families multiply affected with bipolar disorder. Several classes of coding and non-coding (regulatory) variants segregating in these pedigrees were enriched for neuronal excitability genes. Most affected individuals inherited several of these variants, suggesting that genetic risk is generally oligogenic. Targeted sequencing of 26 neuronal excitability genes in an additional 3457 cases and 2384 controls confirmed rare-variant burdens in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, and CAMK2A. Variants in promoters and 3 and 5 untranslated regions contributed more strongly than coding variants to risk for bipolar disorder, both in pedigrees and in the case-control cohort. Ongoing work is aimed at confirming these findings in additional samples and characterizing the functional impact of the implicated genetic variants. If confirmed, these results could have important implications for our understanding of the causes of bipolar disorder and provide clues for better treatment. We are also searching for genetic markers that might help predict an individual's response to lithium, one of the most effective known treatments for bipolar disorder. To this end, we organized a large international collaboration, known as the Consortium on Lithium Genetics (ConLiGen), which aims to characterize lithium response in a large group of patients using reliable instruments, and then perform a genome-wide association study. In collaboration with the University of Bonn, we completed genome-wide SNP array genotyping on over 3000 cases. Association analysis was performed using definitions of lithium response that showed high inter-site reliability. We identified a genome-wide significant signal in a region on chromosome 21 that appears to encode a long-noncoding RNA molecule. Individuals with the response-associated markers were 50% more likely to respond to lithium. Ongoing work will test this finding for replication in additional samples. If replicated, these results would point to a novel pathway whereby lithium exerts its therapeutic effects on bipolar disorder.

IRB协议80-m-0083 NCT00001174 从1993年开始，与美国的10个学术中心合作，我们招募了3,000多名双极或相关情绪障碍的人。所有参与者进行了诊断访谈，并提供了血液样本进行DNA分析。 DNA和临床数据可通过NIMH遗传学中心获得。 遗传连锁研究表明，几个染色体区域可能包含有助于该样品中情绪障碍的基因。为了鉴定单个因果基因，我们在2007年进行了全基因组躁郁症的首次基因组关联研究。结果暗示了几种基因，每个基因都很小，这表明躁郁症是一种多基因疾病。我们2011年对双相情感障碍的独立病例对照研究的荟萃分析支持与先前研究中有关的ANK3的染色体3p21，Trank1，Lman2L和PTGFR附近的标记，LMAN2L和PTGFR附近的标记以及2个独立区域的关联。这些发现中的许多现已在独立样本中复制。 NARSAD支持的正在进行的工作正在使用大量病例和对照样本中使用全基因组关联方法来检测X染色体上的其他风险基因，到目前为止，GWAS方法在双相情感障碍中很少研究。 我们已经表明，基于大量标记的模型可以区分具有很高意义但仅适度预测值的独立数据集中的情况和对照。这些研究还表明，偏爱躁郁症的常见等位基因也易于严重抑郁和精神分裂症，但不易受诸如帕金森病等神经系统疾病。我们与精神病基因组学联盟的跨疾病组进行的协作工作已经证实，精神分裂症与双相情感障碍，精神分裂症和重度抑郁症，双极和重度抑郁症，ADHD和ADHD和主要抑郁症之间存在实质性的遗传相关性。这些结果表明，主要的精神疾病中共有的遗传危险因素可能反映了共同的病理生理。 为了确定可能对主要情绪障碍的个人风险产生更大影响的遗传变异，我们对遗传多样性降低和大家庭的选定人群进行了基因组测序研究。大家庭增加了确定患有情绪障碍的遥远亲戚的机会，而属于不同核家庭的个人通常是相关的，这是基因组测序研究的理想选择。到目前为止，我们已经收集了来自阿米什人和门诺派社区的近1400个人，这些人的独特遗传史使他们特别良好的候选人进行了此类研究。所有血液样本均由Rutgers细胞和DNA存储库处理，他们还建立了淋巴细胞细胞系并将DNA作为一般科学界的资源分配。我们还将在确定的家庭中继续收集家庭。我们的目标是与父母和后代一起收集至少100个案例。与Nimh IRP的Leibenluft小组合作研究了后代，该小组对这些高风险儿童进行了额外的认知和情感测试。 基因组测序始于2012年，使用仅捕获外显子组或基因组表达部分的技术。到目前为止，我们已经完成了阿米什人或门诺派血统的个体中约80个外显子序列。尽管没有发现大多数病例中大多数案例共享的罕见，破坏性突变，但我们已经确定了超过1000种与遥远相关病例共享的有希望的变体。这些已提交给双极测序联盟（BSC），它们将成为对测序病例，对照组和家族进行大型荟萃分析的一部分。皮肤活检是在测序个体上获得的，并转化为成纤维细胞。几个成纤维细胞系已重编程为诱导的多能干细胞（IPSC）进行功能基因组研究。 去年，在系统生物学研究所（ISB）的支持和协作下，我们完成了该系列105个人的整个基因组序列。持续的分析旨在检测遗传变异，这些变异因其对基因调节的影响而影响BD风险。我们还正在检查可以在整个基因组序列中很容易检测到的小缺失和插入。那些重叠已知的基因并倾向于与家庭情绪障碍分离的人尤其重要。 同样与ISB以及双相情感障碍基因组研究（BIG）合作，我们分析了对41个患有双相情感障碍的41个家庭成员进行的全基因组序列。在这些谱系中分离的几类编码和非编码（调节）变体富含神经元兴奋性基因。大多数受影响的个体继承了其中几种变体，表明遗传风险通常是寡。在另外3457例病例和2384个对照组中，对26个神经元兴奋性基因的靶向测序证实了ANK3，Cacna1b，Cacna1c，Cacna1c，Cacna1d，Cacng2，Cacng2和Camk2a中的稀有负担。启动子和3和5个未翻译区域的变体比在谱系和病例对照组中对躁郁症的风险进行编码的贡献更为强烈。持续的工作旨在证实这些发现在其他样本中，并表征涉及的遗传变异的功能影响。如果得到证实，这些结果可能对我们对双相情感障碍原因的理解具有重要意义，并为更好的治疗提供了线索。 我们还正在寻找可能有助于预测个人对锂的反应的遗传标记，这是双相情感障碍最有效的治疗方法之一。为此，我们组织了一项大型国际合作，称为锂遗传学联盟（Conligen），旨在使用可靠的仪器在大量患者中表征锂反应，然后进行全基因组关联研究。与波恩大学合作，我们在3000多个病例上完成了全基因组SNP阵列基因分型。使用锂反应的定义进行了关联分析，该锂反应显示出高地点间可靠性。我们在21号染色体上的区域中鉴定了一个全基因组的显着信号，该信号似乎编码了长期非编码的RNA分子。与响应相关标记的个体对锂有反应的可能性高50％。正在进行的工作将测试此发现以在其他样本中复制。如果复制，这些结果将指向一种新的途径，锂会对二极性疾病发挥治疗作用。