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，我们与美国 10 个学术中心合作，招募了超过 3,000 名患有躁郁症或相关情绪障碍的个体作为样本。所有参与者都进行了诊断访谈，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，该样本中的几个染色体区域可能含有导致情绪障碍的基因。为了确定单个致病基因，我们于 2007 年进行了首次双相情感障碍全基因组关联研究。结果涉及多个基因，每个基因的影响都很小，表明双相情感障碍是一种多基因疾病。我们 2011 年对双相情感障碍独立病例对照研究的荟萃分析支持与染色体 3p21 上的一组基因、TRANK1、LMAN2L 和 PTGFR 附近的标记以及先前研究中涉及的 ANK3 的 2 个独立区域的关联。其中许多发现现已在独立样本中得到重复。在 NARSAD 的支持下，正在进行的工作是在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，迄今为止，通过 GWAS 方法很少对双相情感障碍进行研究。 我们已经证明，基于大量标记的模型可以区分独立数据集中的病例和对照，具有很高的显着性，但预测价值不大。这些研究还表明，易患双相情感障碍的常见等位基因也易患重度抑郁症和精神分裂症，但不会导致帕金森病等神经系统疾病。我们与精神病基因组学联盟跨疾病小组的合作已证实，精神分裂症与双相情感障碍、精神分裂症与重度抑郁症、双相情感障碍与重度抑郁症、以及 ADHD 与重度抑郁症之间存在显着的遗传相关性。这些结果指出主要精神疾病之间存在共同的遗传风险因素，这可能反映了共同的病理生理学。 为了确定可能对重大情绪障碍的个体风险产生更大影响的遗传变异，我们在遗传多样性减少的选定人群和大家庭中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远亲的机会，并且属于不同核心家庭的个体通常是相关的，形成了基因组测序研究的扩展亲属理想。到目前为止，我们已经从阿米什人和门诺派社区收集了近 1400 名个体，他们独特的遗传历史使他们成为此类研究的特别好的候选者。所有血液样本均由罗格斯细胞和 DNA 存储库处理，该存储库还建立类淋巴母细胞系并将 DNA 作为一般科学界的资源分发。我们还将继续收集已确定身份的家庭。我们的目标是再收集至少 100 个病例及其父母和后代。与 NIMH IRP 的 Leibenluft 博士小组合作对后代进行研究，该小组对这些高危儿童进行了额外的认知和情感测试。 基因组测序于 2012 年开始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个体的约 80 个外显子组序列。尽管在我们的研究中没有发现大多数病例所共有的罕见、破坏性突变，但我们已经发现了 1000 多个远亲病例所共有的有希望的变异。这些数据已提交给双极测序联盟 (BSC)，在那里它们将成为测序病例、对照和家庭大型荟萃分析的一部分。对已测序的个体进行皮肤活检并转化为成纤维细胞。一些成纤维细胞系已被重新编程为诱导多能干细胞 (iPSc)，用于功能基因组研究。 去年，在系统生物学研究所 (ISB) 的支持和合作下，我们完成了该收藏中 105 个人的全基因组测序。正在进行的分析旨在检测通过对基因调控的影响而影响 BD 风险的遗传变异。我们还在检查可以在整个基因组序列中轻松检测到的小缺失和插入。那些与已知基因重叠并倾向于与家庭情绪障碍分离的基因可能尤其重要。 我们还与 ISB 和双相情感障碍基因组研究 (BiGS) 合作，分析了对 41 个患有双相情感障碍的家庭的 200 名成员进行的全基因组序列。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遗传了其中几种变异，表明遗传风险通常是寡基因的。对另外 3457 例病例和 2384 例对照中的 26 个神经元兴奋性基因进行靶向测序，证实了 ANK3、CACNA1B、CACNA1C、CACNA1D、CACNG2 和 CAMK2A 中的罕见变异负担。无论是在家系中还是在病例对照队列中，启动子以及 3 个和 5 个非翻译区的变异比编码变异对双相情感障碍的风险贡献更大。正在进行的工作旨在在其他样本中证实这些发现，并表征相关遗传变异的功能影响。如果得到证实，这些结果可能对我们了解双相情感障碍的原因产生重要影响，并为更好的治疗提供线索。 我们还在寻找可能有助于预测个体对锂的反应的遗传标记，锂是已知的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来表征一大群患者的锂反应，然后进行全基因组关联研究。我们与波恩大学合作，对 3000 多个病例完成了全基因组 SNP 阵列基因分型。使用锂响应的定义进行关联分析，显示出较高的位点间可靠性。我们在 21 号染色体上的一个区域中发现了一个全基因组的重要信号，该区域似乎编码长链非编码 RNA 分子。具有反应相关标记的个体对锂反应的可能性高出 50%。正在进行的工作将测试这一发现是否可以在其他样本中复制。如果重复的话，这些结果将指出锂对双相情感障碍发挥治疗作用的新途径。