The Genetic and Genomic Study of MicroRNA in Bipolar and Schizophrenia

双相情感障碍和精神分裂症中 MicroRNA 的遗传学和基因组研究

• 批准号: 7268430
• 负责人: RICHARD A GIBBS
• 金额: $ 17.65万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268430
• 关键词: Affect; Base Pairing; Bioinformatics; Biological; Bipolar Disorder; Brain; Brain region; Caucasians; Caucasoid Race; Cells; Classification; Clinical; Cluster Analysis; Collection; Complex; Computer Simulation; Correlation Studies; DNA Resequencing; DNA Sequence; Data; Data Set; Deposition; Depth; Development; Diagnosis; Diagnostic; Disease; Disease Association; Disease susceptibility; Etiology; Facility Construction Funding Category; Follow-Up Studies; Gender; Gene Expression; Gene Frequency; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Goals; Grant; Guidelines; Human; Human Genome; Individual; Internet; Knowledge; Lead; Length; Linkage Disequilibrium Mapping; Medical; Mental disorders; Methods; MicroRNAs; Microsatellite Repeats; Minor; Molecular; National Institute of Mental Health; Nucleotides; Numbers; Patients; Play; Polymerase Chain Reaction; Population; Predisposition; Prefrontal Cortex; Process; RNA Interference; Regulation; Relative (related person); Research Institute; Research Personnel; Role; Sampling; Schizophrenia; Site; Statistical Methods; Stratification; Testing; Time; Tissues; Validation; Variant; X Chromosome; autosome; base; brain tissue; case control; expectation; functional genomics; genetic association; genetic variant; improved; in vivo; novel; programs; sample collection; trait

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are single-stranded RNAs (ssRNA) of 19-25 nucleotides in length that function as guide molecules in post-transcriptional gene silencing, by base pairing with target mRNAs. Since one miRNA can regulate expressions of multiple genes and about 1/3 of the human genes are regulated by miRNAs, variants in miRNAs have intriguing potential roles in the psychiatric diseases. To date there has been little study of genomic variation in miRNA genes, or the relationships between miRNA variants and psychiatric disorders, or where miRNA variants are correlated with variations in gene expressions in the brain. To promote such knowledge, we propose to use deep resequencing to exhaustively identify variants in all known human miRNAs. Then we will study the correlation between miRNA variants and gene expression in brain, and association of miRNA variants with schizophrenia (SZ) and bipolar disorder (BD). We will resequence all 462 known human miRNA genomic DNA sequences in 310 Caucasian individuals including BD, SZ, and normal controls (CN). 210 of the 310 individuals have already had microarray study of gene expression in brain or lymphoblastoid cells. Resequencing will identify all common and many rare variants. We will then test association of disease with genotypes of these variants in a large collection of case-control BD and SZ samples from the NIMH Genetics Initiative, including 3000 BD, 3000 SZ and 2250 CN. We will also test for correlations between sequence variants in miRNAs and gene expression data (as quantitative traits) in Stanley brain samples and CEPH lymphoblastoid cell samples. We will use appropriate statistical methods to approach multiple testing and potential population stratification problems. These findings will potentially enhance our understanding of the miRNA genes and their potential roles in etiology of BD and SZ. Development of new diagnoses and treatments may result.

描述（由申请人提供）：微小RNA（miRNA）是长度为19-25个核苷酸的单链RNA（ssRNA），其通过与靶mRNA的碱基配对在转录后基因沉默中起指导分子的作用。由于一个miRNA可以调控多个基因的表达，而人类约1/3的基因受miRNA的调控，因此miRNA的变异在精神疾病中具有潜在的作用。迄今为止，关于miRNA基因的基因组变异、miRNA变异与精神疾病之间的关系、miRNA变异与大脑中基因表达变异的相关性的研究很少。为了促进这种知识，我们建议使用深度重测序来彻底鉴定所有已知人类miRNA中的变体。本研究将探讨miRNA变异与脑组织基因表达的相关性，以及miRNA变异与精神分裂症（SZ）和双相情感障碍（BD）的关系。我们将对310名白人个体（包括BD、SZ和正常对照（CN））的所有462个已知人类miRNA基因组DNA序列进行重测序。310人中有210人已经进行了脑或淋巴母细胞基因表达的微阵列研究。重测序将识别所有常见和许多罕见的变异。然后，我们将在NIMH遗传学倡议的大量病例对照BD和SZ样本（包括3000 BD，3000 SZ和2250 CN）中测试疾病与这些变异基因型的相关性。我们还将在Stanley脑样本和CEPH淋巴母细胞样细胞样本中测试miRNA序列变异与基因表达数据（作为定量特征）之间的相关性。我们将使用适当的统计方法来处理多重检验和潜在的人群分层问题。这些发现将潜在地增强我们对miRNA基因及其在BD和SZ病因学中的潜在作用的理解。可能会导致新的诊断和治疗方法的发展。