Integrative Genomic Analyses of NMDA Receptor Pathway in Schizophrenia

精神分裂症 NMDA 受体通路的综合基因组分析

• 批准号: 8887155
• 负责人: Hakon Hakonarson
• 金额: --
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-08 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887155
• 关键词: Adolescent; Amygdaloid structure; Autopsy; Behavioral; Brain; Brain region; Collaborations; DNA; Data; Development; European; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genomic DNA; Genomics; Genotype; Infant; Institutes; Instruction; Lead; Link; Macromolecular Complexes; Measures; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Pathology; Pathway interactions; Patients; Phenotype; Play; Protein Isoforms; Public Domains; Reporting; Research; Role; Sampling; Schizophrenia; Symptoms; Technology; Testing; Transcript; Variant; aged; comparison group; deep sequencing; genetic variant; genome wide association study; interest; member; neonate; novel; programs; rare variant; research study; social skills; trait; transcriptome sequencing; transcriptomics

This project aims to investigate genomic underpinnings for NMDAR hypofunction in schizophrenia and its possible association with the behavioral phenotypes of asociality during development. NMDARs exist as a macromolecular complex, in which members of various pathways can interact and influence NMDAR funcfion. Thus, the NMDAR pathway could be a molecular substrate for convergent interacfions of genefic variants that can lead to behavioral phenotypes of schizophrenia. We hypothesize that the NMDAR pathway as a whole may contain common and rare genetic variants that are enriched in schizophrenia. Some of these variants may impact the function of basolateral amygdala (BLA) via modulation of gene transcripts. As such, they may play a critical role for the expression of behavioral traits of asociality during development. The NMDAR pathway is highly represented in the BLA transcriptome and our recent GWAS study has shown that common variants of the NMDAR pathways as a whole were associated with schizophrenia. To assess the genomic impact of NMDAR pathway on negative symptoms, we will conduct deep sequencing for NMDAR pathway genes in DNAs from 100 patients with schizophrenia. To assess their roles in BLA function, we will analyze the transcriptome of postmortem BLAs of 50 schizophrenia patients and their matched controls using RNA-Seq, which will then be tested for their association with DNA variants. Genetic variants linked to transcript alterations in the BLA with may play a role in the expression of schizophrenia phenotypes during development. We will assess the association between NMDAR pathway genetic variants that can modulate BLA transcripts with asociality behavioral phenotypes of 1000 adolescents who have been examined by GWAS and behavioral phenotypes. RELEVANCE (See instructions): This project aims to investigate genomic underpinnings for NMDAR hypofunction in schizophrenia and its possible association with the behavioral phenotypes of asociality during development. NMDARs exist as a macromolecular complex, in which members of various pathways can interact and influence NMDAR function. Thus, the NMDAR pathway could be a molecular substrate for convergent interactions of genetic variants that can lead to behavioral phenotypes of schizophrenia.

该项目旨在研究精神分裂症及其相关疾病中 NMDAR 功能低下的基因组基础 可能与发育过程中的不社交行为表型有关。 NMDAR 作为 大分子复合物，其中各种途径的成员可以相互作用并影响 NMDAR 功能。因此，NMDAR 途径可能是基因聚合相互作用的分子底物。 可能导致精神分裂症行为表型的变异。我们假设 NMDAR 通路 整体上可能包含常见和罕见的遗传变异，这些变异在精神分裂症中丰富。其中一些 变异可能通过基因转录的调节影响基底外侧杏仁核（BLA）的功能。像这样， 它们可能在发育过程中反社会行为特征的表达中发挥关键作用。 NMDAR 通路在 BLA 转录组中具有高度代表性，我们最近的 GWAS 研究表明 结果表明，NMDAR 通路的常见变异作为一个整体与精神分裂症相关。到 评估NMDAR通路对阴性症状的基因组影响，我们将针对阴性症状进行深度测序 100 名精神分裂症患者 DNA 中的 NMDAR 通路基因。评估他们在 BLA 中的角色 功能，我们将分析 50 名精神分裂症患者死后 BLA 的转录组及其 使用 RNA-Seq 匹配对照，然后测试它们与 DNA 变异的关联。遗传 与 BLA 转录改变相关的变异可能在精神分裂症的表达中发挥作用 发育过程中的表型。我们将评估 NMDAR 通路遗传变异之间的关联 可以调节 1000 名青少年的不社交行为表型的 BLA 转录本 通过 GWAS 和行为表型进行检查。 相关性（参见说明）： 该项目旨在研究精神分裂症及其相关疾病中 NMDAR 功能低下的基因组基础 可能与发育过程中的反社会行为表型有关。 NMDAR 作为 大分子复合物，其中各种途径的成员可以相互作用并影响 NMDAR 功能。因此，NMDAR 途径可能是基因聚合相互作用的分子底物。 可能导致精神分裂症行为表型的变异。