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: 9118374
• 负责人: Hakon Hakonarson
• 金额: $ 11.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118374
• 关键词: Adolescent; Amygdaloid structure; Autopsy; Behavioral; Brain; Brain region; Collaborations; DNA; Data; Development; European; Functional disorder; Gene Expression; 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; 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NMDAR功能障碍的基因组基础 可能与发展过程中无社会性的行为表型相关。 NMDAR作为一个 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FENTENT INTERATE的分子底物 可以导致精神分裂症行为表型的变体。我们假设NMDAR途径 总体而言，可能包含富含精神分裂症的常见且稀有的遗传变异。其中一些 变体可能通过调节基因转录本来影响基底外侧杏仁核（BLA）的功能。像这样， 它们可能在发展过程中表达无社会性行为特征的表达。 NMDAR途径在BLA转录组中高度代表，我们最近的GWAS研究具有 表明NMDAR途径的常见变体与精神分裂症有关。到 评估NMDAR途径对负症状的基因组影响，我们将进行深入的测序 来自100例精神分裂症患者的DNA中的NMDAR途径基因。评估他们在BLA中的角色 功能，我们将分析50名精神分裂症患者及其的验尸后BLA的转录组及其 使用RNA-Seq进行匹配的对照，然后将对它们与DNA变体的关联进行测试。遗传 与BLA中的转录物改变有关的变体可能在精神分裂症的表达中起作用 发育过程中的表型。我们将评估NMDAR途径遗传变异之间的关联 可以通过1000名青少年的无情行为表型来调节BLA成绩单 通过GWAS和行为表型检查。 相关性（请参阅说明）： 该项目旨在研究精神分裂症及其NMDAR功能障碍的基因组基础 可能与发展过程中无社会性的行为表型相关。 NMDAR作为一个 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途径可能是用于遗传相互作用的分子底物 可以导致精神分裂症行为表型的变体。