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患者NMDAR功能低下的基因组基础及其 可能与发展过程中的行为表型的社会性。NMDAR作为一种 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， 变异导致精神分裂症的行为表型。我们假设NMDAR通路 作为一个整体，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富集。其中一些 变异体可能通过基因转录物的调节影响基底外侧杏仁核（BLA）的功能。因此，在本发明中， 在发育过程中，它们可能对反社会行为特征的表达起着关键作用。 NMDAR途径在BLA转录组中高度代表，我们最近的GWAS研究表明， 显示NMDAR通路的常见变异体作为一个整体与精神分裂症有关。到 为了评估NMDAR通路对阴性症状的基因组影响，我们将进行深度测序， 100例精神分裂症患者DNA中NMDAR通路基因的研究评估他们在BLA中的作用 功能，我们将分析50例精神分裂症患者的死后BLA的转录组， 使用RNA-Seq匹配对照，然后测试它们与DNA变体的关联。遗传 与BLA中的转录物改变相关的变异可能在精神分裂症的表达中起作用 在发育过程中。我们将评估NMDAR通路遗传变异与 它可以调节1000名青少年的BLA转录本与社会行为表型， 通过GWAS和行为表型检查。 相关性（参见说明）： 该项目旨在研究精神分裂症患者NMDAR功能低下的基因组基础及其 可能与发展过程中的行为表型的社会性。NMDAR作为一种 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途径可能是遗传物质相互作用的分子底物。 变异导致精神分裂症的行为表型。