Integrative Genomic Analyses of NMDA Receptor Pathway in 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 可能与发育过程中的无社会行为表型有关。NMDAR作为 大分子复合体，其中不同途径的成员可以相互作用并影响NMDAR 功能。因此，NMDAR通路可能是基因融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 作为一个整体，可能包含在精神分裂症中丰富的常见和罕见的基因变异。其中一些 变异体可能通过基因转录调控影响杏仁基底外侧核(BLA)的功能。因此， 它们可能对无社会行为特征在发育过程中的表达起着关键作用。 NMDAR途径在BLA转录组中有很高的代表性，我们最近的GWAS研究已经 研究表明，作为一个整体，NMDAR通路的常见变体与精神分裂症有关。至 评估NMDAR途径对阴性症状的基因组影响，我们将对 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中的角色 功能，我们将分析50例精神分裂症患者死后BLAS的转录组及其 使用RNA-Seq匹配对照，然后将测试它们与DNA变体的关联。遗传 与血乳酸基因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途径基因变异之间的关联 它可以调节1000名患有无社会行为的青少年的BLA转录本 用GWA型和行为表型进行检测。 相关性(请参阅说明)： 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 可能与发育过程中的无社会行为表型有关。NMDAR作为 大分子复合体，其中不同途径的成员可以相互作用并影响NMDAR 功能。因此，NMDAR途径可能是基因收敛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。

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.