Functional genomic resource and integrative model of dopaminergic circuitry associated with psychiatric disease

项目概述：功能基因组资源补充与整合模型 与精神疾病相关的多巴胺能回路 作为对PA-20-272“现有NIH赠款和合作协议的行政补充”的回应 （家长管理Supp临床试验可选），”我们建议验证少量额外的靶基因， 由亲本U 01鉴定（U 01 DA 048279：多巴胺能神经递质的功能基因组资源和整合模型 与精神疾病相关的电路）。父母奖旨在构建转录组和表观基因组 （包括中脑多巴胺能神经元及其周围神经元的3D基因组/染色体构象）图 非神经元细胞，并评估与复杂精神疾病的已知遗传风险因素的关系， 包括精神病与药物滥用共病。我们将应用综合方法进行功能分析 遗传变异和网络，包括但不限于贝叶斯网络重建和预测 变量因果关系的算法，以确定精神分裂症和双相情感障碍病理学的关键驱动因素，以及药物 成瘾共病这些方法将同时整合多个不同维度的数据：DNA 变异，RNA表达，染色质可及性，基因组的3D结构，以及已知的途径和基因 在临床表型数据的背景下的网络信息。项目数据的基本来源 来自目前对人类中脑功能组学的研究，CommonMind和PsychENCODE consortia（全基因组测序和皮质功能组学数据），精神病基因组学联盟， 百万退伍军人项目（遗传变异和疾病表型）。百万退伍军人计划（MVP） 收集了约70万人的基因分型和表型数据，其中包括5万人的亚组 被诊断为SCZ和BD的退伍军人以及被诊断为其他神经精神疾病的更大群体 特征（复发性抑郁症，自杀和药物滥用）。我们将使我们新生成的转录组 和来自成人中脑的表观基因组数据集，以及网络和预测模型，可用于 研究社区根据NIMH数据共享政策。

PROJECT SUMMARY: Supplement to Functional genomic resource and integrative model of dopaminergic circuitry associated with psychiatric disease In response to PA-20-272, “Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional),” we propose to validate a small number of additional target genes identified by parent U01 (U01DA048279: Functional genomic resource and integrative model of dopaminergic circuitry associated with psychiatric disease). The parent award aims to construct transcriptome and epigenome (incl. 3D genome/chromosomal conformation) maps for midbrain dopaminergic neurons and for their surrounding nonneuronal cells, and to assess the relationship to known genetic risk factors for complex mental illness, including psychosis with substance abuse co-morbidity. We will apply integrative methods for functional analysis of genetic variation and networks, including but not limited to Bayesian network reconstruction and prediction algorithms of variant causality to identify key drivers of schizophrenia and bipolar disease pathology, and drug addiction co-morbidity. These methods will simultaneously integrate multiple different dimensions of data: DNA variation, RNA expression, chromatin accessibility, 3D structure of the genome, and known pathway and gene network information in the context of clinical phenotype data. The fundamental source of data for the project comes from the current studies on human midbrain functional omics, the CommonMind and PsychENCODE consortia (whole genome sequencing and cortical functional omics data), the Psychiatric Genomics Consortium, and the Million Veterans Project (genetic variation and disease phenotypes). The Million Veterans Project (MVP) has collected genotyping and phenotypic data from ~700,000 individuals, including a subgroup of 50,000 veterans diagnosed with SCZ and BD and a larger group of individuals diagnosed with other neuropsychiatric traits (recurrent depression, suicide and substance abuse). We will make our newly generated transcriptome and epigenome datasets from adult midbrain, as well as the network and predictive models, available to the research community in accordance with NIMH data sharing policies.