Multiethnic genomic epigenomic and transcriptomic fine-mapping and functional validation analysis of schizophrenia and bipolar disorder risk loci

精神分裂症和躁郁症风险位点的多种族基因组表观基因组和转录组精细定位和功能验证分析

• 批准号: 10116719
• 负责人: Panagiotis Roussos
• 金额: $ 85.13万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116719
• 关键词: Affect; African; Asians; Biological; Biological Assay; Bipolar Disorder; Brain; Brain Diseases; CRISPR interference; Catalogs; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Cohort Studies; Complex; Consensus; Data; Detection; Diagnostic; Enhancers; Epigenetic Process; European; Female; Future; Gene Expression; Genes; Genetic; Genetic Risk; Genome; Genomics; Goals; Hispanics; Human; Libraries; Link; Linkage Disequilibrium; Mediating; Mental disorders; Meta-Analysis; Methods; Modeling; Molecular; Morbidity - disease rate; Neurons; Nucleic Acid Regulatory Sequences; Organ; Participant; Pathway interactions; Phenotype; Population; Protein Isoforms; Quantitative Trait Loci; Regulation; Regulator Genes; Regulatory Element; Reporter; Risk; Sampling; Schizophrenia; South Asian; Specificity; Testing; Tissues; Transcript; Untranslated RNA; Validation; Variant; Work; brain tissue; causal variant; cell type; epigenome; epigenomics; excitatory neuron; genetic risk factor; genetic variant; genome editing; genome wide association study; genome-wide; genomic locus; human data; induced pluripotent stem cell; inhibitory neuron; insight; male; mortality; multi-ethnic; novel; novel strategies; promoter; psychiatric genomics; resilience; risk variant; schizophrenia risk; severe mental illness; societal costs; statistics; therapeutic development; trait; transcriptomics

PROJECT SUMMARY Serious mental illness (SMI) that includes schizophrenia (SCZ) and bipolar disorder (BD) are common, complex and debilitating psychiatric disorders that together affect over 2% of the population and carry considerable morbidity, mortality, and personal and societal cost. Over the last decade, large-scale genome wide association studies (GWAS) have identified hundreds of loci contributing to the risk of SCZ and BD. Advancing these statistical associations to causal mechanisms for SMIs is very challenging due to incomplete understanding of the non-coding regulatory mechanisms in the human brain tissue and the local correlation of risk variants. Therefore, a systematic analysis that performs fine-mapping to jointly identify and validate a credible set of causal variants in SMI and molecular features that includes transcripts and regulatory sequences, in relevant tissues and cell types is a critical next step. The overarching goal of our proposal is to leverage genomics and multiscale functional omics (gene expression and epigenome regulation) data and perform fine mapping to detect and validate causal variants, transcripts and regulatory sequences in SMI. In Aim 1, we will perform large-scale trans- ancestry GWAS of SCZ and BD to expand the current repertoire of risk (and resilience) loci and refine the credible sets of causal variants underlying genome-wide significant associations. In Aim 2, we will integrate putative causal variants with multiscale functional omics data from human brain tissue that capture gene expression and epigenome regulation at the bulk, cell type-specific and single cell level to identify credible sets of transcripts and regulatory sequences. In Aim 3, we will functionally validate putative causal variants and regulatory sequences, by using novel approaches that combine massively parallel reporter assays and genome editing in excitatory and inhibitory neurons derived from human induced pluripotent stem cells. Our computational and experimental aims bridge the gap between the fine-mapping of causal variants, the molecular gene- regulatory effects of risk variants on enhancer activity and gene expression and their biological effects at the cellular level. If successful, our project can elucidate the genes, pathways, and mechanisms underlying SCZ and BD, and provide new insights and avenues for therapeutic development.

项目摘要 包括精神分裂症（SCZ）和躁郁症（BD）在内的严重精神疾病（SMI）很常见，复杂 以及使超过2％人口的精神疾病使人衰弱的精神疾病并具有相当大的影响 发病率，死亡率以及个人和社会成本。在过去的十年中，大型基因组宽协会 研究（GWAS）已经确定了数百个基因座，导致SCZ和BD的风险。推进这些 与SMI的因果机制有关的统计关联非常具有挑战性，因为对 人脑组织中的非编码调节机制和风险变异的局部相关性。 因此，进行精细映射以共同识别和验证可信因果的系统分析 相关组织中的SMI和分子特征的变体，包括转录本和调节序列 细胞类型是关键的下一步。我们建议的总体目标是利用基因组学和多尺度 功能上的OMICS（基因表达和表观基因组调节）数据，并执行精细的映射以检测和 验证SMI中的因果变异，转录本和调节序列。在AIM 1中，我们将进行大规模的反式 SCZ和BD的Ancestry GWAS，以扩大当前风险（和弹性）基因座的曲目 可靠的因果变异集的基础基因组范围的显着关联。在AIM 2中，我们将整合 假定的因果变体，具有捕获基因的人脑组织的多尺度功能元数数据 在整体，细胞类型特异性和单细胞水平上的表达和表观基因组调节，以识别可靠的集合 转录本和调节序列。在AIM 3中，我们将在功能上验证推定的因果变体，并且 调节序列，使用新型方法结合了大规模平行的报告基因组和基因组 在人类诱导的多能干细胞衍生的兴奋性和抑制性神经元中进行编辑。我们的计算 实验目标桥接了因果变体的细微映射，分子基因的差距 风险变异对增强子活性和基因表达及其在生物学作用上的调节作用 细胞水平。如果成功，我们的项目可以阐明SCZ和SCZ和机制的基因，途径和机制 BD，并为治疗发展提供新的见解和途径。