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

项目总结 包括精神分裂症(SCZ)和双相情感障碍(BD)在内的严重精神疾病(SMI)是常见的、复杂的 和衰弱的精神疾病，加起来影响超过2%的人口，并带来相当大的 发病率、死亡率以及个人和社会代价。在过去的十年里，大规模的基因组广泛关联 研究(Gwas)已经确定了数百个导致SCZ和BD风险的基因。推进这些 统计关联到SMI的因果机制是非常具有挑战性的，因为对 人脑组织中的非编码调节机制和风险变量的局部相关性。 因此，执行精细映射以联合识别和验证一组可信的因果关系的系统分析 SMI的变体和相关组织中的分子特征，包括转录本和调控序列 而细胞类型是下一步的关键。我们提案的首要目标是利用基因组学和多尺度 功能组学(基因表达和表观基因组调节)数据，并执行精细作图以检测和 验证SMI中的因果变体、转录本和调控序列。在目标1中，我们将进行大规模的运输- SCZ和BD的祖先GWA扩展了当前的风险(和复原力)基因座库，并完善了 全基因组重大关联背后的可信的因果变异集。在目标2中，我们将整合 从人脑组织获取基因的多尺度功能组学数据推定的因果变异 在整体、特定细胞类型和单细胞水平上的表达和表观基因组调控，以确定可信的集合 转录本和调控序列。在目标3中，我们将从功能上验证假定的因果变量和 调控序列，通过使用大量平行报告分析和基因组相结合的新方法 编辑来自人类诱导的多能干细胞的兴奋性和抑制性神经元。我们的计算 实验目的是弥合因果变量精细图谱、分子基因-- 风险变异体对增强子活性和基因表达的调节作用及其生物学效应 细胞水平。如果成功，我们的项目可以阐明SCZ和SCZ的基因、途径和机制 BD，并为治疗发展提供新的见解和途径。

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.