Comprehensive computational analysis of genetic and regulatory differences between individuals with African and European ancestries across four brain regions

项目摘要/摘要 健康差距已经持续了几个世纪。对生物变异的研究差距更大， 基因和环境数据的爆炸性增长几乎完全集中在欧洲人的数据上 祖先(EA)。在神经科学和基因组学中，最近有非洲血统(AA)的人所占比例较低 超过5%的大规模基因组研究，但经历重大心理健康危机的可能性高出20%。至 将这一问题进一步复杂化，研究已将AA和EA之间的遗传差异联系起来，导致分化 对抗精神病药物的反应。因此，对神经精神障碍的大规模研究受到限制。 对非欧洲血统个体的诊断准确性，阻碍了有效公平的发展 神经疗法和潜在的健康差距扩大。尽管有明显的迫切需求，但没有 研究人类大脑中AA和EA之间的遗传或调控差异的大规模研究。这 一项提案试图通过将AA与经过充分研究的EA个人进行比较来解决这一研究差距。首字母 本提案的目的是确定AA(n=784)和EA(n=678)之间的遗传和调控差异 死后尾状核(n=420)、齿状回(n=161)、背外侧前额叶皮质(n=434)和 海马体(n=447)，由最大的精神疾病死后大脑集合之一汇编而成。 这种多样化的大规模死后脑组织将使我们能够检验基因变异的假说 出生前和出生后对祖先大脑区域特异性转录和表观遗传学变化的影响 出生后的生活。这幅马赛克(最大化科学和学术独立事业的机会) 博士后职业转型奖促进多元化将以优秀的职业发展为支撑 利伯脑发育研究所和约翰霍普金斯大学的资源，以及来自 由全球公认的人类遗传学和高级统计学领域的专家组成的指导团队 方法：研究方法。它将提供第一次对神经科学祖先的检查，这将促进我们的 了解人脑中的遗传变异。

Project Summary / Abstract Health disparities have endured for centuries. The disparity in research for biological variations is even greater, where the explosion of genetic and environmental data has focused almost exclusively on those of European ancestry (EA). In neuroscience and genomics, individuals with recent African ancestry (AA) account for less than 5% of large-scale genomic studies but are 20% more likely to experience a major mental health crisis. To compound this issue further, studies have linked genetic differences between AA and EA for divergent responses to antipsychotics. As a result, large-scale studies for neuropsychiatric disorders have limited diagnostic accuracy for non-European ancestry individuals, hindering the development of effective equitable neurotherapeutics and potentially increasing health disparities. Despite the clear urgent need, there are no large-scale studies examining genetic or regulatory differences between AA and EA in the human brain. This proposal seeks to address this gap in research by comparing AA with well-studied EA individuals. The initial goal of this proposal is to identify genetic and regulatory difference between AA (n=784) and EA (n=678) in postmortem caudate nucleus (n=420), dentate gyrus (n=161), dorsolateral prefrontal cortex (n=434), and hippocampus (n=447), compiled from one of the largest postmortem brain collections of psychiatric disorders. This diverse large-scale postmortem brain tissue will allow us to test the hypotheses of genetic variations influence on brain region-specific transcriptional and epigenetic changes for ancestry across prenatal and postnatal life. This MOSAIC (Maximizing Opportunities for Scientific and Academic Independent Careers) Postdoctoral Career Transition Award to Promote Diversity will be supported by excellent career development resources at the Lieber Institute for Brain Development and Johns Hopkins University, and training from a mentoring team of globally recognized experts in the fields of human genetics and advanced statistical methods. It will provide a first of its kind examination of ancestry in neuroscience, which will advance our understanding of genetic variation in the human brain.