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

对四个大脑区域的非洲和欧洲血统个体之间的遗传和监管差异进行全面的计算分析

• 批准号: 10351433
• 负责人: Kynon Jade M Benjamin
• 金额: $ 10万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351433
• 关键词: Address; Affect; African; African ancestry; Antipsychotic Agents; Autopsy; Brain; Brain Diseases; Brain region; Career Transition Award; Cells; Collaborations; Collection; Complex; Computer Analysis; DNA Methylation; Data; Data Set; Development; Disease; Disease susceptibility; Environment; Epigenetic Process; European; Exons; Explosion; Future; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Genotype; Goals; Grant; Heritability; Hippocampus (Brain); Human; Human Genetics; Individual; Institutes; Life; Link; Machine Learning; Mental Health; Mental disorders; Mentors; Mentorship; Methods; Methylation; Modeling; Mosaicism; Neurosciences; Phase; Play; Prefrontal Cortex; Quantitative Trait Loci; Reduce health disparities; Research; Research Personnel; Research Project Grants; Resource Development; Role; SNP array; Sampling; Schizophrenia; Statistical Methods; Techniques; Testing; Training; Transcript; Universities; Variant; Work; base; biological research; bisulfite sequencing; brain tissue; career; career development; caudate nucleus; causal variant; cell type; cohort; dentate gyrus; diagnostic accuracy; differential expression; drug discovery; epigenetic variation; experience; experimental study; fetal; follow-up; genetic analysis; genomic data; health disparity; improved; indexing; nervous system disorder; neurodevelopment; neuropsychiatric disorder; personalized medicine; postnatal; prenatal; response; skills; success; trait; transcriptome sequencing; whole genome

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.

项目总结/摘要 健康差距已经持续了几个世纪。生物变异研究的差距甚至更大， 在那里，基因和环境数据的爆炸几乎完全集中在欧洲人身上， 祖先（EA）。在神经科学和基因组学中，最近有非洲血统（AA）的个体占较少 在大规模基因组研究中，有超过5%的人患有精神疾病，但有20%的人更有可能经历重大的精神健康危机。到 更进一步，研究表明AA和EA之间的遗传差异与不同的 抗精神病药的反应因此，对神经精神疾病的大规模研究有限， 非欧洲血统个体的诊断准确性，阻碍了有效公平 神经治疗学和潜在的增加健康差距。尽管有明显的迫切需要，但没有 大规模的研究检查AA和EA在人类大脑中的遗传或调节差异。这 一项提案试图通过将AA与经过充分研究的EA个体进行比较来解决研究中的这一差距。初始 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（n=447），从一个最大的死后大脑收集的精神疾病。 这种多样的大规模死后脑组织将使我们能够测试遗传变异的假设 产前和产后对祖先大脑区域特异性转录和表观遗传变化的影响 产后生活MOSAIC（最大化科学和学术独立职业的机会） 博士后职业过渡奖，以促进多样性将支持优秀的职业发展 利伯大脑发育研究所和约翰霍普金斯大学的资源，以及来自 由人类遗传学和高级统计学领域全球公认的专家组成的指导小组 方法.它将提供神经科学中第一次对祖先的检查，这将推动我们的研究。 了解人类大脑中的遗传变异。