Genetic architecture of the human brain and neuropsychiatric disorders

人脑的遗传结构和神经精神疾病

• 批准号: 10053727
• 负责人: Chi-Hua Chen
• 金额: $ 53.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-03 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053727
• 关键词: Affect; Age; Aging; Area; Atlases; Brain; Brain Diseases; Brain imaging; Brain region; Clinical; Data; Databases; Development; Diagnosis; Diagnostic; Diffusion; Disease; Drug Targeting; Early Diagnosis; Early Intervention; Elements; Environmental Exposure; Environmental Risk Factor; Failure; Fiber; Functional Imaging; Genes; Genetic; Genetic Epistasis; Genetic Heterogeneity; Genetic Models; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Goals; Hereditary Disease; Heritability; Heterogeneity; Human; Imaging technology; Incidence; Individual; Knowledge; Lead; Link; Longevity; Magnetic Resonance Imaging; Maps; Measures; Medicine; Mental disorders; Methods; Modeling; Molecular; Multimodal Imaging; Neurologic; Neurologic Symptoms; Pathogenicity; Pattern; Phenotype; Population; Population Heterogeneity; Prevention; Primates; Research; Resources; Risk; Sampling; Single Nucleotide Polymorphism; Source; Specific qualifier value; Structure; Subgroup; Surface; Testing; Therapeutic; Thick; Translating; Twin Multiple Birth; Variant; Work; aging brain; base; biobank; brain abnormalities; brain behavior; cohort; drug development; frontal lobe; gene environment interaction; gene interaction; genetic architecture; genetic signature; genetic variant; genome wide association study; genome-wide analysis; gray matter; high risk; imaging genetics; imaging modality; improved; in vivo; individual variation; insight; nervous system disorder; neurodevelopment; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutics; pleiotropism; polygenic risk score; precision medicine; pressure; prevent; psychiatric symptom; risk variant; schizophrenia risk; sex; success; therapeutic development; therapy development; trait; transcriptome; white matter

Project Summary Our goal is to determine gene-brain-behavior relationships, including those that underlie neuropsychiatric disorders. These disorders are common and increasing in incidence worldwide. However, there are significant clinical gaps in current treatment and objective diagnosis. Drug development trial failure rates are disproportionately high for brain disorders due to largely unknown differences in genetic bases between model species’ and human’s brains, which prevent translational success. A major challenge hindering progress in neuropsychiatric medicine is our limited understanding of the genetics underlying the complexity of human brain structure and function. Our first objective in the current study is to uncover genetic variants associated with brain imaging phenotypes (Aim 1). Our second objective is to test the genetic effects of regulatory and phylogenically annotated genomic elements on the human brain (Aim 2). Our third objective is to determine the impact of neuropsychiatric genetic risks and their environmental interactions on the brain (Aim 3). Previously we produced the first genetic atlas of the human cortex based on magnetic resonance imaging (MRI) data of twins using fuzzy clustering. This work not only confirmed that human brain phenotypes are heritable traits but also demonstrated a clear region-specific genetic pattern, which facilitates identification of genetic variants associated with brain subdivisions. Our recent work demonstrated the value of using this atlas to determine the segments of the genome that are enriched for genetic effects influencing brain structure. In this proposal, we will leverage a ten-fold enlarged sample with both MRI and single nucleotide polymorphism (SNP) data, and advanced genetic and imaging methods to significantly expand the scope of our work. The larger sample increases power for discovering SNPs associated with individual brain structures and will enable us to examine genetic heterogeneity by age, sex, and genetic ancestries. Characterizing subgroups is critical for precision medicine approaches and to increase statistical power using genetically more homogeneous groups (Aim 1). We will also characterize pleiotropy and regulatory epistasis effects on the brain by multimodal imaging (structural, diffusion and functional imaging). This will provide insight into shared and distinct genetic influences among different brain regions. We hypothesize that variations in the highly expanded human cortex are associated with regulatory genetic effects (Aim 2). Third, building on improved genetic knowledge of the brain, we will determine its genetic relationship with neuropsychiatric disorders. We will estimate effects of psychiatric and neurological genetic risks and environmental exposures on deviations of MRI phenotypes from normal neurodevelopmental and aging trajectories (Aim 3). The current project has strong potential to significantly increase our understanding of genetic basis of the human brain, and to determine genetic and environmental factors that drive brain deviations from typical trajectories across lifespan, with a long-term goal to ultimately improve diagnostics, early intervention and therapeutic development for neuropsychiatric disorders.

项目摘要 我们的目标是确定基因-大脑-行为的关系，包括那些神经精神病学的基础 紊乱这些疾病很常见，在世界范围内发病率不断增加。然而，有重要的 目前治疗和客观诊断的临床差距。药物开发试验失败率为 由于模型之间遗传基础的差异在很大程度上是未知的， 物种和人类的大脑，阻止翻译成功。阻碍在以下方面取得进展的一个主要挑战 神经精神医学是我们对人类复杂性背后的遗传学的有限理解。 大脑结构和功能我们目前研究的第一个目标是发现与癌症相关的遗传变异。 脑成像表型（Aim 1）。我们的第二个目标是测试基因调控的影响， 人类大脑中的遗传学注释基因组元件（目标2）。我们的第三个目标是确定 神经精神遗传风险及其环境相互作用对大脑的影响（目标3）。先前 我们根据1999年的磁共振成像（MRI）数据制作了第一个人类大脑皮层的遗传图谱， 双胞胎使用模糊聚类。这项工作不仅证实了人类大脑表型是可遗传的特征， 还显示了明确的区域特异性遗传模式，这有助于识别遗传变异 与大脑分区有关。我们最近的工作证明了使用该图谱来确定 基因组中富含影响大脑结构的遗传效应的片段。在本提案中，我们 将利用具有MRI和单核苷酸多态性（SNP）数据的十倍放大样本，并且 先进的遗传学和成像方法，以显着扩大我们的工作范围。所述较大样本 增加了发现与个体大脑结构相关的SNP的能力，并将使我们能够检查 年龄、性别和遗传祖先的遗传异质性。表征子群对于精度至关重要 医学方法，并使用遗传上更同质的群体来增加统计功效（目标1）。 我们还将通过多模式成像来描述多效性和调节上位性对大脑的影响 （结构、扩散和功能成像）。这将提供深入了解共享和独特的遗传影响 在不同的大脑区域。我们假设，高度膨胀的人类大脑皮层的变化是 与调控遗传效应相关（目标2）。第三，基于对大脑遗传知识的改进， 我们将确定它与神经精神疾病的遗传关系。我们将评估精神疾病的影响 以及神经遗传风险和环境暴露对MRI表型偏离正常的影响 神经发育和衰老轨迹（目标3）。本项目具有很强的潜力， 增加我们对人类大脑遗传基础的了解，并确定遗传和环境 这些因素促使大脑偏离整个生命周期的典型轨迹，其长期目标是最终 改善对神经精神疾病诊断、早期干预和治疗发展。