The Genetics of Personalized Functional MRI Networks

个性化功能 MRI 网络的遗传学

• 批准号: 10650032
• 负责人: Aaron Felix Alexander-Bloch
• 金额: $ 87.45万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-16 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650032
• 关键词: Acceleration; Adolescence; Adolescent; Adult; Age; Anatomy; Area; Atlases; Award; Behavioral; Brain; Candidate Disease Gene; Childhood; Classification; Clinical; Clinical Trials; Cognition; Cognitive deficits; Communities; Copy Number Polymorphism; Data; Data Set; Detection; Development; DiGeorge Syndrome; Elderly; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Genes; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genome; Genomics; Goals; Heritability; Human; Individual; Informatics; Inherited; Investigation; Joints; Longevity; Machine Learning; Magnetic Resonance Imaging; Maps; Measures; Mental Health; Mental disorders; Methodology; Methods; Modeling; Neuroanatomy; Outcome; Participant; Persons; Phenotype; Physicians; Psychopathology; Reporting; Reproducibility; Research; Risk; SNP array; Sampling; Scientist; Site; Standardization; Surface; Syndrome; Testing; Time; Translational Research; Twin Multiple Birth; Variant; Work; Youth; association cortex; behavioral health; biobank; brain size; career; case control; cognitive development; cohort; developmental genetics; executive function; functional genomics; functional outcomes; gene network; genetic architecture; genetic association; genome wide association study; genomic locus; image processing; imaging genetics; improved; innovation; insight; network dysfunction; neurodevelopment; neurogenetics; neuroregulation; novel; open data; precision genetics; risk variant; sensory cortex; sex; tool; transcriptome

ABSTRACT Variability in the spatial layout of human brain functional networks on the anatomic cortex is a novel phenotype that can be extracted from functional magnetic resonance imaging (fMRI) with transformative potential for combined imaging-genetics studies of human brain function. Early results show that the individual-specific topography of Personalized Functional Networks (PFNs) is strongly associated with domains of psychopathology and cognition, including executive functioning (EF) which is impacted in multiple mental health conditions and undergoes profound changes during the period of adolescence. PFNs capture individualized aspects of brain function that have unique associations with clinical and developmental outcomes, compared to standard fMRI approaches, which can measure activity in these same functional networks but fail to incorporate the variation in functional network topography that exists among individuals. The over-arching hypothesis of this proposal is that targeting PFNs will rapidly accelerate the discovery of genetic contributions to the organization of brain function, leading to mechanistic insights into genetic risks for behavioral health conditions related to brain function. To this end, we will probe PFNs in genetically informative open fMRI datasets including the Adolescent Brain and Cognitive Development Study (ABCD, n=11,572, n=850 twin pairs, 5 longitudinal time points during study period) and the UK Biobank (UKBB, n>40,000), as well as locally acquired fMRI data on the 22q11.2 deletion syndrome (22qDS, n=100; controls n=500). Analyses will yield a cohesive investigation of inherited polygenic effects and rare, typically de novo copy number variants (CNVs), each of which are hypothesized to influence individualized functional network topography. First, we will use longitudinal twin models in ABCD to investigate the twin heritability of PFNs and their genetic correlation with behavioral domains such as EF, for example, testing the hypothesis that the genetic correlation between EF and association cortex PFNs will increase during adolescence (Aim 1). Second, we will perform genome- and transcriptome-wide association studies (GWAS and TWAS) of PFN topography in ABCD and UKBB to prioritize specific, functionally active genetic loci (Aim 2). Third, we will investigate the influence of rare CNVs on PFNs, using analysis of case-control Penn/CHOP 22q11.2DS data, in ABCD, CNV Risk Scores that we recently showed to correlate with deviations from the typical development of brain anatomy in a community cohort (Aim 3). Allanalyses will be conducted with fully reproducible, transparent imaging processing and genetic pipelines, capitalizing on the PI and assembled team's joint expertise in advanced fMRI methods, genomics, and informatics. Cumulatively, the completion of these aims will result in a major advance in our understanding of the genetic contributions to brain function and its relationship to psychiatric risk, leading to future experimental and clinical trials of targeted neuromodulation guided by individualized neurogenetics.

抽象的 人脑功能网络的空间布局在解剖学皮层上是一种新型表型 可以从功能性磁共振成像（fMRI）中提取，具有变革性的潜力 人脑功能的成像基因研究。早期结果表明个人特定于 个性化功能网络（PFN）的地形与心理病理领域密切相关 和认知，包括在多种心理健康状况和 在青春期期间经历了深刻的变化。 PFN捕获大脑的个性化方面 与标准fMRI相比，与临床和发展结果具有独特关联的功能 方法，可以测量这些相同功能网络中的活动，但无法合并变化 在个人之间存在的功能网络地形中。该提议的总体假设是 靶向PFN将迅速加速对大脑组织的遗传贡献 功能，导致对与大脑有关的行为健康状况的遗传风险的机械洞察力 功能。为此，我们将在包括青少年（青少年 大脑和认知发展研究（ABCD，n = 11,572，n = 850双对，5个纵向时间点 研究期）和英国生物银行（UKBB，n> 40,000），以及本地获得的fMRI数据22q11.2 删除综合征（22QD，n = 100；控制n = 500）。分析将对继承的凝聚力研究 多基因效应和罕见的，通常是从头拷贝数变体（CNV），每个变体都被认为 影响个性化的功能网络地形。首先，我们将在ABCD中使用纵向双胞胎模型 研究PFN的双遗传力及其与行为领域（例如EF）的遗传相关性 例如，测试以下假设：EF与缔合皮层PFN之间的遗传相关性将会 青春期增加（AIM 1）。其次，我们将执行全基因组和全转录组关联 ABCD和UKBB的PFN地形研究（GWAS和TWA），以优先考虑特定功能活性 遗传基因座（AIM 2）。第三，我们将使用病例控制的分析研究稀有CNV对PFN的影响 Penn/Chop 22Q11.2DS数据，在ABCD中，CNV风险评分，我们最近显示为与偏差相关 从社区队列中脑解剖结构的典型发展（AIM 3）。将进行Allanalyses 具有完全可重现的透明成像处理和遗传管道，利用PI和 汇编团队在高级功能磁共振成像方法，基因组学和信息学方面的共同专业知识。累计， 这些目标的完成将导致我们对大脑遗传贡献的理解 功能及其与精神病风险的关系，导致未来的实验和临床试验 神经调节以个性化的神经遗传学为指导。