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 解剖皮层上人脑功能网络空间布局的变异性是一种新的表型 可以从功能性磁共振成像 (fMRI) 中提取，具有变革潜力 人脑功能的影像遗传学联合研究。早期结果表明，个体特异性 个性化功能网络（PFN）的拓扑与精神病理学领域密切相关 和认知，包括受多种心理健康状况影响的执行功能 (EF) 青春期期间发生了深刻的变化。 PFN 捕获大脑的个性化方面 与标准功能磁共振成像相比，功能与临床和发育结果具有独特的关联 方法，可以测量这些相同功能网络中的活动，但无法纳入变化 存在于个体之间的功能网络拓扑。该提案的总体假设是 以 PFN 为目标将迅速加速发现基因对大脑组织的贡献 功能，从而深入了解与大脑相关的行为健康状况的遗传风险 功能。为此，我们将在遗传信息丰富的开放 fMRI 数据集中探测 PFN，包括青少年 大脑和认知发展研究（ABCD，n=11,572，n=850 对双胞胎，期间的 5 个纵向时间点 研究期）和英国生物银行（UKBB，n>40,000），以及本地获取的 22q11.2 的 fMRI 数据 缺失综合征（22qDS，n=100；对照n=500）。分析将对遗传进行综合研究 多基因效应和罕见的、典型的从头拷贝数变异（CNV），每一种都被假设为 影响个性化的功能网络拓扑。首先，我们将使用ABCD中的纵向孪生模型来 研究 PFN 的双胞胎遗传力及其与 EF 等行为领域的遗传相关性， 例如，检验 EF 和关联皮层 PFN 之间的遗传相关性的假设 青春期期间增加（目标 1）。其次，我们将进行全基因组和转录组关联 ABCD 和 UKBB 中 PFN 拓扑的研究（GWAS 和 TWAS），以优先考虑特定的、功能活跃的 遗传位点（目标 2）。第三，我们将通过病例对照分析来研究罕见 CNV 对 PFN 的影响 Penn/CHOP 22q11.2DS 数据，采用 ABCD、CNV 风险评分，我们最近证明与偏差相关 来自社区队列中大脑解剖学的典型发育（目标 3）。将进行所有分析 具有完全可重复、透明的成像处理和遗传管道，利用 PI 和 汇集了团队在先进功能磁共振成像方法、基因组学和信息学方面的联合专业知识。累计起来， 这些目标的完成将导致我们对大脑遗传贡献的理解取得重大进展 功能及其与精神风险的关系，从而导致未来有针对性的实验和临床试验 由个体化神经遗传学指导的神经调节。