Master regulators of unexplained variation in disease risk

疾病风险无法解释的变异的主要调节因素

• 批准号: 10492766
• 负责人: JOSEPH H. NADEAU
• 金额: $ 191.92万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10492766
• 关键词: Address; Animal Model; Architecture; Area; Atlases; Biological; Biological Models; Biomedical Research; Catalogs; Chromosomes; Communities; Complex; Data; Databases; Development; Diagnosis; Diagnostic; Dimensions; Disease; Diseases in Twins; Elderly; Environment; Epigenetic Process; Etiology; Gene Activation; Gene Expression; Gene Silencing; Genetic; Genome; Genotype; Heterogeneity; Human; Human Genetics; Inbreeding; Individual; International; Knowledge; Lead; Link; Mainstreaming; Measures; Medicine; Metabolic; Methods; Molecular; Monozygotic twins; Mouse Strains; Mus; Neurologic; Organism; Outcome; Persons; Phenotype; Phylogenetic Analysis; Physiological; Population Analysis; Precision Medicine Initiative; Process; Property; Protocols documentation; Quantitative Trait Loci; Regulator Genes; Reporting; Science; Seminal; Standardization; Surveys; Testing; Therapeutic Intervention; Variant; Vertebrates; Work; biological systems; cohort; data resource; disease heterogeneity; disorder risk; driving force; genome-wide; human disease; innovation; insight; interest; non-Gaussian model; non-genetic; precision medicine; trait

PROJECT SUMMARY Precision medicine requires an understanding of the origins and molecular control over complex traits and disease. The field is largely driven by human genetics, which adheres to a 1918 dogma that phenotype is determined solely by genetics and the environment. Yet, evidence from monozygotic twins and isogenic animal models indicate that up to 50% of phenotypic variation across diverse physiological traits and diseases cannot be explained by genetics or environment – there is something `more' that is unique to each individual, and that cannot be determined by analyzing population-level mean effects. These findings also indicate that even if we did have `complete' genetic and environmental knowledge, a substantial portion of disease heterogeneity would remain unaccounted for. The operating hypothesis for this project is that a substantial fraction of unexplained disease heterogeneity reflects inherently probabilistic properties of the biological system that lead to fixed, deterministic, real biological variation. There is compelling evidence for an evolved molecular circuitry that controls phenotypic variability as a quantitative trait. Thus, understanding variability as a quantitative trait is essential to understanding the etiology of phenotypic diversity (in general) and an individual's disease potential (in particular). Here, we will begin to finally answer the precision medicine questions of: what is the normal or expected disease potential for me? And, what are the origins and regulatory controls of non-genetic, non- environmental phenotypic and disease variability in humans? The first steps towards addressing these questions and identifying mechanisms through which probabilistic processes lead to disease heterogeneity is to create a catalogue of putative variance regulators and genes; a phenotypic, epigenetic, and cellular variance atlas charting the landscape of probabilistic variation in an isogenic model system (mice); and, to demonstrate that the regulatory architecture of variance control is conserved between mouse and humans. If it is true that a significant portion of unexplained disease heterogeneity is due to the molecular control of variability itself, then we will have uncovered an entirely new area of disease etiology that can be harnessed by the community to develop fundamentally new predictive, diagnostic, and therapeutic interventions, irrespective of the disease of interest.

项目概要 精准医学需要了解复杂特征的起源和分子控制， 该领域很大程度上是由人类遗传学驱动的，它遵循 1918 年的一条教条：表型是决定性的。 然而，来自同卵双胞胎和同基因动物的证据仅由遗传和环境决定。 模型表明，不同生理特征和疾病之间高达 50% 的表型变异不能 可以用遗传或环境来解释——每个人都有一些独特的“更多”东西，而且 无法通过分析人口水平的平均效应来确定。这些发现也表明，即使我们 如果确实拥有“完整”的遗传和环境知识，那么很大一部分疾病异质性将 该项目的操作假设是，很大一部分无法解释。 疾病异质性反映了生物系统固有的概率特性，导致固定的、 有令人信服的证据表明进化的分子电路是确定性的、真实的生物变异。 将表型变异作为数量性状进行控制 因此，将变异性理解为数量性状。 对于了解表型多样性（一般而言）的病因学和个体的疾病潜力至关重要 （特别是）在这里，我们将开始最终回答以下精准医学问题：什么是正常或正常？ 我预期罹患疾病的可能性是什么？ 人类的环境表型和疾病变异性是解决这些问题的第一步吗？ 确定概率过程导致疾病异质性的机制是为了创建一个 假定的方差调节因子和基因的目录；表型、表观遗传和细胞方差图谱 绘制同基因模型系统（小鼠）中概率变异的图谱，并证明这一点； 如果确实如此，则方差控制的调节结构在小鼠和人类之间是保守的。 无法解释的疾病异质性的很大一部分是由于变异本身的分子控制，那么 我们将发现一个全新的疾病病因学领域，社区可以利用它来 开发全新的预测、诊断和治疗干预措施，无论疾病是什么 兴趣。