Does organismal robustness explain the missing heritability in complex diseases?

机体稳健性能否解释复杂疾病中缺失的遗传性？

• 批准号: 8144732
• 负责人: Christine Queitsch
• 金额: $ 231.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144732
• 关键词: Accounting; Animal Model; Cardiovascular system; Complex; DNA; Diabetes Mellitus; Diagnosis; Disease; Environmental Exposure; Environmental Risk Factor; Failure; Family; Fishes; Gene Mutation; Genetic; Genetic Models; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Heritability; Human; Individual; Little' s Disease; Malignant Neoplasms; Measures; Modeling; Mutation; Patients; Penetrance; Plants; Population; Psyche structure; RNA; Testing; Translating; Variant; abstracting; base; disorder risk; fly; genetic variant; genome wide association study; human disease; molecular marker; public health relevance; research study; trait

DESCRIPTION (Provided by the applicant) Abstract: Complex diseases such as diabetes, cancer, cardiovascular, and mental disease tend to cluster in families. Hence, they likely involve genetic factors in addition to environmental influences. The identification of these genetic factors has proven challenging. Although genome-wide association studies (GWAS) have identified many genetic polymorphisms that are associated with complex diseases, most of these confer little disease risk and do not explain the observed heritability in families. This discrepancy, called 'missing heritability', is explained with insufficient genotyping, imprecise diagnoses, and inflated heritability estimates. Under the prevalent hypothesis, genetic predispositions will translate into disease in combination with numerous genetic modifiers and environmental factors. I propose an alternative hypothesis: genetic predispositions will translate into disease in individuals with decreased organismal robustness. Patients with copy number variants associated with complex disease are more likely than controls to carry additional CNV. Curiously, many additional CNV are unique to particular patients, suggesting an almost infinite number of genetic modifiers. Alternatively, the increased CNV burden may be an expression of a less robust and therefore sensitized genetic background. In plants, flies, and fish, decreased organismal robustness increases the penetrance of known genetic variants and reveals formerly cryptic genetic variation. Increased penetrance of known genetic variants and expression of formerly cryptic variants significantly increases heritability of complex traits. If these findings were applied to complex human disease, all individuals would first be assessed for their degree of organismal robustness and then for genetic variants associated with disease only in those with decreased robustness. This approach hinges on identifying objective markers for organismal robustness, preferably based on DNA or RNA, which can be easily assessed in large human populations. I propose to identify objective molecular markers for organismal robustness in a genetic model organism, the plant A. thaliana, by comparing control individuals to individuals rendered less robust through targeted mutation of master regulators. I previously established A. thaliana as a well-suited model for organismal robustness and identified two functionally distinct master regulators that maintain robustness. My hypothesis further predicts that organismal robustness differs among humans in the absence of mutations in master regulators. I will use the newly identified markers and traditional morphological measures to test whether wild, genetically diverse A. thaliana populations show a distribution of organismal robustness. As proof of principle for my hypothesis, I will then test whether less robust A. thaliana individuals show higher expressivity of genetic variants and mutations as predicted by my model. If so, I will have identified molecular markers for organismal robustness that are readily applicable to humans. By accounting for organismal robustness, complex diseases will become more deterministic, allowing us to better identify the contributing environmental factors and to tailor treatments. Public Health Relevance: The missing heritability in complex human diseases has been explained with the failure to identify the numerous genetic modifiers and environmental exposures leading to disease. Prompted by recent findings on increased mutation burden in patients with complex disease and our model organism studies, I propose an alternative explanation: genetic predispositions will translate into disease in individuals with generally decreased organismal robustness. Employing a genetically tractable model organism, I propose to develop molecular markers for organismal robustness that are applicable in large human populations and to test their predictive power in proof-of-principle experiments.

描述（申请人提供） 摘要：糖尿病，癌症，心血管和精神疾病等复杂疾病往往会聚集在家庭中。因此，除了环境影响外，它们可能还涉及遗传因素。这些遗传因素的识别已被证明具有挑战性。尽管全基因组关联研究（GWAS）已经确定了许多与复杂疾病相关的遗传多态性，但其中大多数赋予了很少的疾病风险，并且无法解释家庭中观察到的遗传力。这种差异被称为“缺失的遗传力”，用基因分型，不精确的诊断和膨胀的遗传力估计来解释。在普遍的假设下，遗传易感性将与许多遗传修饰剂和环境因素结合使用。我提出了一个替代假设：遗传易感性将转化为有机鲁棒性降低的个体的疾病。与复杂疾病相关的拷贝数变异的患者比对照组更有可能携带额外的CNV。奇怪的是，许多其他CNV是特定患者独有的，这表明几乎无限的遗传修饰剂。另外，增加的CNV负担可能是较不健壮的遗传背景的表达。在植物，苍蝇和鱼类中，有机体鲁棒性降低会增加已知遗传变异的渗透性，并揭示了以前的神秘遗传变异。已知遗传变异的外观和以前的神秘变体的表达显着提高了复杂性状的遗传力。如果将这些发现应用于复杂的人类疾病，所有个体将首先评估其有机鲁棒性程度，然后仅在稳健性降低的患者中与疾病相关的遗传变异。这种方法取决于确定有机鲁棒性的客观标记，最好基于DNA或RNA，可以在大量的人群中轻松评估。我建议通过将对照个体与通过靶向调节剂的靶向突变进行比较，鉴定遗传模型生物A. thaliana植物A. thaliana植物A. thaliana的物体鲁棒性的客观分子标记。我之前曾将A. thaliana建立为有机鲁棒性的合理模型，并确定了两个保持稳健性的功能不同的主调节器。我的假设进一步预测，在不存在大型调节剂突变的情况下，人体之间的生物鲁棒性有所不同。我将使用新确定的标记和传统的形态学措施来测试野生，遗传多样的塔利亚纳人种群是否显示出有机鲁棒性的分布。作为我假设的原理证明，我将测试我模型所预测的遗传变异和突变的较高的thaliana个体是否表现出更高的表达性。如果是这样，我将确定容易适用于人类的有机鲁棒性的分子标记。通过考虑有机鲁棒性，复杂的疾病将变得更加确定性，使我们能够更好地确定促成环境因素并量身定制治疗。 公共卫生相关性：已经解释了复杂的人类疾病中缺失的遗传力，未能识别导致疾病的众多遗传修饰剂和环境暴露。在最近关于复杂疾病患者突变负担和我们的模型生物研究中的突变负担增加的发现引起的，我提出了另一种解释：遗传易感性将转化为有机体稳健性降低的个体中的疾病。我提出采用遗传学模型的生物体，他建议开发适用于大型人类种群的有机鲁棒性的分子标记，并在原理证明实验中测试其预测能力。