Dissecting Epistasis and Pleiotropy in Autism towards Personalized Medicine

描述(由申请人提供) 摘要：基因组时代预示着人类遗传学将很快转化为个性化医学。对人类群体大样本的全基因组关联研究表明，常见多态或罕见变异的主要影响不太可能导致预测疾病风险和治疗反应的能力提高。上位性(基因-基因相互作用)和多效性(同一基因的不同效应)在模式生物复杂性状的遗传结构中发挥着重要作用，但在人类生物学中尚未被探索。该项目旨在通过研究Ras-MAPK途径先天性疾病的自闭症特征，以创新的方式克服目前人类遗传学中的挑战。自闭症是一种复杂的可遗传疾病，影响近1%的人口，像大多数复杂的遗传疾病一样，目前的遗传关联模型无法解释这种遗传性。RAS-MAPK疾病是一种遗传性疾病，具有已知的突变，包括对颅面部、心脏、皮肤、肌肉骨骼和眼睛发育的影响，以及癌症风险的增加和神经认知障碍的不同表现。我们的初步数据显示，这些疾病与自闭症密切相关，相同基因的常见多态与特发性家族性自闭症相关。因此，Ras-MAPK通路障碍为探索自闭症复杂特征中的上位性和多效性提供了一个理想的模型。我们将确定患有RAS-MAPK障碍的受试者，测量与自闭症相关的特征，并为已知的RAS-MAPK基因的相互作用进行全基因组图谱绘制。然后，我们将从这些疾病患者的成纤维细胞中建立诱导多能干细胞模型，以利用分化为不同命运的细胞来研究其表达和功能分析。该项目不仅在理解基因变异如何调节疾病风险方面具有巨大的翻译潜力，而且对治疗方法也具有直接的影响。 公共卫生相关性：据估计，自闭症谱系障碍最近影响了近1%的美国人，并可在治疗选择极其有限的情况下，在一生中导致个人和家庭严重残疾。通过更好地了解自闭症的遗传结构和常见并存疾病的原因，可以改进诊断、预后、预防和治疗方案。该项目可能引领将遗传学转化为治疗其他常见复杂遗传疾病的药物。

DESCRIPTION (Provided by the applicant) Abstract: The era of the genome promised that human genetics would quickly translate into personalized medicine. Genome-wide association studies on large samples from human populations have indicated that main effects of common polymorphisms or rare variants are unlikely to lead to improved ability to predict disease risk and therapeutic response. Epistasis (gene-gene interaction) and pleiotropy (diverse effects of the same gene) are known to play major roles in the genetic architecture of complex traits in model organisms, but have not yet been explored in human biology. This project aims to overcome the current challenge in human genetics in an innovative way by studying autism traits in congenital disorders of the Ras-MAPK pathway. Autism is a complex heritable disorder affecting nearly 1% of the population, and like most complex genetic disorders, the heritability is unaccounted for by current models of genetic association. Ras-MAPK diseases are genetic disorders with known mutations that include effects on craniofacial, cardiac, cutaneous, musculoskeletal and ocular development, as well as carrying increased risk of cancer and varying expression of neurocognitive impairment. Our preliminary data shows that these disorders are strongly associated with autism and that common polymorphisms in the same genes are associated with idiopathic familial autism. Therefore, Ras-MAPK pathway disorders provide an ideal model by which to explore epistasis and pleiotropy in the complex trait of autism. We will ascertain subjects with Ras-MAPK disorders, measure autism-related traits, and perform genome-wide mapping for interactors with the known Ras-MAPK genes. We will then establish induced pluripotent stem cell models from fibroblasts of patients with these disorders in order to investigate expression and functional assays utilizing cells differentiated into varying fates. This project has great translational potential not only for understanding how genetic variants mediate disease risk, but also with immediate implications for treatment approaches. Public Health Relevance: Autism Spectrum Disorders have recently been estimated to affect nearly 1% of Americans, and can cause severe disability to individuals and families across the lifespan with extremely limited treatment options. With better understanding of the genetic architecture of autism and causes of common co-morbidities, diagnosis, prognosis, prevention and treatment options could be improved. This project could lead the way to translating genetics into medicine for other common complex genetic disorders.