Dissecting Epistasis and Pleiotropy in Autism towards Personalized Medicine

描述（由申请人提供） 翻译后摘要：基因组的时代承诺，人类遗传学将迅速转化为个性化的医疗。对来自人群的大样本进行的全基因组关联研究表明，常见多态性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）已知在模式生物复杂性状的遗传结构中起主要作用，但尚未在人类生物学中探索。该项目旨在通过研究Ras-MAPK通路先天性疾病中的自闭症特征，以创新的方式克服人类遗传学目前的挑战。自闭症是一种复杂的遗传性疾病，影响近1%的人口，像大多数复杂的遗传性疾病一样，遗传性是目前遗传关联模型无法解释的。Ras-MAPK疾病是具有已知突变的遗传性疾病，包括对颅面、心脏、皮肤、肌肉骨骼和眼部发育的影响，以及携带增加的癌症风险和神经认知障碍的不同表达。我们的初步数据显示，这些疾病与自闭症密切相关，并且相同基因中的常见多态性与特发性家族性自闭症相关。因此，Ras-MAPK通路障碍为探索孤独症复杂性状中的上位性和多效性提供了一个理想的模型。我们将确定主题与Ras-MAPK障碍，测量自闭症相关的特质，并进行全基因组定位与已知的Ras-MAPK基因的相互作用。然后，我们将从患有这些疾病的患者的成纤维细胞中建立诱导多能干细胞模型，以研究利用分化成不同命运的细胞的表达和功能测定。该项目具有巨大的转化潜力，不仅可以了解遗传变异如何介导疾病风险，而且对治疗方法具有直接影响。 公共卫生相关性：自闭症谱系障碍最近估计影响近1%的美国人，并可能导致严重残疾的个人和家庭在整个生命周期中的治疗选择极其有限。随着对自闭症遗传结构和常见并发症原因的更好理解，可以改进诊断，预后，预防和治疗方案。该项目可以引领将遗传学转化为其他常见复杂遗传疾病的医学。

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.