Mendelian Disease - Asthma Comorbidity to Find Subgroup-Specific Asthma Genes

 描述(申请人提供)：哮喘是一种异质、复杂的综合征，无疑是多种不同“疾病”的混合体，每一种疾病都源于不同的基因变异和环境暴露史，导致发作性气流阻塞、收缩高反应性、粘液高分泌以及气道壁炎症和重塑的总体素质相似。在这里，我们建议使用一种新的方法来识别哮喘亚群的不同遗传贡献，其中孟德尔疾病(MD)被用作替代遗传标记。哮喘比MD更常见，在患有或不患有任何特定MD的患者中都会发生。然而，如果患有MD的患者中哮喘的比例高于没有这种疾病的患者，那么MD就构成了哮喘的遗传风险因素，而且这种关联进一步表明导致MD的基因之一在哮喘的发病机制中存在非MD引起的变异。尽管MD很少见，但对记录常见疾病和孟德尔疾病的极大(行政/账单或电子病历衍生)数据集的检查允许进行这样的赔率计算。在特定目标#1中，我们将在电子计算机管道中应用于来自&gt；1亿人的数据，识别哮喘亚组特定相关的MD，然后在特定目标#2中优先考虑他们的潜在基因以进行生物学评估。这些研究将为不同致病的哮喘亚组背后的不同分子机制提供新的见解。此外，这些研究的成功完成将建立一种全新的范式，用于解开复杂的常见疾病，其基础是它们与孟德尔疾病的共同出现，如极大的数据库中所记录的那样。

 DESCRIPTION (provided by applicant): Asthma is a heterogeneous, complex syndrome that undoubtedly represents an amalgam of multiple distinct "diseases", each stemming from a different constellation of gene variations and environmental exposure histories that results in a generally similar diathesis of episodic airflow obstruction, constrictor hyperresponsiveness, mucus hypersecretion, and airway wall inflammation and remodeling. Here, we propose to identify differential genetic contributions to asthma subgroups using a novel approach in which Mendelian diseases (MDs) are used as surrogate genetic markers. Asthma, much more common than MDs, occurs both in patients with or without any particular MD. However, if asthma is overrepresented among patients with a MD relative to those without that disease, then having that MD constitutes a genetic risk factor for asthma, and the association fur- ther implicates non-MD-causing variations in one of the MD-causing genes in the pathogenesis of asthma. Even though MDs are rare, examination of extremely large (administrative/billing or electronic medical record- derived) datasets that document both common and Mendelian diseases allows for such odds-ratio calculation. In Specific Aim #1, we will apply an in silico pipeline to data from >100 million individuals that identifies asthma subgroup specifically-associated MDs, then prioritizes their underlying genes for biological evaluation in Specific Aim #2. These studies will provide new insights into the distinguishing molecular mechanisms underlying pathogenetically distinct asthma subgroups. Moreover, successful completion of these studies will establish an entirely new paradigm for unraveling complex common diseases, based on their co-occurrence with Mendelian diseases as documented in extremely large databases.