Family-specific genetic variants contributing to asthma susceptibility

描述(由研究人员提供)：哮喘是儿童时期最常见的慢性疾病，人们普遍认为哮喘易感性存在主要的遗传因素。全基因组关联研究，依靠疾病的“共同疾病，共同变异”模式，已经确定了15个以上与哮喘或相关表型显著相关的基因的共同变异。虽然这些发现中的大多数都是重复的，但这些变异中的任何一个带来的风险都很低(典型的OR&lt；1.7)。因此，有很大一部分遗传成分归因于哮喘的发展和严重程度，还没有被解释，被称为“缺失遗传性”。这种缺失的遗传性问题并不是哮喘独有的问题，大多数常见疾病都认识到了这一点。有人提出，罕见的变异可能是常见疾病中一个重要的、但尚未被探索的参与者，实际上可能解释了一些尚未产生致病变异的强烈关联。在这里，我们假设了一个模型，即单个家庭分离导致哮喘易感性的“家庭特有”突变。与大多数罕见的孟德尔疾病不同的是，疾病只需要一个致病突变，我们假设至少有一个家族特有的突变是必要的，但不足以使疾病在家庭中的个体中发展。只有当这些私人突变发生在常见的哮喘易感性变异的背景下时，疾病才会发展。这项应用利用基于家族的全外显子组测序策略来识别与哮喘分离的家族特异性变异，并研究功能变异在所有已知哮喘基因中的分布。我们将利用围产期、儿科和环境流行病学中心进行的几项研究的家庭性质，从其中一项原始研究中收集到哮喘表型信息的儿童中选择哮喘先证者。我们建议重新联系至少有两名哮喘儿童和一名非哮喘儿童的哮喘家庭，采集血液进行DNA检测，更新父母和儿童的哮喘表型信息，并进行基于家庭的全外显子组测序分析。我们将使用全外显子组测序来鉴定家庭特有的突变 研究然后进行基于家庭的关联分析，以确定包含与哮喘相关的多个家庭特有变异的基因。然后，我们将对这一发现中确定的基因进行测序，并对另一半哮喘家族的外显子组测序数据进行排序，以验证这些发现。最后，我们将研究整个外显子组数据中变异的频谱，以确定哮喘患者的已知哮喘基因是否比他们的非哮喘亲属具有更多的功能变异。

DESCRIPTION (provided by investigator): Asthma is the most common chronic illness in childhood and it is widely recognized that there is a major genetic component to asthma susceptibility. Genome-wide association studies, relying on the "common disease, common variant" model of disease, have identified common variants in more than 15 genes significantly associated with asthma or related phenotypes. While the majority of these findings have been replicated, the risk conferred by any one of these variants is low (typical OR < 1.7). Thus, there is a significant portion of the genetic component attributed to asthma development and severity that has not been accounted for, termed "missing heritability." This missing heritability problem is not unique to asthma and has been recognized for the majority of common diseases. It has been proposed that rare variants may be an important, yet unexplored, player in common diseases and may in fact explain some of the strong associations that have not yet yielded causative variants. Here, we hypothesize a model whereby individual families are segregating "family-specific" mutations contributing to asthma susceptibility. In contrast to the majority of rare Mendelian disorders where only one causative mutation is required for disease, we hypothesize that at least one family- specific mutation is necessary, but not sufficient for diseas development within individuals in the family. It is only when these private mutations occur in the context of common asthma susceptibility variants that the disease will develop. This application utilizes a family-based whole-exome sequencing strategy to identify family-specific variants segregating with asthma and study the distribution of functional variants across all known asthma genes. We will take advantage of the family-based nature of several studies conducted at the Center for Perinatal, Pediatric and Environmental Epidemiology by selecting asthmatic probands from the children that had asthma phenotype information collected in one of the original studies. We propose to re-contact asthma families with at least two asthmatic children and one non-asthmatic child to collect blood for DNA, update the asthma phenotype information in the parents and children, and conduct family-based whole-exome sequencing analyses. We will identify family-specific mutations using whole-exome sequencing of half of the families in the study and then perform a family-based association analysis to identify genes containing multiple family-specific variants associated with asthma. We will then sequence the genes identified in this discovery exome sequencing data in the other half of the asthma families to validate these findings. Finally, we will look across the frequency spectrum of variants in our whole-exome data to determine if asthma patients have more functional variants in known asthma genes than their non-asthmatic relatives.