Family-specific genetic variants contributing to asthma susceptibility

家族特异性遗传变异导致哮喘易感性

基本信息

  • 批准号:
    8857695
  • 负责人:
  • 金额:
    $ 2.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-01-15 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

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.
描述(由研究者提供):哮喘是儿童期最常见的慢性疾病,人们普遍认为哮喘易感性的主要遗传因素。全基因组关联研究依赖于“常见疾病,常见变异”的疾病模型,已经确定了超过15个与哮喘或相关表型显著相关的基因的常见变异。虽然这些发现中的大多数已经被复制,但这些变体中的任何一种所带来的风险都很低(典型OR < 1.7)。因此,有相当一部分的遗传成分归因于哮喘的发展和严重程度,这还没有被解释,称为“缺失遗传性”。“这种缺失的遗传性问题并不是哮喘所独有的,并且已经被大多数常见疾病所认识。有人提出,罕见变异可能是常见疾病中一个重要但尚未探索的参与者,事实上可能解释了一些尚未产生致病变异的强关联。在这里,我们假设一个模型,即个别家庭分离的“家庭特异性”突变有助于哮喘易感性。与大多数罕见的孟德尔疾病相比,其中疾病仅需要一个致病突变,我们假设至少一个家族特异性突变是必要的,但不足以在家族中的个体内发展疾病。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,疾病才会发展。本申请利用基于家族的全外显子组测序策略来鉴定与哮喘分离的家族特异性变体,并研究所有已知哮喘基因中功能变体的分布。我们将利用在围产期、儿科和环境流行病学中心进行的几项研究的以家庭为基础的性质,从一项原始研究中收集的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个哮喘儿童和一个非哮喘儿童的哮喘家庭,采集血液用于DNA,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的方法,对2010年12月至2011年12月期间的500个家族中的一半进行鉴定, 研究,然后进行基于家族的关联分析,以鉴定包含与哮喘相关的多个家族特异性变体的基因。然后,我们将对在另一半哮喘家族的外显子组测序数据中发现的基因进行测序,以验证这些发现。最后,我们将在我们的全外显子组数据中查看变体的频谱,以确定哮喘患者是否比他们的非哮喘亲属在已知的哮喘基因中具有更多的功能变体。

项目成果

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Andrew DeWan其他文献

Andrew DeWan的其他文献

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{{ truncateString('Andrew DeWan', 18)}}的其他基金

Detecting pleiotropic effects through integration of omics data
通过组学数据整合检测多效性效应
  • 批准号:
    9889994
  • 财政年份:
    2019
  • 资助金额:
    $ 2.81万
  • 项目类别:
Detecting pleiotropic effects through integration of omics data
通过组学数据整合检测多效性效应
  • 批准号:
    10350616
  • 财政年份:
    2019
  • 资助金额:
    $ 2.81万
  • 项目类别:
Detecting pleiotropic effects through integration of omics data
通过组学数据整合检测多效性效应
  • 批准号:
    10117042
  • 财政年份:
    2019
  • 资助金额:
    $ 2.81万
  • 项目类别:
Identification of microRNA variants associated with acute lymphoblastic leukemia
与急性淋巴细胞白血病相关的 microRNA 变异的鉴定
  • 批准号:
    9378958
  • 财政年份:
    2017
  • 资助金额:
    $ 2.81万
  • 项目类别:
Family-specific genetic variants contributing to asthma susceptibility
家族特异性遗传变异导致哮喘易感性
  • 批准号:
    8605552
  • 财政年份:
    2013
  • 资助金额:
    $ 2.81万
  • 项目类别:
Family-specific genetic variants contributing to asthma susceptibility
家族特异性遗传变异导致哮喘易感性
  • 批准号:
    8777974
  • 财政年份:
    2013
  • 资助金额:
    $ 2.81万
  • 项目类别:
Family-specific genetic variants contributing to asthma susceptibility
家族特异性遗传变异导致哮喘易感性
  • 批准号:
    8417850
  • 财政年份:
    2013
  • 资助金额:
    $ 2.81万
  • 项目类别:
Fetal Genetic Contributions to Preeclampsia
胎儿遗传对先兆子痫的影响
  • 批准号:
    8445231
  • 财政年份:
    2012
  • 资助金额:
    $ 2.81万
  • 项目类别:
Fetal Genetic Contributions to Preeclampsia
胎儿遗传对先兆子痫的影响
  • 批准号:
    8302781
  • 财政年份:
    2012
  • 资助金额:
    $ 2.81万
  • 项目类别:

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积极情绪与小儿哮喘:改善哮喘管理和健康的创新积极心理学模型
  • 批准号:
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  • 财政年份:
    2008
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WHAT FAMILY PROCESSES AFFECT CHILDHOOD ASTHMA OUTCOME?
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WHAT FAMILY PROCESSES AFFECT CHILDHOOD ASTHMA OUTCOME?
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  • 财政年份:
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  • 财政年份:
    1997
  • 资助金额:
    $ 2.81万
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