The X-factor of complex disease: From population genetics to GWAS of Chromosome X

复杂疾病的X因素:从群体遗传学到X染色体的GWAS

基本信息

  • 批准号:
    8731772
  • 负责人:
  • 金额:
    $ 37.27万
  • 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:
    2013-09-09 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Chromosome X plays a distinctive and notable role in human health and disease, but there is a fundamental gap in studying its function in complex human disease, because the vast majority of genome-wide association studies (GWAS) disregarded or incorrectly analyzed X-linked data. Hence, there is an urgent need for methods that will enable investigation of the X-linked basis of complex diseases, especially those that exhibit gender disparity in risk, age of onset, severity, o symptoms. Such methods must account for differences between chromosome X and the rest of the genome, including differences in the modes of inheritance, sexual dimorphism in susceptibility, dosage compensation (X-inactivation), population genetic patterns, and ascertainment biases. The overarching long-term goal of the research program is to improve the search for sex-linked complex disease genes and to elucidate how evolutionary history has shaped human genetic variation differently on the sex chromosomes. The objective of this application is to discover X-linked loci underlying various complex diseases while putting forth improved statistical and computational methods and software that are specially designed for chromosome X. The underlying rationale is that the proposed research will help uncover a portion of the heritable basis of complex disease that has yet to be explained by GWAS loci ('missing heritability'), reveal the role of chromosome X in disease etiology, and advance the exploration of the sex-linked basis of sex-specific disease patterns. Guided by extensive preliminary data and analysis, this objective will be met by pursuing three specific aims: (1) Develop new statistical and computational methodologies to facilitate powerful association studies that accommodate chromosome X; (2) Discover and replicate X-linked disease genes in existing and emerging GWAS datasets spanning different diseases and populations; (3) develop a software package for X-linked association studies. The innovation of the proposed research stems from the novel analytical methodologies that accurately deal with the challenges surrounding the analysis of chromosome X. Its contribution will be significant because it will bring chromosome X-which has so far been largely omitted-into the GWAS landscape and, specifically, will find novel X-linked associations underlying complex human disease while making analytical methods available for the next generation of association studies. This contribution will be further multiplied by offering a software package implementing all methods to the scientific community, thus allowing researchers to uncover X-linked genes underlying additional complex diseases and in additional populations. Collectively, the proposed research is significant as it will substantially advance our understanding of the role chromosome X plays in complex human disease.
描述(由申请人提供): X染色体在人类健康和疾病中发挥着独特而显著的作用,但在研究其在复杂人类疾病中的功能方面存在着根本性的差距,因为绝大多数全基因组关联研究(GWAS)忽视或错误地分析了X连锁数据。因此,迫切需要能够调查复杂疾病的X连锁基础的方法,特别是那些在风险、发病年龄、严重程度和症状方面表现出性别差异的疾病。这种方法必须考虑到X染色体和基因组其他部分之间的差异,包括遗传模式的差异、易感性的性别二型性、剂量补偿(X失活)、群体遗传模式和确定偏差。该研究计划的总体长期目标是改进对与性别相关的复杂疾病基因的搜索,并阐明进化史如何以不同的方式塑造人类在性染色体上的遗传变异。这项应用的目的是发现各种复杂疾病背后的X连锁基因,同时提出改进的统计和计算方法以及专门为X染色体设计的软件。潜在的理论基础是,拟议的研究将有助于揭示复杂疾病的部分可遗传基础,这些基础尚未被GWAS基因座(缺失遗传性)解释,揭示X染色体在疾病病因学中的作用,并推进对性别特定疾病模式的性别连锁基础的探索。在广泛的初步数据和分析的指导下,将通过实现三个具体目标来实现这一目标:(1)开发新的统计和计算方法,以促进适应X染色体的强大的关联研究;(2)在跨越不同疾病和人口的现有和新出现的GWAs数据集中发现和复制X连锁疾病基因;(3)开发X连锁关联研究软件包。拟议研究的创新来自于准确应对围绕X染色体分析的挑战的新颖分析方法。它的贡献将是重大的,因为它将把迄今基本上被省略的X染色体带入GWAS的版图,具体地说,将发现复杂人类疾病背后的新的X连锁关联,同时使分析方法可用于下一代关联研究。这一贡献将进一步扩大,向科学界提供一个实施所有方法的软件包,从而使研究人员能够在更多的复杂疾病和更多的人群中发现与X相关的基因。总而言之,这项拟议的研究具有重要意义,因为它将极大地促进我们对X染色体在复杂人类疾病中所起作用的理解。

项目成果

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Alon Keinan其他文献

Alon Keinan的其他文献

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{{ truncateString('Alon Keinan', 18)}}的其他基金

The X-factor of complex disease: From population genetics to GWAS of Chromosome X
复杂疾病的X因素:从群体遗传学到X染色体的GWAS
  • 批准号:
    8501817
  • 财政年份:
    2013
  • 资助金额:
    $ 37.27万
  • 项目类别:
The X-factor of complex disease: Development, implementation, and extensive application of methods for analysis of the X chromosome in GWA, sequence-based association, and eQTL studies
复杂疾病的 X 因素:GWA、基于序列的关联和 eQTL 研究中 X 染色体分析方法的开发、实施和广泛应用
  • 批准号:
    9309205
  • 财政年份:
    2013
  • 资助金额:
    $ 37.27万
  • 项目类别:

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