Functional Analysis of Genome Wide Associations in Colorectal Cancer

描述(由申请人提供)：对结直肠癌(CRC)的全基因组关联(GWA)研究导致确定了一些显著相关的命中，这些命中已经在其他人群中得到了强有力的复制。在接下来的几年里，随着使用更高密度的SNP阵列对CRC进行的更大的GWA研究以及对现有GWA研究的荟萃分析或汇集分析的完成，关联的数量可能会大幅增加。到目前为止，几乎没有重视确定与这些发现有关的因果变异，更没有针对发展对其生物影响的理解的努力。如果不进行旨在确定通过全球气候变化研究确定的因果变异的功能相关性的研究，就不可能完全了解这种方法的生物学影响。这项建议的目标是制定综合战略，利用多学科方法对儿童权利全球行动研究产生的HITS进行功能分析。这不是一个微不足道的挑战，因为迄今为止通过GWA研究确定的大多数关联并不针对外显子中的非同义变异，而是涉及位于基因附近或需要综合分析方法的基因缺失区域内的变异。我们将通过在这些地区开发精细的地图信息，从已发表的CRC GWA研究中寻找经过验证的命中率。我们将结合最先进的条形码多重深度重测序，并利用来自芯片序列、RNA序列和计算机分析的信息，在将使用生化分析进行功能测试的基因或监管区域中识别候选因果变异。我们的目标是确定通过GWA研究确定的因果基因(S)，并表征因果变体的功能意义。通过这样做，我们的目标是充分利用GWA研究的前景，并为全面理解通过基因组范围关联(GWA)研究确定的关联的生物学影响提供一个框架。我们的工作是受到越来越多的障碍的推动，以充分利用GWA研究的生物学意义，如果成功，我们的方法应该适用于正在进行的GWA对CRC以及其他复杂遗传病的研究中确定的新关联。 公共卫生相关性：我们建议的目标是制定综合战略，使用多学科方法对来自CRC全基因组关联(GWA)研究的HITS进行功能分析。我们的工作是受到越来越多的障碍的推动，以充分利用GWA研究的生物学意义，如果成功，我们的方法应该适用于正在进行的GWA对CRC以及其他复杂遗传病的研究中确定的新关联。

DESCRIPTION (provided by applicant): Genome-wide association (GWA) studies of colorectal cancer (CRC) have led to the identification of a number of significantly associated hits that have been robustly replicated in other populations. The number of associations is likely to grow considerably over the next few years as larger GWA studies of CRC using higher density SNP arrays as well as meta- or pooled analyses of existing GWA studies are completed. To date there has been little emphasis on identifying the causal variant associated with these findings and even less effort directed towards developing an understanding of their biological impact. Without conducting studies designed to characterize the functional relevance of causal variants identified through GWA studies a complete understanding of the biological implications of such approaches will not be achieved. The goal of this proposal is to develop comprehensive strategies for the functional analysis of hits arising from CRC GWA studies using a multidisciplinary approach. This is not an insignificant challenge as most of the associations identified to date through GWA studies do not target non-synonymous variants in exons but instead involve variants that lie near genes or within gene-poor regions that require comprehensive analytical approaches. We will pursue validated hits arising from published CRC GWA studies by developing fine mapping information across these regions. We will incorporate state-of-the-art barcoded multiplex deep re-sequencing, and leverage information from ChIP-seq, RNA-seq and in silico analyses to identify candidate causal variants in genic or regulatory regions that will be functionally tested using biochemical analyses. Our goal is to identify the causal gene(s) identified through GWA studies and to characterize the functional significance of the causal variants. By doing so we aim to fully exploit the promise of GWA studies and provide a framework for a comprehensive understanding of the biological implications of associations identified through genome wide association (GWA) studies. Our work is motivated by the growing roadblock to fully exploiting the biological significance of GWA studies and if successful our approaches should be applicable to novel associations identified in ongoing GWA studies of CRC but also other complex genetic diseases. PUBLIC HEALTH RELEVANCE: The goal of our proposal is to develop comprehensive strategies for the functional analysis of hits arising from CRC genome wide association (GWA) studies using a multidisciplinary approach. Our work is motivated by the growing roadblock to fully exploiting the biological significance of GWA studies and if successful our approaches should be applicable to novel associations identified in ongoing GWA studies of CRC but also other complex genetic diseases.