Functional Analysis of Genome Wide Associations in Colorectal Cancer

描述（由申请人提供）：结直肠癌（CRC）的全基因组关联（GWA）研究已经鉴定出许多显著相关的命中，这些命中已在其他人群中稳健复制。随着使用更高密度SNP阵列的CRC更大GWA研究以及现有GWA研究的Meta或汇总分析的完成，相关性的数量可能在未来几年内大幅增长。到目前为止，很少有人强调确定与这些发现相关的因果变异，甚至更少的努力是为了了解其生物学影响。如果不进行旨在表征通过GWA研究确定的因果变异的功能相关性的研究，就无法完全理解这种方法的生物学意义。该提案的目标是采用多学科方法，为CRC GWA研究中出现的命中事件的功能分析制定综合策略。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基因贫乏区域内的变异，需要综合分析方法。我们将通过在这些地区开发精细的映射信息，从已发表的CRC GWA研究中获得经验证的命中。我们将采用最先进的条形码多重深度再测序，并利用来自ChIP-seq，RNA-seq和计算机分析的信息，以确定基因或调控区域中的候选致病变异体，这些变异体将使用生化分析进行功能测试。我们的目标是确定通过GWA研究确定的致病基因，并表征致病变体的功能意义。通过这样做，我们的目标是充分利用GWA研究的承诺，并提供一个框架，通过全基因组关联（GWA）研究确定协会的生物学意义的全面理解。我们的工作是由越来越多的障碍，充分利用GWA研究的生物学意义的动机，如果成功，我们的方法应该适用于新的协会正在进行的GWA研究CRC，但也其他复杂的遗传疾病。 公共卫生相关性： 我们的建议的目标是制定全面的战略，从CRC全基因组关联（GWA）研究中产生的命中功能分析使用多学科的方法。我们的工作是由越来越多的障碍，充分利用GWA研究的生物学意义的动机，如果成功，我们的方法应该适用于新的协会正在进行的GWA研究CRC，但也其他复杂的遗传疾病。

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.