FHS-SCAN Genome Wide Association Scan for Atherosclerosis Pathway Genes

这项研究的总体目标是确定影响冠状动脉钙化(CAC)的基因。 动脉粥样硬化负荷的直接测量，以及动脉粥样硬化途径的内表型。我们 使用大型、多中心、地理多样化、流行病学定义的、纵向的、广泛的和深入的 NHLBI家族心脏研究的表型(在所有主要的动脉粥样硬化途径域上)-亚临床 全基因组联合扫描的动脉粥样硬化网络(FHS-SCAN)数据。我们相信我们的 ：AMILY研究允许优化GWAS研究设计的几个方面。为了最大限度地减少类型I错误， 保持统计能力，避免分层偏差，纳入联系证据，并取得最低成就 可承受的成本，我们将采用两阶段研究设计。在第一阶段，1000名无关的FHS-SCAN高加索人 受试者(500例高钙化动脉病变和等量的低钙化对照)将 使用Illumina 500K HumMap芯片进行基因分型，由基于基因的单倍型标记单 核苷酸多态(HtSNP)。不相关的病例对照是最强大的设计之一 基因发现和能力是重要的，以抵消在一个 GWARD。但使用无关数据的主要危险是由于人口分层导致的假阳性命中。这个 这种两阶段设计的美妙之处在于，在阶段2中，那些在阶段1中显示关联的SNP (针对多次比较进行了调整)将在其余2767名受试者的FHS扫描样本中进行基因分型， 包括第1阶段病例/对照的家庭成员。阶段2中的基于家庭的关联分析将 排除由于人口分层造成的假阳性。此外，我们可以利用我们在上获得的链接结果 这些家庭对关联结果的解释有所增强。这个家庭设计的FHS-SCAN 资源允许我们通过以下选择来优化阶段1样本的主要用途(发现能力) 不相关的案例-对照，并针对其主要目的优化阶段2样本(验证/消除 假阳性)通过利用整个家庭。这种两阶段的方法对检测任何基因都有很高的能力 在动脉粥样硬化途径中，至少有3-6%的性状可以通过至少在 R2=0.80的功能变体。随着丰富的FHS受试者的表型特征在扩展 3代家系和可用的连锁结果，全基因组关联扫描将允许快速 并有效地发现与人类动脉粥样硬化发展相关的基因。这样的发现 将具有重要的意义：它们可以增强我们对新陈代谢和机制的理解 导致动脉粥样硬化和冠脉终点的过程，从而提示可能的 干预或治疗。

The overall aim of this study is to identify genes influencing coronary artery calcification (CAC), a direct measure of atherosclerotic burden, as well as endophenotypesfor the atherosclerosis pathway. We use the large, multicenter, geographically diverse, epidemiologically defined, longitudinal, broadly and deeply phenotyped (on all major atherosclerosis pathway domains) NHLBI Family Heart Study-SubClinical Atherosclerosis Network (FHS-SCAN) data for a genome wide association scan (GWAS). We believe our :amily study allows optimization of several aspects of GWAS study design. To minimize Type I error, maintain statistical power, avoid stratification bias, incorporate linkage evidence, and to achievelowest Dossible cost, we will employ a two-stage study design. In Stage 1, 1,000 unrelated FHS-SCANCaucasian ubjects (500 cases with highly calcified arterial lesions and an equal number of low CAC controls) will be genotyped using the Illumina 500K HumMap chip, consisting of gene-based haplotype-tagging single nucleotide polymorphisms (htSNPs). Unrelated case-controlsare one of the most powerful designs for gene discovery, and power is important to offset the need to correct for so many multiple comparisons in a GWAS. But the main danger of using unrelateds is false-positive hits due to population stratification. The beauty of this two stage design, is that in Stage 2 those SNPs showing evidence for associationin Stage 1 (adjusted for multiple comparisons) will be genotyped in the remaining FHS-SCAN sample of 2,767 subjects, which include family members of Stage 1 cases/controls. Family-based association analyses in Stage 2 will rule out false positives due to population stratification. Further, we can utilize our linkage results obtained on these families to augment the interpretation of the association results. This family design of the FHS-SCAN resource allows us to optimize the Stage 1 sample for its main purpose (power for discovery) by subselecting unrelated cases-controls, and to optimize the Stage 2 sample for its main purpose (validation/elimination of false positives) by utilizing entire families. This two stage approach has high power to detect any gene explaining at least 3-6% of a trait in the atherosclerosis pathway, through ht-SNPs that are at least within R2=0.80 of a functional variant. With the wealth of phenotypic characterization of FHS subjects in extended 3-generational families and the available linkage results, a genomewide association scan would allow rapid and efficient discovery of genes related to the development of atherosclerosis in humans. Such findings would be of great significance: they could enhance our understanding of the metabolic andmechanistic processes that lead to atherosclerosis and coronary endpoints and, thereby, suggest possible points of intervention or therapy.