FHS-SCAN Genome Wide Association Scan for Atherosclerosis Pathway Genes

本研究的总体目的是确定影响冠状动脉钙化（CAC）的基因， 直接测量动脉粥样硬化负荷，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、流行病学定义、纵向、广泛和深入的 表型（所有主要动脉粥样硬化通路域）NHLBI家族心脏研究-亚临床 动脉粥样硬化网络（FHS-SCAN）数据进行全基因组关联扫描（GWAS）。我们相信我们的 ：amily研究允许优化GWAS研究设计的几个方面。为了尽量减少I类错误， 保持统计功效，避免分层偏见，纳入关联证据，并实现最低 由于费用有限，我们将采用两阶段研究设计。在第一阶段，1,000名无关的FHS-SCANCaucasian 随后（500例高度钙化动脉病变和相同数量的低CAC对照）将 使用Illumina 500 K HumMap芯片进行基因分型，该芯片由基于基因的单倍型标记单克隆抗体组成。 核苷酸多态性（htSNPs）。不相关的病例对照是最强大的设计之一， 基因发现，和权力是重要的，以抵消需要纠正这么多的多重比较，在一个 GWAS。但使用无关的主要危险是由于人群分层而导致的假阳性。的 这两个阶段设计的美妙之处在于，在第二阶段，那些在第一阶段显示关联证据的SNP （针对多重比较进行调整）将在2，767例受试者的剩余FHS-SCAN样本中进行基因分型， 包括第1阶段病例/对照的家庭成员。第二阶段以家庭为基础的关联分析将 排除由于人口分层而导致的假阳性。此外，我们可以利用我们的连锁结果获得的 这些家庭，以增加解释的关联结果。FHS-SCAN系列设计 资源允许我们通过子选择，针对其主要目的（发现能力）优化阶段1样本 不相关的病例-对照，并优化第2阶段样品的主要目的（验证/消除 假阳性）通过利用整个家庭。这两个阶段的方法有很高的权力，以检测任何基因 通过ht-SNP解释动脉粥样硬化途径中至少3-6%的性状，所述ht-SNP至少在 功能变体的R2=0.80。随着FHS受试者表型特征的丰富， 3-世代家庭和可用的连锁结果，全基因组关联扫描将允许快速 并有效发现与人类动脉粥样硬化发展相关的基因。这些发现 将具有重大意义：它们可以增强我们对代谢和机制的理解， 导致动脉粥样硬化和冠状动脉终点的过程，从而表明可能的点， 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.