FHS-SCAN Genome Wide Association Scan for Atherosclerosis Pathway Genes

描述（由申请人提供）：本研究的总体目的是鉴定影响冠状动脉钙化（CAC）的基因，CAC是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在表型。我们使用大型、多中心、地理多样、流行病学定义、纵向、广泛和深入表型（所有主要动脉粥样硬化途径域）的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）。我们相信我们的家庭研究可以优化GWAS研究设计的几个方面。为了最大限度地减少I类错误，保持统计功效，避免分层偏倚，纳入关联证据，并实现尽可能低的成本，我们将采用两阶段研究设计。在第1阶段，将使用Illumina 500 K HumMap芯片对1，000例无关的FHS-SCAN高加索受试者（500例高度钙化动脉病变和相同数量的低CAC对照）进行基因分型，该芯片由基于基因的单倍型标记单核苷酸多态性（htSNP）组成。不相关的病例对照是基因发现的最强大的设计之一，并且功效对于抵消在GWAS中校正如此多的多重比较的需要是重要的。但使用无关的主要危险是由于人群分层而导致的假阳性。该两阶段设计的优点在于，在第2阶段中，在第1阶段（针对多重比较调整）中显示关联证据的那些SNP将在剩余的2，767名受试者的FHS-SCAN样本中进行基因分型，所述受试者包括第1阶段病例/对照的家庭成员。第2阶段中基于家族的关联分析将排除由于人群分层导致的假阳性。此外，我们可以利用我们在这些家庭获得的连锁结果，以增加关联结果的解释。FHS-SCAN资源的这一系列设计使我们能够通过子选择不相关的病例对照来优化第1阶段样本的主要目的（发现能力），并通过利用整个系列来优化第2阶段样本的主要目的（验证/消除假阳性）。这种两阶段方法具有高功效，通过至少在功能变体的R2=0.80内的ht-SNP来检测解释动脉粥样硬化途径中至少3-6%的性状的任何基因。随着FHS受试者在扩展的3代家族中的表型表征的丰富和可用的连锁结果，全基因组关联扫描将允许快速和有效地发现与人类动脉粥样硬化发展相关的基因。这些发现将具有重要意义：它们可以增强我们对导致动脉粥样硬化和冠状动脉终点的代谢和机械过程的理解，从而提出可能的干预或治疗点。

DESCRIPTION (provided by applicant): The overall aim of this study is to identify genes influencing coronary artery calcification (CAC), a direct measure of atherosclerotic burden, as well as endophenotypes for 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 family 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 achieve lowest possible cost, we will employ a two-stage study design. In Stage 1, 1,000 unrelated FHS-SCAN Caucasian subjects (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-controls are 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 association in 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 genome wide 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 and mechanistic processes that lead to atherosclerosis and coronary endpoints and, thereby, suggest possible points of intervention or therapy.