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A custom correlation coefficient (CCC) approach for fastidentification of multi-SNP association patterns in genome-wide SNPsdata

机译：自定义相关系数（CCC）方法可实现快速全基因组SNP中多SNP关联模式的鉴定数据

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Complex diseases are often associated with sets of multiple interacting genetic factors and possibly with unique sets of the genetic factors in different groups of individuals (genetic heterogeneity). We introduce a novel concept of Custom Correlation Coefficient (CCC) between single nucleotide polymorphisms (SNPs) that address genetic heterogeneity by measuring subset correlations autonomously. It is used to develop a 3-step process to identify candidate multi-SNP patterns: (1) pairwise (SNP-SNP) correlations are computed using CCC; (2) clusters of so-correlated SNPs identified; and (3) frequencies of these clusters in disease cases and controls compared to identify disease-associated multi-SNP patterns. This method identified 42 candidate multi-SNP associations with hypertensive heart disease (HHD), among which one cluster of 22 SNPs (6 genes) included 13 in SLC8A1 (aka NCX1, an essential component of cardiac excitation-contraction coupling) and another of 32 SNPs had 29 from a different segment of SLC8A1. While allele frequencies show little difference between cases and controls, the cluster of 22 associated alleles were found in 20% of controls but no cases and the other in 3% of controls but 20% ofcases. These suggest that both protective and risk effects on HHD could beexerted by combinations of variants in different regions ofSLC8A1, modified by variants from other genes. The resultsdemonstrate that this new correlation metric identifies disease-associatedmulti-SNP patterns overlooked by commonly used correlation measures.Furthermore, computation time using CCC is a small fraction of that required byother methods, thereby enabling the analyses of large GWAS datasets.
机译：复杂疾病通常与多种相互作用的遗传因素有关，并可能与不同群体的个体中遗传因素的独特集合有关（遗传异质性）。我们介绍了单核苷酸多态性（SNP）之间的自定义相关系数（CCC）的新概念，该特征通过自动测量子集的相关性解决遗传异质性。它用于开发一个三步过程来识别候选的多个SNP模式：（1）使用CCC计算成对（SNP-SNP）相关性； （2）识别出如此相关的SNP簇； （3）比较疾病病例和对照中这些簇的频率，以鉴定与疾病相关的多SNP模式。该方法确定了42个与高血压心脏病（HHD）的候选多SNP关联，其中22个SNP簇（6个基因）包括SLC8A1中的13个（又名NCX1，这是心脏兴奋-收缩耦合的重要组成部分），另外32个SNP具有来自SLC8A1不同片段的29个。虽然等位基因频率在病例和对照之间几乎没有差异，但是在20％的对照中发现22个相关等位基因的簇，但没有病例，而在3％的对照中发现另一个，而20％案件。这些表明对HHD的保护作用和危险作用都可能是通过变体组合在不同区域发挥作用SLC8A1，已被其他基因的变体修饰。结果证明了这种新的相关性指标可以识别与疾病相关的疾病常用的相关度量忽略了多个SNP模式。此外，使用CCC的计算时间仅是CCC所需时间的一小部分其他方法，从而可以分析大型GWAS数据集。

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