Supplementary Material for: The Use of Haplotypes in the Identification of Interaction between SNPs

Although haplotypes can provide great insight into the complex relationships between functional polymorphisms at a locus, their use in modern association studies has been limited. This is due to our inability to directly observe haplotypes in studies of unrelated individuals, but also to the extra complexity involved in their analysis and the difficulty in identifying which is the truly informative haplotype. Using a series of simulations, we tested a number of different models of a haplotype carrying two functional single nucleotide polymorphisms (SNPs) to assess the ability of haplotypic analysis to identify functional interactions between SNPs at the same locus. We found that, when phase is known, analysis of the haplotype is more powerful than analysis of the individual SNPs. The difference between the two approaches becomes less either as an increasing number of non-informative SNPs are included, or when the haplotypic phase is unknown, while in both cases the SNP association becomes progressively better at identifying the association. Our results suggest that when novel genotyping and bioinformatics methods are available to reconstruct haplotypic phase, this will permit the emergence of a new wave of haplotypic analysis able to consider interactions between SNPs with increased statistical power.

尽管单倍型（haplotype）能够为某一基因座上的功能多态性之间的复杂关联提供深刻见解，但在现代关联研究中，单倍型的应用却受到了限制。这一方面源于我们无法在无关个体的研究中直接观测单倍型，另一方面也因为单倍型分析涉及额外的复杂度，且难以甄别真正具有信息价值的单倍型。本研究通过一系列模拟实验，针对携带两个功能型单核苷酸多态性（single nucleotide polymorphism，SNP）的单倍型构建了多种不同模型，以此评估单倍型分析用于识别同一基因座上SNP之间功能互作的能力。研究结果显示，当单倍型分型已知时，单倍型分析的效力要优于单个SNP的分析。随着纳入的非信息性SNP数量增加，或是单倍型分型未知时，两种分析方法之间的效力差异都会缩小；而在这两种场景下，SNP关联分析识别关联的能力都会逐步提升。本研究结果表明，当可借助新型基因分型与生物信息学方法重建单倍型分型时，将有望掀起新一轮单倍型分析浪潮，该类分析能够以更高的统计效力考量SNP之间的互作关系。