Statistical, population genetics and genetic epidemiolog

该项目涉及统计遗传学问题，特别是在开发和评估绘制人类性状变异的方法方面。我们一直在研究多位点方法，这些方法可以提高表型模型的效率，并且相对于随机交配假设具有稳健性。我们已经开发了一种新的方法来预测疾病易感性和药物不良反应等特征的遗传变异的统计图谱。该方法是基于一项观察，即在遗传关联区域中，等位基因之间的相关程度（连锁不平衡，LD）在病例组和对照组之间可能不同。通过对LD“色图”的目视检查，可以比较样品之间LD的程度和图案。然而，这些图所传达的模式受到随机变化的影响，因此有必要对LD差异进行统计评估。构建“LD对比”检验的一个困难是，在存在遗传关联的基于表型的样本中，偏离Hardy-Weinberg（随机交配）比例很可能表现出来。即使潜在种群处于Hardy-Weinberg平衡，单倍型随机配对的偏差也可能发生。因此，标准的单倍型分期技术是不可靠的。LD对比方法处理这个问题。当高易感性与一对“阴阳单倍型”（即在许多SNP位点携带不同等位基因的单倍型）相关联时，这种方法被发现特别有效。

This project is concerned with statistical genetics problems, particularly in the area of developing and evaluating methods for mapping human trait variation. We have been investigating multi-locus approaches that provide increased efficiency across models of phenotype, and robustness with respect to the random mating assumption. We have developed a novel approach to statistical mapping of genetic variants predictive of traits such as disease susceptibility and adverse reactions to drugs. The approach is based on an observation that in a region of genetic association, the extent of correlation between alleles (linkage disequilibrium, LD) can be different between the case and the control groups. The extent and the pattern of LD can be compared between samples by a visual inspection of LD "color plots". However, patterns conveyed by such plots are subject to random variation, and a statistical assessment of the LD difference is necessary. A difficulty in constructing an "LD contrast" test is that the deviations from the Hardy-Weinberg (random mating) proportions are likely to manifest in phenotype-based samples in the presence of genetic association. The deviations from random pairing of haplotypes are likely to occur even if the underlying population is in Hardy-Weinberg equilibrium. Thus, standard techniques of phasing haplotypes are unreliable. The LD contrast method deals with this issue. The method is found especially efficient when high susceptibilities are linked to a pair of "yin yang haplotypes", i.e. haplotypes carrying different alleles at many SNP sites. Dr. Kyoko Shibata (Research Fellow) has been working in the direction of improving the likelihood-based statistical methods for association of haplotypes and diplotypes with continuous traits. Dr. Shibata has been applying her methods to study genetic components of pain sensitivity.