Development and implementation of linkage-analysis methods for the genetic mapping of complex traits

本项目的目标是评估、进一步发展和实施复杂性状遗传定位的连锁分析方法。项目的第一部分涉及mod得分分析，其中参数LOD得分在特征模型参数上最大化。我们的团队之前已经实现了常染色体遗传位点的二分类特征的MOD-score分析。通过进行模拟和分析反思，将评估在何种程度上疾病模型参数可以通过MOD-score分析对不同规模的家系进行估计。MOD评分检测复杂性状连锁的能力，包括那些具有印迹或代谢干扰的性状，将与其他方法的能力进行比较。研究人员还计划调查男性和女性基因图谱之间的差异在多大程度上可以虚假地得出印记存在的结论。此外，将对x染色体位点进行二分类性状的MOD-score分析。进一步的目标是为定量表型设计和实施MOD-score分析。该项目的第二部分解决了全基因组参数连锁分析的实施，该分析明确地模拟了两个性状位点。这样一种系统的二维方法将允许对两个基因座相互作用进行全基因组评估，也可以对那些仅观察一个基因座时无法观察到明显影响的性状进行遗传定位。

The goal of this project is to assess, further develop, and implement methods of linkage analysis for the genetic mapping of complex traits. The first part of the project is concerned with MOD-score analysis, in which the parametric LOD score is maximized over the trait-model parameters. Our group has previously implemented a MOD-score analysis of dichotomous traits for autosomal genetic loci. By performing simulations as well as by analytical reflections, it will be assessed to what degree the disease-model parameters can be estimated by a MOD-score analysis for pedigrees of different sizes. The power of MOD scores to detect linkage for complex traits, including those with imprinting or metabolic interference, will be compared to the power of other methods. It is also planned to investigate to what degree a difference between the male and female genetic map can spuriously lead to the conclusion that imprinting is present. In addition, MOD-score analysis of dichotomous traits will be implemented for X-chromosomal loci. A further goal is to devise and implement a MOD-score analysis for quantitative phenotypes. The second part of the project addresses the implementation of a genome-wide parametric linkage analysis which explicitly models two trait loci. Such a systematic two-dimensional approach will allow for the genome-wide evaluation of two-locus interactions, and also for the genetic mapping of those traits for which no marked effect can be observed when looking at only one locus.