Strauch K, Fimmers R, Kurz T, Deichmann K A, Wienker T F, Baur M P
Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, 53105 Bonn, Germany.
Am J Hum Genet. 2000 Jun;66(6):1945-57. doi: 10.1086/302911. Epub 2000 May 4.
We present two extensions to linkage analysis for genetically complex traits. The first extension allows investigators to perform parametric (LOD-score) analysis of traits caused by imprinted genes-that is, of traits showing a parent-of-origin effect. By specification of two heterozygote penetrance parameters, paternal and maternal origin of the mutation can be treated differently in terms of probability of expression of the trait. Therefore, a single-disease-locus-imprinting model includes four penetrances instead of only three. In the second extension, parametric and nonparametric linkage analysis with two trait loci is formulated for a multimarker setting, optionally taking imprinting into account. We have implemented both methods into the program GENEHUNTER. The new tools, GENEHUNTER-IMPRINTING and GENEHUNTER-TWOLOCUS, were applied to human family data for sensitization to mite allergens. The data set comprises pedigrees from England, Germany, Italy, and Portugal. With single-disease-locus-imprinting MOD-score analysis, we find several regions that show at least suggestive evidence for linkage. Most prominently, a maximum LOD score of 4.76 is obtained near D8S511, for the English population, when a model that implies complete maternal imprinting is used. Parametric two-trait-locus analysis yields a maximum LOD score of 6.09 for the German population, occurring exactly at D4S430 and D18S452. The heterogeneity model specified for analysis alludes to complete maternal imprinting at both disease loci. Altogether, our results suggest that the two novel formulations of linkage analysis provide valuable tools for genetic mapping of multifactorial traits.
我们提出了对复杂遗传性状连锁分析的两种扩展方法。第一种扩展方法允许研究人员对由印记基因引起的性状进行参数化（LOD评分）分析，即对显示亲本来源效应的性状进行分析。通过指定两个杂合子外显率参数，可以根据性状表达的概率对突变的父源和母源进行不同的处理。因此，单疾病位点印记模型包含四个外显率，而不是仅三个。在第二种扩展方法中，针对多标记设置制定了具有两个性状位点的参数化和非参数化连锁分析，可选择考虑印记情况。我们已将这两种方法都实现到了GENEHUNTER程序中。新工具GENEHUNTER - IMPRINTING和GENEHUNTER - TWOLOCUS被应用于人类家庭对螨过敏原致敏的数据。数据集包括来自英格兰、德国、意大利和葡萄牙的家系。通过单疾病位点印记MOD评分分析，我们发现了几个至少显示出连锁暗示证据的区域。最显著的是，当使用暗示完全母源印记的模型时，英国人群在D8S511附近获得了4.76的最大LOD评分。参数化双性状位点分析在德国人群中产生了6.09的最大LOD评分，恰好出现在D4S430和D18S452处。为分析指定的异质性模型暗示两个疾病位点均存在完全母源印记。总之，我们的结果表明，连锁分析的这两种新方法为多因素性状的基因定位提供了有价值的工具。
