Feng Rui, Leckman James F, Zhang Heping
Department of Epidemiology and Public Health and Yale Child Study Center, Yale University of School of Medicine, New Haven, CT 06250-8034, USA.
Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16739-44. doi: 10.1073/pnas.0404623101. Epub 2004 Nov 17.
Linkage analysis is used routinely to map genes for human diseases and conditions. However, the existing linkage-analysis methods require that the diseases or conditions either be dichotomized or measured by a quantitative trait, such as blood pressure for hypertension. In the latter case, normality is generally assumed for the trait. However, many diseases and conditions, such as cancer and mental and behavioral conditions, are rated on ordinal scales. The objective of this study was to establish a framework to conduct linkage analysis for ordinal traits. We propose a latent-variable, proportional-odds logistic model that relates inheritance patterns to the distribution of the ordinal trait. We use the likelihood-ratio test for testing evidence of linkage. By means of simulation studies, we find that the power of our proposed model is substantially higher than that of the binary-trait-based linkage analysis and that our test statistic is robust with regard to certain parameter misspecifications. By using our proposed method, we performed a genome scan of the hoarding phenotype in a data set with 53 nuclear families, which were collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). Standard linkage scans using hoarding as a dichotomous trait were also performed by using GENEHUNTER and ALLEGRO. Both GENEHUNTER and ALLEGRO failed to reveal any marker significantly linked to the binary hoarding phenotypes. However, our method identified three markers at 4q34-35 (P = 0.0009), 5q35.2-35.3 (P = 0.0001), and 17q25 (P = 0.0005) that manifest significant allele sharing.
连锁分析通常用于绘制人类疾病和病症的基因图谱。然而，现有的连锁分析方法要求疾病或病症要么被二分法分类，要么通过定量性状来测量，例如高血压的血压。在后一种情况下，通常假定该性状呈正态分布。然而，许多疾病和病症，如癌症以及精神和行为病症，是按有序量表进行评级的。本研究的目的是建立一个对有序性状进行连锁分析的框架。我们提出了一种潜在变量比例优势逻辑模型，该模型将遗传模式与有序性状的分布联系起来。我们使用似然比检验来检验连锁证据。通过模拟研究，我们发现我们提出的模型的功效显著高于基于二元性状的连锁分析，并且我们的检验统计量在某些参数设定错误的情况下具有稳健性。通过使用我们提出的方法，我们在一个由国际抽动秽语综合征遗传学联盟（TSAICG）收集的包含53个核心家庭的数据集上对囤积行为表型进行了全基因组扫描。还使用GENEHUNTER和ALLEGRO对囤积行为作为二分性状进行了标准连锁扫描。GENEHUNTER和ALLEGRO均未发现任何与二元囤积行为表型显著连锁的标记。然而，我们的方法在4q34 - 35（P = 0.0009）、5q35.2 - 35.3（P = 0.0001）和17q25（P = 0.0005）处鉴定出三个表现出显著等位基因共享的标记。
