Liang Kung-Yee, Hsu Fang-Chi, Beaty Terri H
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Genet Epidemiol. 2003 Dec;25(4):285-92. doi: 10.1002/gepi.10271.
Linkage disequilibrium (LD) or association studies using case-parent trios have become a common approach to locate unobserved susceptibility genes underlying complex diseases. With the availability of ever more dense marker maps, how to utilize the information carried by multiple markers simultaneously remains challenging. Recently, Liang et al. ([2001a] Am. J. Hum. Genet. 68: 937-950) proposed a multipoint LD method to estimate the location of a susceptibility gene within a framework map along with its sampling uncertainty. Two important features of this method are that 1) it uses all trios whether parents are heterozygous for a given marker or not, and 2) it provides a single test statistic for the null hypothesis of no linkage or no LD to the region, avoiding the multiple testing problem encountered when performing individual transmission disequilibrium tests (TDT) for each marker individually. In this paper, we discuss how this method can be expanded to address important issues pertaining to complex diseases in a unified fashion. These issues include, among others, gene-gene and gene-environment interactions, genetic heterogeneity, phenotypic refinement, and paternal vs. maternal transmission. We applied this method to asthmatic case-parent trios from the Collaborative Study on the Genetics of Asthma (CSGA), and found that the previous evidence for linkage and LD in a 13.6 cM region of chromosome 11 can be attributed to maternal transmission, while there was no evidence of excess paternal transmission. Furthermore, such discrepancy in preferential transmission was most evident among probands with early onset age (6 years old or younger).
利用病例-父母三联体进行连锁不平衡（LD）或关联研究已成为定位复杂疾病潜在未观察到的易感基因的常用方法。随着标记图谱变得越来越密集，如何同时利用多个标记携带的信息仍然具有挑战性。最近，梁等人（[2001a]《美国人类遗传学杂志》68: 937 - 950）提出了一种多点LD方法来估计易感基因在框架图谱中的位置及其抽样不确定性。该方法的两个重要特点是：1）无论父母对于给定标记是否杂合，它都使用所有三联体；2）它为该区域无连锁或无LD的零假设提供单个检验统计量，避免了对每个标记单独进行个体传递不平衡检验（TDT）时遇到的多重检验问题。在本文中，我们讨论了如何扩展该方法以统一方式解决与复杂疾病相关的重要问题。这些问题包括基因-基因和基因-环境相互作用、遗传异质性、表型细化以及父系与母系传递等。我们将此方法应用于哮喘遗传学合作研究（CSGA）中的哮喘病例-父母三联体，发现先前在11号染色体13.6 cM区域连锁和LD的证据可归因于母系传递，而没有父系传递过多的证据。此外，这种优先传递的差异在发病年龄早（6岁或更小）的先证者中最为明显。
