Cordell Heather J
Department of Medical Genetics, University of Cambridge, Cambridge, UK.
Genet Epidemiol. 2004 Apr;26(3):186-205. doi: 10.1002/gepi.10306.
The case/pseudocontrol approach is a general framework for family-based association analysis, incorporating several previously proposed methods such as the transmission/disequilibrium test and log-linear modelling of parent-of-origin effects. In this report, I examine the properties of methods based on a case/pseudocontrol approach when applied to a linked marker rather than (or in addition to) the true disease locus or loci, and when applied to sibships that have been ascertained on, or that may simply contain, multiple affected sibs. Through simulations and analytical calculations, I show that the expected values of the observed relative risk parameters (estimating quantities such as effects due to a child's own genotype, maternal genotype, and parent-of-origin) depend crucially on the ascertainment scheme used, as well as on whether there is non-negligible recombination between the true disease locus and the locus under study. In the presence of either recombination or ascertainment on multiple affected offspring, methods based on conditioning on parental genotypes are shown to give unbiased genotype relative risk estimates at the true disease locus (or loci) but biased estimates of population genotype relative risks at a linked marker, suggesting that the resulting estimates may be misleading when used to predict the power of future studies. Methods that allow for exchangeability of parental genotypes are shown (in the presence of either recombination or ascertainment on multiple affected offspring) to produce false-positive evidence of maternal genotype effects when there are true parent-of-origin or mother-child interaction effects, even when analyzing the true locus. These results suggest that care should be taken in both the interpretation and application of parameter estimates obtained from family-based genetic association studies.
病例/伪对照方法是基于家系的关联分析的通用框架，它整合了几种先前提出的方法，如传递/不平衡检验和起源亲本效应的对数线性建模。在本报告中，我研究了基于病例/伪对照方法的方法在应用于连锁标记而非（或除了）真正的疾病位点时，以及应用于已确定或可能仅包含多个患病同胞的同胞对时的特性。通过模拟和分析计算，我表明观察到的相对风险参数（估计诸如孩子自身基因型、母亲基因型和起源亲本效应等数量）的期望值关键取决于所使用的确定方案，以及真正的疾病位点与所研究位点之间是否存在不可忽略的重组。在存在重组或对多个患病后代进行确定的情况下，基于对亲本基因型进行条件设定的方法在真正的疾病位点能给出无偏的基因型相对风险估计，但在连锁标记处对群体基因型相对风险的估计有偏差，这表明当用于预测未来研究的效能时，所得估计可能会产生误导。在存在重组或对多个患病后代进行确定的情况下，允许亲本基因型可交换的方法在存在真正起源亲本或母子相互作用效应时，即使在分析真正的位点时，也会产生母亲基因型效应的假阳性证据。这些结果表明，在解释和应用从基于家系的基因关联研究中获得的参数估计时应谨慎。
