Weinberg Clarice R
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Am J Hum Genet. 2003 Feb;72(2):438-47. doi: 10.1086/346171. Epub 2003 Jan 17.
Suppose DNA is available from affected individuals, their parents, and their grandparents. Particularly for early-onset diseases, maternally mediated genetic effects can play a role, because the mother determines the prenatal environment. The proposed maximum-likelihood approach for the detection of apparent transmission distortion treats the triad consisting of the affected individual and his or her two parents as the outcome, conditioning on grandparental mating types. Under a null model in which the allele under study does not confer susceptibility, either through linkage or directly, and when there are no maternally mediated genetic effects, conditional probabilities for specific triads are easily derived. A log-linear model permits a likelihood-ratio test (LRT) and allows the estimation of relative penetrances. The proposed approach is robust against genetic population stratification. Missing-data methods permit the inclusion of incomplete families, even if the missing person is the affected grandchild, as is the case when an induced abortion has followed the detection of a malformation. When screening multiple markers, one can begin by genotyping only the grandparents and the affected grandchildren. LRTs based on conditioning on grandparental mating types (i.e., ignoring the parents) have asymptotic relative efficiencies that are typically >150% (per family), compared with tests based on parents. A test for asymmetry in the number of copies carried by maternal versus paternal grandparents yields an LRT specific to maternal effects. One can then genotype the parents for only the genes that passed the initial screen. Conditioning on both the grandparents' and the affected grandchild's genotypes, a third log-linear model captures the remaining information, in an independent LRT for maternal effects.
假设可以获取患病个体、其父母以及祖父母的DNA。特别是对于早发性疾病，母系介导的遗传效应可能起作用，因为母亲决定产前环境。所提出的用于检测明显传递扭曲的最大似然方法将由患病个体及其父母组成的三联体视为结果，并以祖父母的交配类型为条件。在一个零模型中，所研究的等位基因无论是通过连锁还是直接作用都不会导致易感性，并且当不存在母系介导的遗传效应时，特定三联体的条件概率很容易推导出来。对数线性模型允许进行似然比检验（LRT）并能够估计相对外显率。所提出的方法对遗传群体分层具有稳健性。缺失数据方法允许纳入不完整的家庭，即使缺失的人是患病的孙辈，就像在检测到畸形后进行人工流产的情况一样。在筛选多个标记时，可以先仅对祖父母和患病孙辈进行基因分型。与基于父母的检验相比，基于以祖父母交配类型为条件（即忽略父母）的LRT具有通常大于150%（每个家庭）的渐近相对效率。对母系祖父母与父系祖父母携带的拷贝数的不对称性进行检验会产生一个特定于母系效应的LRT。然后可以仅对通过初始筛选的基因对父母进行基因分型。以祖父母和患病孙辈的基因型为条件，第三个对数线性模型在一个独立的针对母系效应的LRT中捕捉剩余信息。
