Abecasis G R, Cookson W O, Cardon L R
Wellcome Trust Center for Human Genetics, University of Oxford, UK.
Eur J Hum Genet. 2000 Jul;8(7):545-51. doi: 10.1038/sj.ejhg.5200494.
High-resolution mapping is essential for the positional cloning of complex disease genes. In outbred populations, linkage disequilibrium is expected to extend for short distances and could provide a powerful fine-mapping tool. Current family-based association tests use nuclear family members to define allelic transmission and controls, but ignore other types of relatives. Here we construct a general approach for scoring allelic transmission that accommodates families of any size and uses all available genotypic information. Family data allows for the construction of an expected genotype for every non-founder, and orthogonal deviates from this expectation are a measure of allelic transmission. These allelic transmission scores can be used to extend previously described tests of linkage disequilibrium for dichotomous or quantitative traits. Some of these tests are illustrated, together with a permutation framework for estimating exact significance levels. Simulation studies are used to investigate power and error rates of the approach. As a practical application, the method is used to investigate the relationship between circulating angiotensin-1 converting enzyme (ACE) levels and polymorphisms in the ACE gene using previously published data.
高分辨率定位对于复杂疾病基因的位置克隆至关重要。在远交群体中，连锁不平衡预计在短距离内延伸，并且可以提供一个强大的精细定位工具。当前基于家系的关联测试使用核心家庭成员来定义等位基因传递和对照，但忽略了其他类型的亲属。在这里，我们构建了一种用于对等位基因传递进行评分的通用方法，该方法适用于任何规模的家系，并使用所有可用的基因型信息。家系数据允许为每个非奠基者构建预期基因型，偏离该预期的正交偏差是等位基因传递的一种度量。这些等位基因传递分数可用于扩展先前描述的针对二分或数量性状的连锁不平衡测试。文中展示了其中一些测试，以及用于估计精确显著性水平的置换框架。通过模拟研究来考察该方法的功效和错误率。作为一个实际应用，该方法被用于利用先前发表的数据研究循环血管紧张素转换酶（ACE）水平与ACE基因多态性之间的关系。
