Identifying susceptibility genes by using joint tests of association and linkage and accounting for epistasis
Identifying susceptibility genes by using joint tests of association and linkage and accounting for epistasis
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DOI：
10.1186/1471-2156-6-s1-s147
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发表时间：
2005-12-30
期刊：
影响因子：
2.9
通讯作者：
Gauderman, J
中科院分区：
文献类型：
--
作者：
Millstein, J;Siegmund, KD;Gauderman, J
模拟遗传分析研讨会14个数据进行了分析，共同测试连锁和关联，并通过占上位性使用候选基因的方法。我们的小组被揭开了“答案。“除了两个非疾病相关基因座中的每个基因座的五个SNP外，还分析了六个疾病基因座中的48个单核苷酸多态性（SNP）。从Aipotu、Kaarangar和Danacaa种群的前10个重复中提取受影响的同胞-亲本数据，并对每个重复进行单独分析。我们开发了一个可能性测试协会和/或连锁使用受影响的同胞对和他们的父母的数据。使用条件logistic回归方法明确建模同胞之间的血统相同（IBD）等位基因共享，并纳入表示预期IBD等位基因共享的协变量（考虑到同胞及其父母的基因型）。通过在由模型中最高阶相互作用项确定的阶段中进行似然比检验来解释相互作用。在第一阶段，独立地测试主效应，在随后的阶段，多位点效应进行了测试的条件下显着的边际效应。减少进行测试的数量是通过预筛选基因组合与拟合优度卡方统计，取决于交配型频率。SNP特异性的连锁和关联的联合效应被确定为基因座D1，D2，D3和D4在多个重复。最强的影响是SNP B 03 T3056，其p值中位数为1.98 x 10（-34）。没有两个或三个位点的影响，发现在一个以上的重复。
Simulated Genetic Analysis Workshop 14 data were analyzed by jointly testing linkage and association and by accounting for epistasis using a candidate gene approach. Our group was unblinded to the "answers." The 48 single-nucleotide polymorphisms (SNPs) within the six disease loci were analyzed in addition to five SNPs from each of two non-disease-related loci. Affected sib-parent data was extracted from the first 10 replicates for populations Aipotu, Kaarangar, and Danacaa, and analyzed separately for each replicate. We developed a likelihood for testing association and/or linkage using data from affected sib pairs and their parents. Identical-by-descent (IBD) allele sharing between sibs was explicitly modeled using a conditional logistic regression approach and incorporating a covariate that represents expected IBD allele sharing given the genotypes of the sibs and their parents. Interactions were accounted for by performing likelihood ratio tests in stages determined by the highest order interaction term in the model. In the first stage, main effects were tested independently, and in subsequent stages, multilocus effects were tested conditional on significant marginal effects. A reduction in the number of tests performed was achieved by prescreening gene combinations with a goodness-of-fit chi square statistic that depended on mating-type frequencies. SNP-specific joint effects of linkage and association were identified for loci D1, D2, D3, and D4 in multiple replicates. The strongest effect was for SNP B03T3056, which had a median p-value of 1.98 x 10(-34). No two- or three-locus effects were found in more than one replicate.