Searching for epistatic interactions in nuclear families using conditional linkage analysis.
Searching for epistatic interactions in nuclear families using conditional linkage analysis.
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DOI：
10.1186/1471-2156-6-s1-s148
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发表时间：
2005-12-30
期刊：
影响因子：
2.9
通讯作者：
Schmidt, S
中科院分区：
文献类型：
--
作者：
Shah, SH;Schmidt, MA;Mei, H;Scott, WK;Hauser, ER;Schmidt, S
基因组筛选通常采用单基因座策略进行连锁分析，但在存在上位性的情况下，这种策略的功效可能较低。有序子集分析 (OSA) 是一种使用连续协变量进行条件连锁分析的方法。我们使用 OSA 评估模拟 Genetic Analysis Workshop 14 数据集中的两个基因座相互作用。我们使用了 Aipotu、Karangar 和 Danacaa 确定的所有核心家庭。使用单核苷酸多态性图谱，使用 SIBLINK 对每条染色体的所有 100 个重复进行多点受影响兄弟对 (ASP) 连锁分析。 OSA 用于检查每条染色体上的连锁，使用每条其他染色体上每个 3-cM 位置的 LOD 分数作为协变量。使用两种方法来识别阳性结果：一种在整个协变量染色体上搜索，另一种以已知疾病位点的位置为条件。单基因座连锁分析显示，疾病位点 D1 至 D4 的 LOD 得分非常高，超过 100 个重复的平均 LOD 得分范围为 4.0 至 7.8。尽管 OSA 没有掩盖这种连锁证据，但它没有检测到任何基因座对之间的模拟相互作用。我们发现使用第一种 OSA 方法时出现了夸大的 I 类错误率，这凸显了纠正多重比较的必要性。因此，使用没有模拟疾病位点的“无效染色体对”，我们计算了校正的α水平。我们无法使用 OSA 检测两个位点的相互作用。这可能是由于缺乏表型亚组的纳入，或者是因为 LOD 评分总结的连锁证据作为 OSA 协变量表现不佳。我们发现 I 型错误率过高，但能够计算出校正的 alpha 水平，以便将来使用此策略搜索两个基因座相互作用的分析。
Genomic screens generally employ a single-locus strategy for linkage analysis, but this may have low power in the presence of epistasis. Ordered subsets analysis (OSA) is a method for conditional linkage analysis using continuous covariates. We used OSA to evaluate two-locus interactions in the simulated Genetic Analysis Workshop 14 dataset. We used all nuclear families ascertained by Aipotu, Karangar, and Danacaa. Using the single-nucleotide polymorphism map, multipoint affected-sibling-pair (ASP) linkage analysis was performed on all 100 replicates for each chromosome using SIBLINK. OSA was used to examine linkage on each chromosome using LOD scores at each 3-cM location on every other chromosome as covariates. Two methods were used to identify positive results: one searching across the entire covariate chromosome, the other conditioning on location of known disease loci. Single-locus linkage analysis revealed very high LOD scores for disease loci D1 through D4, with mean LOD scores over 100 replicates ranging from 4.0 to 7.8. Although OSA did not obscure this linkage evidence, it did not detect the simulated interactions between any of the locus pairs. We found inflated type I error rates using the first OSA method, highlighting the need to correct for multiple comparisons. Therefore, using "null chromosome pairs" without simulated disease loci, we calculated a corrected alpha-level. We were unable to detect two-locus interactions using OSA. This may have been due to lack of incorporation of phenotypic subgroups, or because linkage evidence as summarized by LOD scores performs poorly as an OSA covariate. We found inflated type I error rates, but were able to calculate a corrected alpha-level for future analyses employing this strategy to search for two-locus interactions.