Failure to replicate a genetic association may provide important clues about genetic architecture.
Failure to replicate a genetic association may provide important clues about genetic architecture.
复制标题
DOI：
10.1371/journal.pone.0005639
复制
发表时间：
2009-06-02
期刊：
影响因子：
3.7
通讯作者：
Moore JH
中科院分区：
文献类型：
--
作者：
Greene CS;Penrod NM;Williams SM;Moore JH
复制已成为评估全基因组关联研究统计结果的金标准。不幸的是，这种复制要求可能导致真实的遗传效应被忽略。真实的结果可能由于许多原因而无法复制，包括样本量不足或独立样本间表型定义的变异性。在全基因组关联研究中，多态性的等位基因频率可能由于抽样误差或群体差异而不同。我们假设，当等位基因频率不同且功能多态性与一个或多个其他功能多态性相互作用时，一些统计学显著的独立遗传效应可能无法在独立数据集中复制。为了验证这一假设，我们设计了一个模拟研究，其中病例对照状态是由两个相互作用的多态性与遗传力范围从0.025至0.4，重复样本量范围从400至1600人。我们表明，当第二个相互作用多态性的等位基因频率变化小于0.1时，复制一个多态性的统计学显着独立主效应的能力可能会显着下降。我们还表明，等位基因频率的差异可以导致逆转等位基因的影响，其中一个保护性等位基因成为复制研究中的风险因素。这些结果表明，未能复制一个独立的遗传效应可能会提供重要的线索的复杂性，潜在的遗传结构。我们建议检查未能复制的多态性与其他多态性的相互作用，特别是当样本收集自不同种族背景或不同地理区域的群体时。
Replication has become the gold standard for assessing statistical results from genome-wide association studies. Unfortunately this replication requirement may cause real genetic effects to be missed. A real result can fail to replicate for numerous reasons including inadequate sample size or variability in phenotype definitions across independent samples. In genome-wide association studies the allele frequencies of polymorphisms may differ due to sampling error or population differences. We hypothesize that some statistically significant independent genetic effects may fail to replicate in an independent dataset when allele frequencies differ and the functional polymorphism interacts with one or more other functional polymorphisms. To test this hypothesis, we designed a simulation study in which case-control status was determined by two interacting polymorphisms with heritabilities ranging from 0.025 to 0.4 with replication sample sizes ranging from 400 to 1600 individuals. We show that the power to replicate the statistically significant independent main effect of one polymorphism can drop dramatically with a change of allele frequency of less than 0.1 at a second interacting polymorphism. We also show that differences in allele frequency can result in a reversal of allelic effects where a protective allele becomes a risk factor in replication studies. These results suggest that failure to replicate an independent genetic effect may provide important clues about the complexity of the underlying genetic architecture. We recommend that polymorphisms that fail to replicate be checked for interactions with other polymorphisms, particularly when samples are collected from groups with distinct ethnic backgrounds or different geographic regions.
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