Aspects of Observing and Claiming Allele Flips in Association Studies
Aspects of Observing and Claiming Allele Flips in Association Studies
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DOI：
10.1002/gepi.20458
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发表时间：
2010-04-01
影响因子：
2.1
通讯作者：
Cardon, Lon R.
中科院分区：
文献类型：
--
作者：
Clarke, Geraldine M.;Cardon, Lon R.
显著的等位基因翻转正在增加，其中相同疾病的关联发生在相同双等位基因基因座的相反等位基因处。但是，什么时候一个显著的等位基因翻转是真实的呢？我们解决声称和观察真正的等位基因翻转在实际样品中的统计问题。我们表明，除非等位基因翻转是真实的，观察到一个显着的等位基因翻转的样本中确定类似于从一个共同的人口的概率是可以忽略不计的。我们推导出常用的关联度量的预期值的表达式，这证实了以前的发现，即真正的等位基因翻转的潜在机制是单倍型频率的变化，并进一步显示这种变化如何与遗传效应的变化相互作用，以影响等位基因翻转。我们发现，在代理SNP的关联测试，常见的全基因组关联研究，单倍型频率的变化必须与连锁不平衡（LD）的符号反转触发真正的等位基因翻转。使用HapMap数据和r（而不是r（2））来突出以前未观察到的效应，我们表明，除非遗传效应很大，否则LD的变化不太可能导致来自同一人群的样本中真正的等位基因翻转。然而，随着种群的分化，对于足够大的遗传效应和/或样本量，真正的等位基因翻转是一个越来越可行的原因。我们的结论是，在本地模式的LD，祖先组成的研究样本，研究人群之间的环境暴露的变化的证据可以提供令人信服的实际证据，在防御一个真正的等位基因翻转。Genet.流行病学34：266-274，2010. (C)2009 Wiley-Liss，Inc.
Significant allele flipping, where associations for the same disease occur at opposite alleles of the same bi-allelic locus, is increasing. But when is a significant allele flip genuine? We address the statistical issues of claiming and observing genuine allele flips in actual samples. We show that unless an allele flip is genuine, the probability of observing a significant allele flip in samples ascertained similarly from a common population is negligible. We derive expressions for the expected values of commonly used measures of association, which confirm previous findings that the underlying mechanism of a genuine allele flip is variation in the haplotype frequencies and show further how this variation interacts with variation in the genetic effects to impact allele flipping. We show that for association testing at proxy SNPs, common in genome-wide association studies, variation in haplotype frequencies must coincide with a reversal in the sign of linkage disequilibrium (LD) to trigger genuine allele flips. Using HapMap data and r, rather than r(2), to highlight previously unobserved effects, we show that unless genetic effects are large, variation in LD is unlikely to cause genuine allele flips in samples drawn from the same population. However, as populations diverge, it is an increasingly viable cause of a genuine allele flip for sufficiently large genetic effect and/or sample sizes. We conclude that evidence of variation in local patterns of LD, ancestral composition of study samples, and environmental exposures between study populations can provide compelling practical evidence in defense of a genuine allele flip. Genet. Epidemiol. 34:266-274, 2010. (C) 2009 Wiley-Liss, Inc.