Differential confounding of rare and common variants in spatially structured populations.
Differential confounding of rare and common variants in spatially structured populations.
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DOI：
10.1038/ng.1074
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发表时间：
2012-02-05
期刊：
影响因子：
30.8
通讯作者：
McVean, Gil
中科院分区：
文献类型：
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作者：
Mathieson, Iain;McVean, Gil
通过技术的进步和大规模的合作项目，现在有可能进行强大的全基因组关联研究，有望揭示罕见变异对复杂性状和疾病的贡献。然而，虽然群体结构是关联研究的已知混杂因素，但尚不清楚开发用于控制分层的方法是否对罕见变异同样有效。在这里，我们证明了罕见的变异可以显示出系统性的不同，通常比常见的变异更强的分层，这不一定是纠正现有的方法。我们表明，相同的过程导致通货膨胀的负载为基础的测试，并可以掩盖信号在真正相关的变体。我们发现，即使当FST较低时，人群也可以显示罕见变异的空间结构，但等位基因共享的等位基因频率依赖性指标可以揭示局部分层。这些结果强调了在复杂性状的遗传分析中收集和整合空间信息的重要性。
Well-powered genome-wide association studies, now possible through advances in technology and large-scale collaborative projects, promise to reveal the contribution of rare variants to complex traits and disease. However, while population structure is a known confounder of association studies, it is unknown whether methods developed to control stratification are equally effective for rare variants. Here we demonstrate that rare variants can show a systematically different and typically stronger stratification than common variants, and that this is not necessarily corrected by existing methods. We show that the same process leads to inflation for load-based tests and can obscure signals at truly associated variants. We show that populations can display spatial structure in rare variants even when FST is low, but that allele-frequency dependent metrics of allele sharing can reveal localized stratification. These results underscore the importance of collecting and integrating spatial information in the genetic analysis of complex traits.
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