Department of Genetics, University Medical Centre and University of Groningen, Groningen, The Netherlands.
Hum Mol Genet. 2011 Oct 15;20(R2):R206-13. doi: 10.1093/hmg/ddr386. Epub 2011 Sep 2.
The successes of genome-wide association (GWA) studies have mainly come from studies performed in populations of European descent. Since complex traits are characterized by marked genetic heterogeneity, the findings so far may provide an incomplete picture of the genetic architecture of complex traits. However, the recent GWA studies performed on East Asian populations now allow us to globally assess the heterogeneity of association signals between populations of European ancestry and East Asians, and the possible obstacles for multi-ethnic GWA studies. We focused on four different traits that represent a broad range of complex phenotypes, which have been studied in both Europeans and East Asians: type 2 diabetes, systemic lupus erythematosus, ulcerative colitis and height. For each trait, we observed that most of the risk loci identified in East Asians were shared with Europeans. However, we also observed that a significant part of the association signals at these shared loci seems to be independent between populations. This suggests that disease aetiology is common between populations, but that risk variants are often population specific. These variants could be truly population specific and result from natural selection, genetic drift and recent mutations, or they could be spurious, caused by the limitations of the method of analysis employed in the GWA studies. We therefore propose a three-stage framework for multi-ethnic GWA analyses, starting with the commonly used single-nucleotide polymorphism-based analysis, and followed by a gene-based approach and a pathway-based analysis, which will take into account the heterogeneity of association between populations at different levels.
全基因组关联 (GWA) 研究的成功主要来自欧洲血统人群的研究。由于复杂性状的遗传异质性明显，到目前为止的研究结果可能无法全面描绘复杂性状的遗传结构。然而，最近在东亚人群中进行的 GWA 研究使我们能够全面评估欧洲血统人群和东亚人群之间关联信号的异质性，以及多民族 GWA 研究可能面临的障碍。我们专注于四个不同的性状，这些性状代表了广泛的复杂表型，已经在欧洲人和东亚人中进行了研究：2 型糖尿病、系统性红斑狼疮、溃疡性结肠炎和身高。对于每种性状，我们观察到在东亚人中鉴定出的大多数风险位点与欧洲人共享。然而，我们还观察到，在这些共享位点上的部分关联信号在人群之间似乎是独立的。这表明疾病的发病机制在人群之间是共同的，但风险变异通常是人群特异性的。这些变异可能是真正的人群特异性的，是自然选择、遗传漂变和最近的突变的结果，也可能是由于 GWA 研究中使用的分析方法的局限性造成的虚假结果。因此，我们提出了一个三阶段的多民族 GWA 分析框架，从常用的基于单核苷酸多态性的分析开始，然后是基于基因的方法和基于途径的分析，这将考虑到不同人群之间关联的异质性。
