Center for Bioinformatics and Genomics, and Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112, USA.
J Clin Endocrinol Metab. 2013 Jul;98(7):E1278-82. doi: 10.1210/jc.2013-1637. Epub 2013 Jun 19.
Genome-wide association studies (GWASs) and meta-analyses of GWASs have led to the identification of a number of promising genes for osteoporosis. However, inconsistent findings are seen among and between GWASs and meta-analyses, and inconsistencies have even been observed between meta-analyses whose samples overlapped to a large extent.
We carefully evaluated the usefulness and limitations of GWASs and their meta-analyses, with an emphasis on understanding the reasons for inconsistent results.
Based on published empirical data for osteoporosis, we performed a series of theoretical analyses using simulation studies.
The power of meta-analyses is limited to identifying a particular locus with modest effect size. In the situation in which individual GWASs were not included in the meta-analysis (ie, nonoverlap), the meta-analysis has rather limited power to replicate particular loci identified from the individual GWASs. Between-study heterogeneity may result in a power loss in meta-analyses, implying that adding heterogeneous samples into a meta-analysis may reduce the power, rather than having the anticipated effect of increasing power due to increased sample size.
Discordant findings in GWASs and meta-analyses are not unexpected, even for true susceptible genes. Contrary to the general belief, meta-analyses should not and cannot be used as a gold standard to evaluate the results of individual GWASs. Individual GWASs in homogeneous populations can detect true disease genes that meta-analyses may have low power to replicate.
全基因组关联研究（GWAS）和 GWAS 的荟萃分析已经确定了许多有希望的骨质疏松症基因。然而，GWAS 和荟萃分析之间以及荟萃分析之间的结果并不一致，即使在样本重叠程度很大的荟萃分析之间也存在不一致。
我们仔细评估了 GWAS 及其荟萃分析的有用性和局限性，重点是了解结果不一致的原因。
基于骨质疏松症的已发表经验数据，我们使用模拟研究进行了一系列理论分析。
荟萃分析的功效仅限于识别具有中等效应大小的特定基因座。在个体 GWAS 未包含在荟萃分析中的情况下（即不重叠），荟萃分析复制个体 GWAS 中确定的特定基因座的能力相当有限。研究间异质性可能导致荟萃分析中的功效损失，这意味着将异质样本添加到荟萃分析中可能会降低功效，而不是由于样本量增加而预期增加功效。
即使对于真正的易感基因，GWAS 和荟萃分析中的不一致结果也并不意外。与普遍看法相反，荟萃分析不应该也不能作为评估个体 GWAS 结果的金标准。在同质人群中进行的个体 GWAS 可以检测到荟萃分析可能没有能力复制的真正疾病基因。
