Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado.
Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado.
Biol Psychiatry. 2017 Nov 15;82(10):702-708. doi: 10.1016/j.biopsych.2017.06.033. Epub 2017 Jul 13.
A recent analysis of 25 historical candidate gene polymorphisms for schizophrenia in the largest genome-wide association study conducted to date suggested that these commonly studied variants were no more associated with the disorder than would be expected by chance. However, the same study identified other variants within those candidate genes that demonstrated genome-wide significant associations with schizophrenia. As such, it is possible that variants within historic schizophrenia candidate genes are associated with schizophrenia at levels above those expected by chance, even if the most-studied specific polymorphisms are not.
The present study used association statistics from the largest schizophrenia genome-wide association study conducted to date as input to a gene set analysis to investigate whether variants within schizophrenia candidate genes are enriched for association with schizophrenia.
As a group, variants in the most-studied candidate genes were no more associated with schizophrenia than were variants in control sets of noncandidate genes. While a small subset of candidate genes did appear to be significantly associated with schizophrenia, these genes were not particularly noteworthy given the large number of more strongly associated noncandidate genes.
The history of schizophrenia research should serve as a cautionary tale to candidate gene investigators examining other phenotypes: our findings indicate that the most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well.
最近对迄今为止进行的最大全基因组关联研究中 25 个精神分裂症候选基因多态性的分析表明，这些通常研究的变体与该疾病的相关性并不比随机预期的更高。然而，同一项研究在这些候选基因内确定了其他变体，这些变体与精神分裂症存在全基因组显著关联。因此，即使最受研究的特定多态性没有，历史上与精神分裂症相关的候选基因内的变体也可能与精神分裂症相关，其水平高于随机预期。
本研究使用迄今为止进行的最大精神分裂症全基因组关联研究的关联统计数据作为输入，进行基因集分析，以调查精神分裂症候选基因内的变体是否与精神分裂症的关联更为丰富。
作为一个整体，最受研究的候选基因中的变体与精神分裂症的相关性并不比对照非候选基因集的变体更显著。虽然一小部分候选基因似乎与精神分裂症有显著关联，但鉴于与更强烈关联的非候选基因数量众多，这些基因并没有特别值得注意。
精神分裂症研究的历史应该作为候选基因研究人员研究其他表型的一个警示故事：我们的发现表明，全基因组关联研究对精神分裂症最受研究的候选基因假设没有很好的支持，而且这种情况很可能也适用于其他复杂特征。
