Luo Xiaochen, Stavrakakis Nikolaos, Penninx Brenda W, Bosker Fokko J, Nolen Willem A, Boomsma Dorret I, de Geus Eco J, Smit Johan H, Snieder Harold, Nolte Ilja M, Hartman Catharina A
Interdisciplinary Centre Psychopathology and Emotion Regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Am J Med Genet B Neuropsychiatr Genet. 2016 Mar;171B(2):215-36. doi: 10.1002/ajmg.b.32396. Epub 2015 Nov 14.
Replication has been poor for previously reported candidate genes involved in Major Depressive Disorder (MDD). One possible reason is phenotypic and genetic heterogeneity. The present study replicated genetic associations with MDD as defined in DSM-IV and with a more narrowly defined MDD subtype with a chronic and severe course. We first conducted a systematic review of genetic association studies on MDD published between September 2007 and June 2012 to identify all reported candidate genes. Genetic associations were then tested for all identified single nucleotide polymorphisms (SNPs) and the entire genes using data from the GAIN genome-wide association study (MDD: n = 1,352; chronic MDD subsample: n = 225; controls: n = 1,649). The 1,000 Genomes database was used as reference for imputation. From 157 studies identified inthe literature, 81 studies reported significant associations with MDD, involving 245 polymorphisms in 97 candidate genes, from which we were able to investigate 185 SNPs in 89 genes. We replicated nine candidate SNPs in eight genes for MDD and six in five genes for chronic MDD. However, these were not more than expected by chance. At gene level, we replicated 18 genes for MDD and 17 genes for chronic MDD, both significantly more than expected by chance. We showed that replication rates were improved for MDD compared to a previous, highly similar, replication study based on studies published before 2007. Effect sizes of the SNPs and replication rates of the candidate genes were improved in the chronic subsample compared to the full sample. Nonetheless, replication rates were still poor.
先前报道的与重度抑郁症（MDD）相关的候选基因的重复研究结果并不理想。一个可能的原因是表型和基因的异质性。本研究对DSM-IV定义的MDD以及病程慢性且严重的更狭义定义的MDD亚型进行了基因关联重复研究。我们首先对2007年9月至2012年6月间发表的关于MDD的基因关联研究进行了系统综述，以确定所有报道的候选基因。然后，使用基因关联信息网络（GAIN）全基因组关联研究的数据（MDD：n = 1352；慢性MDD亚样本：n = 225；对照：n = 1649），对所有鉴定出的单核苷酸多态性（SNP）和整个基因进行基因关联测试。1000基因组数据库用作插补的参考。从文献中确定的157项研究中，81项研究报告了与MDD的显著关联，涉及97个候选基因中的245个多态性，从中我们能够研究89个基因中的185个SNP。我们在8个基因中重复了9个与MDD相关的候选SNP，在5个基因中重复了6个与慢性MDD相关的SNP。然而，这些结果并不比偶然预期的多。在基因水平上，我们重复了18个与MDD相关的基因和17个与慢性MDD相关的基因，两者均显著多于偶然预期。我们表明，与基于2007年之前发表的研究的先前高度相似的重复研究相比，MDD的重复率有所提高。与全样本相比，慢性亚样本中SNP的效应大小和候选基因的重复率有所提高。尽管如此，重复率仍然很低。
