MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, UK.
Psychol Med. 2013 Apr;43(4):673-87. doi: 10.1017/S0033291712001286. Epub 2012 Jun 12.
It has been well established that both genes and non-shared environment contribute substantially to the underlying aetiology of major depressive disorder (MDD). A comprehensive overview of genetic research in MDD is presented. Method Papers were retrieved from PubMed up to December 2011, using many keywords including: depression, major depressive disorder, genetics, rare variants, gene-environment, whole genome, epigenetics, and specific candidate genes and variants. These were combined in a variety of permutations.
Linkage studies have yielded some promising chromosomal regions in MDD. However, there is a continued lack of consistency in association studies, in both candidate gene and genome-wide association studies (GWAS). Numerous factors may account for variable results including the use of different diagnostic approaches, small samples in early studies, population stratification, epigenetic phenomena, copy number variation (CNV), rare variation, and phenotypic and allelic heterogeneity. The conflicting results are also probably, in part, a consequence of environmental factors not being considered or controlled for.
Each research group has to identify what issues their sample may best address. We suggest that, where possible, more emphasis should be placed on the environment in molecular behavioural genetics to identify individuals at environmental high risk in addition to genetic high risk. Sequencing should be used to identify rare and alternative variation that may act as a risk factor, and a systems biology approach including gene-gene interactions and pathway analyses would be advantageous. GWAS may require even larger samples with reliably defined (sub)phenotypes.
大量研究证实，基因和非共享环境对重度抑郁症（MDD）的发病机制均有重要影响。本文对 MDD 的遗传学研究进行了综述。方法：通过PubMed 检索 2011 年 12 月前的文献，使用了包括“depression”、“major depressive disorder”、“genetics”、“rare variants”、“gene-environment”、“whole genome”、“epigenetics”以及“specific candidate genes and variants”等多个关键词，对相关方法学论文进行了检索，并对这些关键词进行了各种组合。结果：连锁研究已经发现了 MDD 相关的一些有前景的染色体区域。但是，候选基因和全基因组关联研究（GWAS）的关联研究结果仍然缺乏一致性。许多因素都可能导致结果的差异，包括使用不同的诊断方法、早期研究中的小样本、人群分层、表观遗传现象、拷贝数变异（CNV）、罕见变异、表型和等位基因异质性。相互矛盾的结果也可能部分归因于环境因素没有得到考虑或控制。结论：每个研究小组都必须确定其样本可能最好解决的问题。我们建议，在可能的情况下，在分子行为遗传学中，应更加重视环境，以确定除遗传高风险外，处于环境高风险的个体。测序应用于识别可能作为风险因素的罕见和替代变异，以及包括基因-基因相互作用和途径分析在内的系统生物学方法将是有益的。GWAS 可能需要具有可靠定义（亚）表型的更大样本。
