No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples
No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples
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DOI：
10.1176/appi.ajp.2018.18070881
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发表时间：
2019-05-01
影响因子：
17.7
通讯作者：
Keller, Matthew C.
中科院分区：
文献类型：
--
作者：
Border, Richard;Johnson, Emma C.;Keller, Matthew C.
目的：尽管围绕先前研究结果的有效性存在争议，但对重性抑郁症的候选基因和候选基因与环境相互作用假说的兴趣仍然很强。针对这一争议，本研究根据经验确定了18个抑郁症的候选基因，这些基因已经被研究了10次或更多次，并研究了它们与抑郁症表型相关的证据。利用来自大规模人群和病例对照样本的数据（子样本中的Ns范围从62，138到443，264），作者进行了一系列预先登记的分析，检查候选基因多态性的主要影响，多态性与环境的相互作用，以及跨越抑郁症的许多操作定义的基因水平效应（例如，终身诊断、当前严重性、发作复发）和环境调节因子（例如，结果：没有发现任何候选基因多态性与抑郁症表型或任何环境调节效应的多态性相关的明确证据。作为一个集合，抑郁症候选基因与抑郁症表型的相关性并不比非候选基因高。作者表明，表型测量误差是不可能占这些null findings.Conclusions：研究结果不支持以前的抑郁症候选基因的发现，其中大的遗传效应经常报告的样本数量级小于这里检查。相反，研究结果表明，关于抑郁症候选基因的早期假设是不正确的，抑郁症候选基因文献中报道的大量关联可能是假阳性。
Objective: Interest in candidate gene and candidate gene-by-environment interaction hypotheses regarding major depressive disorder remains strong despite controversy surrounding the validity of previous findings. In response to this controversy, the present investigation empirically identified 18 candidate genes for depression that have been studied 10 or more times and examined evidence for their relevance to depression phenotypes.Methods: Utilizing data from large population-based and case-control samples (Ns ranging from 62,138 to 443,264 across subsamples), the authors conducted a series of pre-registered analyses examining candidate gene polymorphism main effects, polymorphism-by-environment interactions, and gene-level effects across a number of operational definitions of depression (e.g., lifetime diagnosis, current severity, episode recurrence) and environmental moderators (e.g., sexual or physical abuse during childhood, socioeconomic adversity).Results: No clear evidence was found for any candidate gene polymorphism associations with depression phenotypes or any polymorphism-by-environment moderator effects. As a set, depression candidate genes were no more associated with depression phenotypes than noncandidate genes. The authors demonstrate that phenotypic measurement error is unlikely to account for these null findings.Conclusions: The study results do not support previous depression candidate gene findings, in which large genetic effects are frequently reported in samples orders of magnitude smaller than those examined here. Instead, the results suggest that early hypotheses about depression candidate genes were incorrect and that the large number of associations reported in the depression candidate gene literature are likely to be false positives.