No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples

Abstract

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 preregistered 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.

Keywords: Biological Markers; Genetics; Mood Disorders-Unipolar; Stress.

Figure 1.

Estimated lower bounds of studies-per-candidate gene. a. Cumulative sums of the estimated number of depression candidate gene studies identified by our algorithm per year per gene from 1991 through 2016. Estimates reflect the number of correctly classified studies among identified studies, excluding studies not detected by our protocol, and thus comprise lower bounds for the true number of studies-per-gene. b. Eighteen candidate genes studied ≥ 10 times between 1991 and 2016. The estimated number of studies focused on the top polymorphism (Table S1.1) is displayed relative to the other identified studies within each gene. No top polymorphisms were identified for DTNBP1 or TPH2 (supplement section S1).

Figure 2.

Main effects and G × E effects of 16 candidate polymorphisms on estimated lifetime depression diagnosis and current depression severity in the UK Biobank. Effect size estimates for 16 candidate polymorphisms (in order of estimated number of tops from left to right, descending) on a. estimated lifetime depression diagnosis and b. past two-week depression symptom severity from the online mental health follow-up assessment in the UKBB sample (n = 115,257). Both polymorphism main effects and polymorphism × environmental moderator interaction effects are presented for each outcomes. Detailed descriptions of the variables, and of the association and power analysis models are provided in S3 and S4, respectively.

Figure 3.

Gene-wise statistics for effects of 18 candidate genes on primary depression outcomes in the UK Biobank. Gene-wise p-values across the genome, highlighting the 18 candidate polymorphisms’ effects on estimated depression diagnosis (filled points) and past two-week depression symptom severity (hollow points) from the online mental health follow-up assessment in the UKBB sample (n = 115,257). Detailed descriptions of the variables, and of the association and power analysis models are provided in S3 and S4, respectively.