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

TLDR

Interest in candidate gene and gene‑by‑environment interaction hypotheses for major depressive disorder remains high despite longstanding controversy over their validity. The study empirically identified 18 candidate genes studied at least ten times and examined their relevance to depression phenotypes. Using preregistered analyses on 62,138–443,264 participants from large population‑based and case‑control samples, the authors tested gene main effects, gene‑by‑environment interactions, and gene‑level effects across multiple depression definitions and environmental moderators. No candidate gene polymorphisms or interactions were associated with depression, and candidate genes were no more predictive than noncandidate genes, suggesting that earlier reported associations are likely false positives.

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.