Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

Genetic Effects in Major Depressive Disorder

Early hypotheses about depression candidate genes are incorrect and the large number of associations reported in the depression candidate gene literature are likely to be false positives, a new study suggests. Utilizing data from a large population-based and case-control samples (ranging from 62,138 to 443,264 across subsamples), researchers 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 and environmental moderators. Among the findings:

  • No clear evidence was found for any candidate gene polymorphism associations with depression phenotypes or any polymorphism-by-environment moderator effects.
  • Depression candidate genes were no more associated with depression phenotypes than noncandidate genes.


Border R, Johnson EC, Evans LM, et al. No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples. Am J Psychiatry. 2019;176(5):376-387. doi: 10.1176/appi.ajp.2018.18070881.


This paper by Border et al. lends to the ongoing debate regarding the possible causes of major depressive disorder. Theoretically, MDD patients inherit genes from their parents (genotype). If enough mutations are inherited, faulty neurotransmission of monoamines for example may occur, and resultant specific MDD symptoms may develop clinically (phenotype).We suspect that because our antidepressants mostly work by enhancing monoamine activity that certain candidate genes associated with the monoamine systems must be mutated and contributing. Some of these candidate genes are now also used in clinical practice as part of pharmacogenomic lab panels to help guide treatment. Unfortunately, our quest to find answers to both the etiology of MDD and to target its treatment via personalized medicine have yet to find definitive answers or applications. —Thomas L. Schwartz, MD; Senior Associate Dean of Education, Interim Chair/Professor of Psychiatry, SUNY Upstate Medical University.