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

Abstract

Interest in candidate gene and candidate geneby-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.

Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing

“…We have therefore focused on the DTC scenario because errors in raw SNP-chip data could cause significant harm to patients without further validation. However, erroneous results from SNP-chips used in research biobanks can also lead to false associations [32] and wasted resource in the development of new treatments against the wrong targets [33].…”

Are current mental health assessment formats consistent with contemporary thinking and practice?

“…From an historical perspective, the structure of mental health assessments developed from the belief that psychiatric conditions are predominantly biological and genetic (Stiffler & Dever ). This has proven not to be the case (Border et al, ; Borsboom et al, ; Torrey & Yolken ). A report on mental health and well‐being from the United Nations Special Rapporteur confirmed that many concepts associated with the biomedical model in mental health have failed to be supported by research.…”

FAAH, SLC6A4, and BDNF variants are not associated with psychosocial stress and mental health outcomes in a population of Syrian refugee youth

“…However, the only outcome measure in our study which partially captures depressive symptoms is AYMH, which has been noted to have only moderate sensitivity in girls and poor sensitivity in boys . In addition, a recent study by Border et al (2019) with over 115,00 participants assayed these genes as well as all variants commonly tested for association with depression (i.e. tested in more than 10 studies) and found no associations between genetic variation and any depressive phenotypes.…”