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No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples
Open accessAbstract
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.
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“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].”
From Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing (2019) · cites this paper as [33]
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“Though resulting measures are typically crude compared to the measures included in smaller studies [240], the trade-off between phenotype depth and sample size may be effective for gene discovery [241], as demonstrated by a recent preliminary report [242] of a GWAS for the Common CC factor.”
From The role of prefrontal cortex in cognitive control and executive function (2022) · cites this paper as [241]
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“However, erroneous results from SNP chips used in research biobanks can also lead to false associations and wasted resource in the development of new treatments against the wrong targets.33 34 35”
From Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation (2021) · cites this paper as [35]
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“One study indicated no support for depression candidate gene findings [122].”
From Biological, Psychological, and Social Determinants of Depression: A Review of Recent Literature (2021) · cites this paper as [122]
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Metadata
- Authors
- Border, R., Johnson, E. C., Evans, L. M., Smolen, A., Berley, N., Sullivan, P. F., & Keller, M. C.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2019-05-01
- Volume
- 176
- Issue
- 5
- Pages
- 376-387
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC6548317
- OpenAlex
- W2919957599
- Semantic Scholar
- 204d532eea4e3f20bc61ae2250587ad86fc82ebf
- Cited by
- 629
- References
- 57
- Citations by year
- 2026: 53 · 2025: 49 · 2024: 68 · 2023: 84 · 2022: 87 · 2021: 111 · 2020: 118 · 2019: 56
- FWCI
- 55.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- American Journal of Psychiatry (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (1532235, 1532236)
- Pfizer
- H. Lundbeck A/S
- National Institute of Mental Health (U01MH109528, R01MH100141, U01MH109536, T32MH016880)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- major depressive disorder, candidate genes, gene-environment interaction, genetic polymorphism, depression subtypes, childhood abuse, socioeconomic adversity, false positives, measurement error
- MeSH terms
- Psychological Trauma, Adverse Childhood Experiences, Major Depressive Disorder, Humans, Phenotype, Polymorphism, Genetic, Recurrence, Severity of Illness Index, Socioeconomic Factors, Reproducibility of Results, Genetic Association Studies, Gene-Environment Interaction
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