A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry
Open accessAbstract
OBJECTIVE: Gene-by-environment interaction (G×E) studies in psychiatry have typically been conducted using a candidate G×E (cG×E) approach, analogous to the candidate gene association approach used to test genetic main effects. Such cG×E research has received widespread attention and acclaim, yet cG×E findings remain controversial. The authors examined whether the many positive cG×E findings reported in the psychiatric literature were robust or if, in aggregate, cG×E findings were consistent with the existence of publication bias, low statistical power, and a high false discovery rate. METHOD: The authors conducted analyses on data extracted from all published studies (103 studies) from the first decade (2000-2009) of cG×E research in psychiatry. RESULTS: Ninety-six percent of novel cG×E studies were significant compared with 27% of replication attempts. These findings are consistent with the existence of publication bias among novel cG×E studies, making cG×E hypotheses appear more robust than they actually are. There also appears to be publication bias among replication attempts because positive replication attempts had smaller average sample sizes than negative ones. Power calculations using observed sample sizes suggest that cG×E studies are underpowered. Low power along with the likely low prior probability of a given cG×E hypothesis being true suggests that most or even all positive cG×E findings represent type I errors. CONCLUSIONS: In this new era of big data and small effects, a recalibration of views about groundbreaking findings is necessary. Well-powered direct replications deserve more attention than novel cG×E findings and indirect replications.
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For the majority of candidate genes reviewed, the positive findings, if any, have not been replicated in childhood aggression GWASs thus far.
“For the majority of candidate genes we reviewed, the positive findings (if any) have not been replicated in childhood aggression GWASs thus far [128].”
From Genetics of child aggression, a systematic review (2024) · cites this paper as [128]
The paper's Abstract > Conclusion says genome-wide association studies have largely failed to replicate reported candidate-gene associations, and its section on false discovery says candidate polymorphisms usually performed no better than chance in GWA results (page numbers unavailable). Those statements support the general replication concern, but the paper does not establish it for the citing authors' reviewed genes or for childhood aggression GWASs specifically. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCurrently evidence that effects of cannabis differ according to variation at AKT1 is not robust.
“however there are substantial concerns around gene environment interaction studies (38,41), and currently evidence that effects of cannabis differ according to variation at AKT1 is not robust.”
From Association Between Cannabis and Psychosis: Epidemiologic Evidence (2016) · cites this paper as [41]
Power to detect GxE interactions is lower than power to detect genetic or environmental main effects.
“power to detect GxE interactions is even lower than power to detect genetic or environmental main effects”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [108]
Enthusiasm for GxE research in other psychiatric disorders has recently been tempered by the absence of replication of many positive results.
“the enthusiasm for GxE research in other psychiatric disorders has recently been tempered by the absence of replication of many positive results.108”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [108]
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- Authors
- Duncan, L. E., & Keller, M. C.
- Affiliations
- Harvard University (US)
- Venue
- American Journal of Psychiatry
- Published
- 2011-10
- Volume
- 168
- Issue
- 10
- Pages
- 1041-1049
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3222234
- OpenAlex
- W2087414280
- Cited by
- 1,032
- References
- 46
- Citations by year
- 2026: 29 · 2025: 26 · 2024: 27 · 2023: 38 · 2022: 49 · 2021: 56 · 2020: 99 · 2019: 75 · 2018: 69 · 2017: 92 · 2016: 120 · 2015: 110 · 2014: 91 · 2013: 86 · 2012: 60
- FWCI
- 8.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (K01MH085812, MH085812)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007289)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- gene-environment interaction, psychiatric genetics, publication bias, statistical power, false discovery rate, replication, type I error, direct replication, sample size
- MeSH terms
- Mental Disorders, Environment, Humans, Psychiatry, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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