A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry

By L. Duncan, Matthew C. Keller. American Journal of Psychiatry, 2011

1,046 citations recorded by the source corpus.

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. Conclusion 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.

Subfields: Experimental and Cognitive Psychology, Genetics

View Paper: https://www.semanticscholar.org/paper/9055dff3199a5af0c92d551964a897605f768c99

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Citations in the corpus

Variation in the Heritability of Educational Attainment: An International Meta-Analysis (2013, background): “…date, social science studies of gene-environment interaction using molecular genetic data have largely focused on small numbers of specific genetic variants, whose contribution to the overall population heritability of an outcome is unknown but almost certainly very small (Duncan and Keller 2011).”
GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment (2013, background): “This is the case both for straightforward main effects and for candidate gene-byenvironment interactions (Duncan and Keller 2011).”
Research review: Polygenic methods and their application to psychiatric traits. (2014, result): “For this reason, studies of candidate G9E interactions in psychiatry have generally lacked replication and the field is plagued by publication bias towards studies with positive results (Duncan & Keller, 2011).”
A Unified Model of Depression (2016, neutral): “Critics of candidate gene research (e.g., Duncan & Keller, 2011) point out that the effects in these studies are small (particularly in relation to heritability estimates) and have proven difficult to replicate.”
All for one and one for all: Mental disorders in one dimension (2018, methodology): “This was because of the inappropriate conflation of a hypothetical process (genetic sensitivity to the environment) and the availability of methods for studying it (early studies only had candidate genes at their disposal) (113).”