ReviewBiological psychiatry2014
Gene × environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution.
Review in Biological psychiatry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 366 papers, 8 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
366 citing papers in PubMed, 8 syntheses or guidelines pooled it.
- Sex-stratified genome-wide association meta-analysis of major depressive disorder.Nature communications · 2025Pooled it
- Genetics of monozygotic twins reveals the impact of environmental sensitivity on psychiatric and neurodevelopmental phenotypes.Nature human behaviour · 2025Pooled it
- Loci on chromosome 20 interact with rs16969968 to influence cigarettes per day in European ancestry individuals.Drug and alcohol dependence · 2024Pooled it
- Re-analysis and meta-analysis of summary statistics from gene-environment interaction studies.Bioinformatics (Oxford, England) · 2023Pooled it
- Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders.Molecular psychiatry · 2023Pooled it
- Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.Communications biology · 2022Pooled it
- A systematic review of gene-by-intervention studies of alcohol and other substance use.Development and psychopathology · 2021Pooled it
- Systematic review and meta-analysis of the moderating effect of rs1799971 in OPRM1, the mu-opioid receptor gene, on response to naltrexone treatment of alcohol use disorder.Addiction (Abingdon, England) · 2020Pooled it
- Effects of a randomized controlled trial of unconditional cash transfers on epigenetic measures of ageing and cognition in children and mothers.Nature human behaviour · 2026Trial
- Greater genetic risk for adult psychiatric diseases increases vulnerability to adverse outcome after preterm birth.Scientific reports · 2021Trial
- Race moderates the effects of Motivational Interviewing on smoking cessation induction.Patient education and counseling · 2020Trial
- Design and model choices shape inference of age-varying genetic effects on complex traits.Nature aging · 2026Article
- Genetics of Educational Attainment and Childhood Problem Behavior: Direct Genetic Effects, Cognitive Pathways, and Sex Differences.Behavior genetics · 2026Article
- Cut through the noise: vocal signals and auditory processing vary along an urbanization gradient in Pacific treefrogs.Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology · 2026Article
- Integrating NRG1 and OXT Polymorphisms, Maternal Psychological Vulnerability, and Obstetric-Neonatal Outcomes: A Genotype-Phenotype Pilot Study.Journal of clinical medicine · 2026Article
- Association Between the Genetic Risk for Attention-Deficit/Hyperactivity Disorder and Cognitive Function in Older Age: The MYHAT Population-Based Study.The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry · 2026Article
- A Principled Framework for Mendelian Randomization in Oral Health Research.Journal of periodontal research · 2026Article
- Associations among discrimination, genetic susceptibility to inflammation, and C-reactive protein.Brain, behavior, & immunity - health · 2026Article
- Gene-Physical Activity Interplay in Depression: Candidate-Gene Interactions, Polygenic Susceptibility, Lifestyle Context, and Mendelian Randomization Evidence-Systematic Review.Journal of clinical medicine · 2026Review
- TGF-β Pathway-Based Polygenic Risk Score Modifies the Association between Red Meat Intake and Colorectal Cancer Risk: Application of a Novel Pathway-Based PRS Method.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2026Article
306 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
1 author.
Funding
Abstract
Candidate gene × environment (G × E) interaction research tests the hypothesis that the effects of some environmental variable (e.g., childhood maltreatment) on some outcome measure (e.g., depression) depend on a particular genetic polymorphism. Because this research is inherently nonexperimental, investigators have been rightly concerned that detected interactions could be driven by confounders (e.g., ethnicity, gender, age, socioeconomic status) rather than by the specified genetic or environmental variables per se. In an attempt to eliminate such alternative explanations for detected G × E interactions, investigators routinely enter the potential confounders as covariates in general linear models. However, this practice does not control for the effects these variables might have on the G × E interaction. Rather, to properly control for confounders, researchers need to enter the covariate × environment and the covariate × gene interaction terms in the same model that tests the G × E term. In this manuscript, I demonstrate this point analytically and show that the practice of improperly controlling for covariates is the norm in the G × E interaction literature to date. Thus, many alternative explanations for G × E findings that investigators had thought were eliminated have not been.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.