Gene-Environment Interactions
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Gene-Environment Interactions
Gene-environment interactions, often abbreviated as G×E or GxE, occur when the biological effects of an environmental exposure differ according to a person's genetic makeup, or when the effects of genetic variation differ according to environmental conditions. Rather than viewing genes and environment as independent causes of health and behavior, G×E research examines how they work together.
The concept has become increasingly important in genetics, epidemiology, environmental health, psychology, nutrition, and precision medicine. Environmental influences studied in this field include diet, physical activity, tobacco smoke, air pollution, ultraviolet radiation, toxic metals, pesticides, infection, social conditions, stress, trauma, occupational exposures, sleep, alcohol, microbiota, and prenatal conditions.
Genetic influences can include individual variants, combinations of variants, HLA types, gene-expression differences, regulatory variants, and polygenic risk scores representing the combined effects of many genetic variants.
Research across many diseases shows that inherited susceptibility does not necessarily produce the same outcome in every environment. Likewise, the same exposure may have different effects in different genetically susceptible populations.
Foundations and Methods
Gene-environment interaction research developed from classical epidemiology, twin and family studies, candidate-gene research, genome-wide association studies, molecular biology, and statistical genetics.
Early studies frequently examined a small number of biologically plausible genes and particular exposures. Modern research increasingly uses genome-wide interaction studies, large biobanks, polygenic risk scores, multi-omics data, exposome measurements, electronic health records, and increasingly sophisticated statistical models.
Detecting genuine interactions is difficult. Interaction effects are often smaller than the independent effects of genes or environmental exposures, meaning very large sample sizes may be required. Researchers also must accurately measure environmental exposure, define phenotypes consistently, account for population structure, correct for multiple statistical tests, and replicate results in independent populations.
A major recurring theme in the literature is that many early candidate-gene interactions have proven difficult to reproduce. Large collaborative studies and meta-analyses have therefore become increasingly important.
Researchers also distinguish between additive and multiplicative interaction. Two risk factors may produce more disease together than expected from their individual contributions without necessarily satisfying every statistical definition of interaction.
Another complication is gene-environment correlation. Genetic differences can sometimes influence the environments people experience or select. Geographic, socioeconomic, behavioral, and family environments can therefore become correlated with genetic variation, complicating interpretation.
Stress, Trauma, and Mental Health
Some of the most widely discussed G×E studies involve stress, childhood adversity, trauma, depression, antisocial behavior, and post-traumatic stress disorder.
Influential research reported interactions between childhood maltreatment and variation in the MAOA gene in relation to antisocial behavior. Other research proposed that variation in the serotonin transporter gene, particularly 5-HTTLPR, modified the relationship between stressful life events and depression.
The serotonin-transporter findings became an important example of the replication problems surrounding candidate-gene research. Different meta-analyses and large collaborative studies reached different conclusions, ranging from evidence of small interactions to little evidence for a broadly generalizable effect.
FKBP5, a gene involved in regulation of the stress-response system, has also been investigated in relation to childhood adversity, depression, and PTSD.
PTSD is particularly relevant to G×E research because traumatic exposure is a necessary environmental component of the disorder. Studies investigate why only some people exposed to severe trauma develop persistent PTSD and whether genetic susceptibility modifies that response.
Psychiatric G×E research increasingly emphasizes polygenic risk, genome-wide methods, epigenetics, longitudinal cohorts, and large collaborative datasets rather than relying on individual candidate genes.
Schizophrenia, ADHD, Alcohol, and Smoking
Schizophrenia research has examined interactions between genetic susceptibility and cannabis use, childhood adversity, infection, migration, urban environments, and psychosocial stress.
ADHD studies have investigated whether psychosocial conditions, socioeconomic status, household instability, and prenatal or perinatal exposures modify inherited influences on attention and behavior.
Alcohol-use research provides examples in which cultural and social environments may moderate genetic risk. Strong social controls, peer networks, stressful environments, and childhood adversity can potentially alter the expression of inherited susceptibility to alcohol dependence.
Smoking studies similarly examine how genetic influences on nicotine dependence and smoking behavior may interact with family, cultural, social, and environmental conditions.
These studies demonstrate that environmental factors do not need to be chemical or physical exposures. Social institutions, family environments, cultural norms, and behavioral opportunities can also form part of a gene-environment interaction.
Obesity, Diet, and Physical Activity
Obesity is one of the most extensively studied areas of G×E research because body weight reflects complex interactions among genetics, diet, activity, sleep, socioeconomic conditions, and other environmental influences.
One of the best-known examples involves the FTO gene. Large studies have found that physical activity can attenuate the association between FTO risk variants and body mass index.
Research has also investigated interactions between polygenic obesity risk and dietary patterns, smoking, alcohol use, sleep, physical activity, and other behaviors.
Modern obesity research increasingly examines many genetic variants simultaneously rather than individual genes. Polygenic scores can estimate inherited predisposition, while large cohorts allow researchers to test whether particular environments increase or reduce the expression of this predisposition.
Nutrition research has consequently developed into the fields of nutrigenetics and nutrigenomics, which investigate how genetic variation influences dietary responses and how nutrients influence gene expression and metabolism.
Despite considerable interest in personalized nutrition, many reported gene-diet interactions remain difficult to reproduce consistently across populations.
Diabetes and Metabolic Disease
Type 2 diabetes develops through the combined effects of genetic susceptibility and environmental factors such as obesity, diet, physical inactivity, and lifestyle.
Studies have examined whether diabetes-associated variants interact with whole-grain consumption, dietary composition, physical activity, and weight-loss interventions. TCF7L2 has received particular attention in studies of carbohydrate metabolism and dietary exposure.
Researchers are also studying whether genetically susceptible individuals receive greater benefit from lifestyle intervention.
Newer studies integrate polygenic scores, metabolomics, microbiome data, gene expression, and other molecular measurements in attempts to develop more individualized approaches to diabetes prevention.
However, systematic reviews repeatedly emphasize substantial heterogeneity across studies and limited replication of many proposed interactions.
Cardiovascular Disease and Lifestyle
Cardiovascular disease arises from combinations of inherited susceptibility and environmental factors including smoking, diet, physical activity, obesity, sleep, alcohol use, pollution, and socioeconomic conditions.
Large population studies increasingly compare cardiovascular outcomes among people with different combinations of polygenic risk and healthy or unhealthy lifestyles.
Smoking is especially important because people with high genetic susceptibility to coronary disease who also smoke may experience substantially greater absolute disease risk.
Gene-diet interactions have also been investigated in cardiovascular disease, although systematic reviews indicate that many proposed associations require further replication.
Environmental cardiovascular research is expanding beyond individual exposures. Studies increasingly examine combined environments involving air pollution, road noise, limited green space, and other features of the built environment.
Air Pollution and Respiratory Disease
Air pollution provides a major example of environmental exposure interacting with genetic susceptibility.
Studies have examined whether variants in genes related to inflammation, oxidative stress, detoxification, airway responsiveness, and immune regulation alter responses to particulate matter, nitrogen dioxide, ozone, traffic pollution, and tobacco smoke.
Asthma has been particularly important in G×E research. Candidate genes such as GSTM1, GSTP1, TNF, CD14, and others have been studied in relation to pollution, smoking, endotoxin, occupational exposures, and farming environments.
Genome-wide interaction studies have searched for additional variants that modify asthma risk associated with traffic pollution and tobacco exposure.
Childhood asthma research also illustrates why replication can be difficult: exposure levels, ancestry, household environments, diagnostic definitions, and developmental stage can differ considerably between populations.
COPD and other respiratory disorders likewise reflect interactions among cigarette smoke, pollution, infection, and genetic susceptibility.
Cancer and Environmental Exposure
Cancer is inherently suited to G×E research because many cancers involve environmental carcinogens acting within genetically variable biological systems.
Tobacco-related cancers have been studied extensively. Genetic variation affecting carcinogen metabolism, DNA repair, inflammation, and detoxification may influence the effects of cumulative smoking exposure.
Bladder cancer research has examined interactions involving NAT2 and occupational or tobacco-related aromatic amine exposure. Lung-cancer research has investigated genetic variants that influence susceptibility to cigarette smoke.
Dietary interactions have also been examined. Genome-wide studies have tested whether colorectal-cancer susceptibility varies with red meat, processed meat, fiber, fruits, vegetables, alcohol, obesity, and smoking.
Breast-cancer research has investigated interactions between susceptibility loci and reproductive history, body mass index, alcohol consumption, smoking, physical activity, and hormonal factors.
Melanoma provides another clear biological model. Genetic differences affecting pigmentation, melanocyte biology, and cancer susceptibility interact with ultraviolet radiation exposure.
Although many plausible cancer interactions have been proposed, establishing reproducible effects usually requires extremely large populations because both cancer and environmental exposures are heterogeneous.
Autoimmune and Immune-Mediated Disease
Autoimmune diseases provide some of the most compelling examples of interactions between inherited susceptibility and environmental triggers.
Rheumatoid arthritis research has repeatedly identified strong relationships among cigarette smoking, HLA-DRB1 shared-epitope alleles, and ACPA-positive disease.
Celiac disease provides an unusually clear example because the environmental trigger—dietary gluten—is known and strong genetic susceptibility is associated with HLA-DQ2 and HLA-DQ8.
Inflammatory bowel disease studies examine interactions involving NOD2 and other susceptibility genes together with smoking, diet, vitamin D, fatty acids, alcohol, microbiota, and intestinal environmental conditions.
Systemic lupus erythematosus research has investigated smoking, ultraviolet exposure, occupational chemicals, hormonal exposures, and genetic susceptibility. Some studies report interactions involving IL10, ESR1, NAT2, and broader polygenic risk.
Psoriasis and eczema research has similarly investigated smoking, alcohol use, early-life animal exposure, immune genes, and other environmental conditions.
Multiple Sclerosis, Vitamin D, and Sun Exposure
Multiple sclerosis is another important model of complex genetic and environmental susceptibility.
HLA-DRB1*15 is one of the strongest genetic risk factors for multiple sclerosis. Studies have repeatedly examined interactions between this genetic background and cigarette smoking.
The absence or presence of other HLA alleles, including HLA-A*02, can further modify these relationships, demonstrating that some biological outcomes involve gene-gene-environment interactions rather than a simple relationship between one gene and one exposure.
Sunlight and vitamin D have also been studied extensively. Low ultraviolet exposure or vitamin-D levels may combine with HLA susceptibility to produce greater multiple-sclerosis risk.
Other environmental factors investigated in multiple sclerosis include Epstein-Barr virus infection, adolescent obesity, passive smoking, and lifestyle factors.
Toxic Metals and Environmental Chemicals
Environmental toxicology increasingly incorporates genetic susceptibility.
Lead, arsenic, cadmium, endocrine-disrupting chemicals, pesticides, and industrial pollutants can affect individuals differently depending on variation in detoxification, metabolism, oxidative stress, DNA repair, transport proteins, and other biological pathways.
Arsenic studies have examined interactions involving DNA-repair genes, arsenic-metabolism genes, MTHFR, GST genes, polygenic susceptibility, and drinking-water exposure.
Cadmium research has investigated genetic differences affecting kidney damage and albuminuria.
Prenatal lead exposure studies have used genome-wide interaction approaches to identify variants that may influence neurodevelopmental susceptibility.
Endocrine-disrupting chemicals such as bisphenol A have also been investigated for genetically variable reproductive effects.
This research has important environmental-health implications because populations exposed to similar pollutant concentrations may not experience identical biological risks.
Molecular Mechanisms and Gene Regulation
Modern G×E research increasingly investigates the molecular mechanisms through which environmental conditions alter genetic effects.
Gene expression is highly context dependent. Regulatory variants that have little detectable effect under ordinary conditions may become important during infection, inflammation, hormonal changes, metabolic stress, or exposure to environmental chemicals.
Expression quantitative trait loci, or eQTLs, can therefore behave differently under different environmental conditions.
Experiments exposing cells to immune stimulation, inflammatory signals, microorganisms, or chemical treatments have identified large numbers of response eQTLs whose regulatory effects become visible only after environmental stimulation.
Some of these environmentally responsive regulatory variants occur in genomic regions associated with autoimmune and other complex diseases.
Epigenetic processes provide another potential interface between genes and environment. DNA methylation, chromatin modification, and other regulatory mechanisms can respond to nutrition, stress, pollutants, aging, and developmental environments.
These mechanisms may help explain how environmental exposure produces persistent changes in gene regulation without altering the underlying DNA sequence.
Pregnancy, Development, and Early-Life Exposure
Gene-environment interactions may be particularly important during prenatal development and childhood because biological systems are rapidly developing and environmental exposures can occur during sensitive periods.
Studies of preterm birth have examined interactions between maternal or fetal inflammatory-response genes and bacterial vaginosis, urinary infections, or vaginal infections.
Research on birth defects has investigated maternal smoking, passive tobacco exposure, air pollution, folate deficiency, and genetic variants involved in detoxification or embryonic development.
Orofacial-cleft studies have examined interactions between maternal smoking and infant TGFA or other susceptibility variants.
Experimental research on neural-tube defects demonstrates how nutritional deficiency can produce severe developmental consequences in genetically susceptible embryos.
Modern studies increasingly distinguish maternal genotype, fetal genotype, timing of exposure, placental biology, and developmental stage.
Neurological Disease and Neurodevelopment
Environmental chemicals, diet, pollution, pesticides, smoking, and lifestyle factors have been studied in relation to genetically influenced neurological and neurodevelopmental disorders.
Autism research has examined potential interactions involving air pollution, pesticides, heavy metals, pharmaceuticals, nutrients, and genetic pathways related to detoxification, metabolism, and neurodevelopment.
Alzheimer disease research considers APOE and other susceptibility genes together with diet, smoking, alcohol use, pollution, cardiovascular risk, physical activity, and aging.
Studies of Parkinson disease have tested interactions between genetic susceptibility and pesticides as well as between genes affecting caffeine metabolism and coffee consumption.
Large cohort studies increasingly investigate whether vascular and lifestyle risks have different effects among people with different APOE genotypes.
Social Environment and Human Development
Gene-environment interaction research also extends beyond disease.
Studies have examined whether socioeconomic conditions, education, family relationships, parental education, residential environment, and social mobility alter the expression of genetic influences on cognition and educational attainment.
Family environments can both modify genetically influenced behavior and be altered by it. This reciprocal process complicates simple distinctions between genetic and environmental causes.
Research on intelligence has examined whether genetic influence varies with socioeconomic and educational conditions.
Studies involving educational polygenic scores suggest that the relationship between inherited differences and educational attainment can vary between social systems and historical periods.
Loneliness and social contact have also been investigated from genetic, epigenetic, developmental, and social perspectives.
These studies reinforce a central principle of G×E research: the effect associated with a genetic variant is not necessarily fixed across all social environments.
Sleep, Alcohol, Salt, and Other Lifestyle Factors
Many everyday behaviors can function as environmental modifiers of genetic susceptibility.
Twin research suggests that genetic influences on body mass index may differ according to sleep duration.
Studies of hypertension have examined interactions between dietary sodium and variants related to nitric-oxide signaling, ACE activity, renal sodium handling, and other cardiovascular pathways.
Alcohol-metabolism genes such as ADH1B and ALDH2 can influence both alcohol processing and susceptibility to alcohol-related effects.
Coffee consumption has been investigated in relation to variants affecting caffeine metabolism and neurological disease risk.
Vitamin-D research provides another example because circulating vitamin-D levels reflect genetic factors as well as sunlight exposure, season, diet, latitude, skin biology, and behavior. Large studies using satellite-derived ultraviolet exposure have identified extensive genotype-by-UV relationships affecting vitamin-D status.
Infection, Microbiome, and Host Genetics
Infectious disease represents an environment in which genetic differences can become especially apparent.
Host genetic variants can influence immune responses to viruses, while infection itself can change gene expression and reveal regulatory effects that are not apparent in healthy individuals.
Studies of COVID-19 have identified genotype-dependent regulation of immune responses during active SARS-CoV-2 infection.
HIV research has examined HLA, CCR5, viral characteristics, smoking, alcohol, obesity, and other factors affecting infection or later disease outcomes.
Type 1 diabetes research investigates whether genetically susceptible immune systems respond differently to enterovirus infection.
The microbiome further complicates gene-environment relationships. Human genetic variation may affect microbial composition or host responses to microorganisms, while diet, antibiotics, geography, infection, and other environmental influences shape the microbiome.
The microbiome can therefore operate simultaneously as an environmental exposure, biological mediator, and outcome of host genetic differences.
From Candidate Genes to Polygenic and Exposome Research
One of the clearest historical trends in G×E research is movement away from isolated candidate-gene hypotheses toward genome-wide, polygenic, and systems-level approaches.
Candidate-gene research helped establish many biologically plausible hypotheses, but small samples and selective reporting produced numerous findings that proved difficult to reproduce.
Modern studies increasingly use hundreds of thousands of participants, genome-wide genetic data, polygenic scores, detailed environmental measurements, electronic records, molecular biomarkers, satellite data, wearable devices, and multi-omics.
The concept of the exposome seeks to characterize the totality of environmental exposures encountered across the life course rather than studying one exposure at a time.
Integrating exposome information with genomics may eventually allow researchers to identify combinations of genetic and environmental factors that contribute to disease susceptibility.
However, doing so creates substantial statistical, computational, privacy, ethical, and environmental-justice challenges.
Precision Medicine and Public Health
Gene-environment research is frequently linked to precision medicine because it may help explain why individuals respond differently to the same diet, medication, pollutant, or lifestyle intervention.
In principle, genetic information could identify people who benefit particularly strongly from avoiding certain exposures or adopting particular preventive behaviors.
However, most G×E findings are not yet sufficiently predictive or reproducible for routine individual clinical recommendations.
The research may also have important public-health applications. Genetic susceptibility should not be interpreted as transferring responsibility for environmental hazards to individuals. If an exposure such as air pollution, tobacco smoke, occupational chemicals, or contaminated water disproportionately harms susceptible populations, reducing the exposure can remain the most effective intervention.
Environmental justice is therefore increasingly relevant to G×E research. Populations facing greater pollution, socioeconomic disadvantage, occupational hazards, limited healthcare access, or other environmental burdens may experience higher disease risk independent of genetics, while genetic susceptibility can further modify individual responses.
Major Research Challenges
Gene-environment interaction research faces several persistent problems.
Environmental exposures are often measured inaccurately. Diet, stress, pollution, physical activity, sleep, and social conditions can vary over time and may be difficult to quantify.
Genetic effects can differ across ancestry groups because allele frequencies, linkage disequilibrium patterns, environments, and historical population structures differ.
Many studies remain heavily concentrated in populations of European ancestry, limiting generalizability and potentially widening disparities in genomic medicine.
Large numbers of statistical tests increase the possibility of false-positive findings. Small interaction effects require very large studies, and results can depend on how both exposure and disease are defined.
Timing also matters. An exposure during fetal development may have a different effect from the same exposure during childhood or adulthood.
Interactions may additionally involve multiple genes, multiple exposures, microbiota, developmental state, age, sex-related biology, and epigenetic regulation simultaneously.
These complexities help explain why convincing G×E discoveries generally require replication across large, well-characterized populations.
Conclusion
Gene-environment interactions challenge the idea that biological traits can be understood by separating heredity from environment. Genes influence how organisms respond to environmental conditions, while environments influence whether, when, and how genetic differences become biologically important.
Evidence for G×E extends across obesity, diabetes, cardiovascular disease, asthma, cancer, autoimmune disease, neurological disorders, pregnancy, mental health, behavior, toxicology, infection, nutrition, and social development.
Some interactions, such as smoking combined with particular autoimmune susceptibility or physical activity modifying obesity-related genetic risk, have accumulated substantial evidence. Other famous candidate-gene claims remain controversial or have failed to reproduce consistently.
The field is therefore moving toward larger datasets, polygenic models, improved exposure measurement, genome-wide interaction studies, molecular experiments, exposome research, and multi-omics.
The larger lesson is that genetic susceptibility is rarely destiny. The biological consequences of genetic variation depend partly on the environments in which people live, develop, work, eat, exercise, experience stress, encounter pollutants, and interact with infectious organisms. Understanding those relationships may improve both biological knowledge and strategies for disease prevention while emphasizing the continuing importance of healthier social and physical environments.
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Foundations, Concepts, and Methods
| Multiple authors | Cell Genomics | 2024-07-10
Places G×E research within precision environmental health, emphasizing the exposome, large biobanks, genome-wide interaction studies, multi-omics, environmental justice, privacy, and individualized prevention.
| Esther Herrera-Luis et al. | Nature Reviews Genetics | 2024-05-28
Reviews gene–environment interactions across human health, including polygenic liability, environmental measurement, statistical models, study design, reporting problems, and prospects for translating G×E findings into public health.
| Jiacheng Miao, Yixuan Wu & Qiongshi Lu | WIREs Computational Statistics | 2023-10-05
Reviews modern statistical approaches for single-variant and polygenic G×E analysis and explains the enormous sample sizes and environmental measurements needed to detect interactions reliably.
| Samuel J. Virolainen et al. | Genes & Immunity | 2022-12-30
Explains how genetic variants can interact non-additively with toxicants, pollution, viruses, sex-related biological factors, and other environmental exposures to influence disease susceptibility.
| Andrew T. DeWan | Methods in Molecular Biology | 2018
Introduces approaches for detecting gene–gene and gene–environment interactions, including genome-wide testing, interaction models, multiple-testing correction, replication, and strategies for improving statistical power.
| W. James Gauderman et al. | American Journal of Epidemiology | 2017
Reviews updated analytical techniques for genome-wide G×E research, including two-step procedures, joint tests, consortium analyses, gene-set methods, power issues, and available software.
| Yuxin Lin, Jiajia Chen & Bairong Shen | Advances in Experimental Medicine and Biology | 2017
Reviews interactions among genetics, lifestyle, environment, epigenetics, and disease and discusses how systems medicine could integrate these influences for precision healthcare.
| Duncan Thomas | Annual Review of Public Health | 2010
Surveys epidemiological designs and statistical methods for investigating G×E in candidate pathways and genome-wide association studies, emphasizing exposure measurement and statistical power.
| Astrid Dempfle et al. | European Journal of Human Genetics | 2008-06-04
Discusses definitions of G×E, methodological requirements, statistical interpretation, replication, sample-size problems, and the difficulty of moving interaction findings into clinical practice.
| David J. Hunter | Nature Reviews Genetics | 2005-04-01
A foundational review explaining how inherited susceptibility and lifestyle or environmental exposures can jointly contribute to complex disease and how epidemiological studies can test such interactions.
Stress, Depression, Trauma, and Candidate-Gene Debates
| Multiple authors | Journal of Affective Disorders | 2018-01-01
Systematic review and meta-analysis reports interactions between FKBP5 variants and early-life stress in depression and PTSD, illustrating how stress-response genes may influence vulnerability after childhood adversity.
| Dries Bleys et al. | Journal of Affective Disorders | 2018
Meta-analysis of more than 50,000 participants reported a small stress-by-5-HTTLPR interaction while also showing substantial heterogeneity between studies.
| Robert C. Culverhouse et al. | Molecular Psychiatry | 2018
Large collaborative analysis found no strong or broadly generalizable 5-HTTLPR-by-stress interaction, demonstrating the importance of large samples and coordinated replication in behavioral genetics.
| Torsten Klengel, Elisabeth Binder et al. | Annual Review of Psychology | 2016-01-04
Integrates genetic epidemiology, molecular genetics, GWAS, epigenetics, stress, trauma, anxiety, depression, and PTSD while emphasizing the need for large collaborative G×E studies.
| Katja Karg et al. | Archives of General Psychiatry | 2011
A larger meta-analysis reached a different conclusion, reporting evidence that the serotonin-transporter short allele moderated the relationship between stress and depression, illustrating continuing G×E controversy.
| Ping Xie et al. | Neuropsychopharmacology | 2010
Finds evidence that FKBP5 variants modify PTSD risk associated with childhood adversity, with particularly strong patterns in some ancestry groups.
| Karestan C. Koenen, Ananda B. Amstadter & Nicole R. Nugent | Journal of Traumatic Stress | 2009-10
Reviews G×E studies of post-traumatic stress disorder and explains why PTSD is particularly useful for interaction research because environmental trauma is explicitly required for diagnosis.
| Neil Risch et al. | JAMA | 2009
Meta-analysis found strong effects of stressful life events on depression but no convincing aggregate interaction between 5-HTTLPR genotype and stressful events, challenging an influential candidate-gene hypothesis.
| Karestan C. Koenen et al. | European Archives of Psychiatry and Clinical Neuroscience | 2008
Reviews genetic influences on PTSD and proposes methodological strategies for discovering reproducible interactions between genetic susceptibility and traumatic experiences.
| Avshalom Caspi et al. | Science | 2002-08-02
Classic study reporting that MAOA genotype modified the association between childhood maltreatment and later antisocial behavior, helping launch modern behavioral G×E research.
Schizophrenia, ADHD, Alcohol, and Smoking
| Marah H. Wahbeh & Dimitrios Avramopoulos | Genes | 2021-11-23
Reviews interactions between genetic risk for schizophrenia and cannabis, infections, childhood adversity, urban environments, migration, psychosocial stress, and other environmental exposures.
| Karen L. Gould et al. | Journal of Abnormal Child Psychology | 2018-02
Examines whether socioeconomic status and household chaos modify genetic influences on ADHD symptoms, illustrating how social environments may shape behavioral genetic effects.
| Evie Assary et al. | Seminars in Cell & Developmental Biology | 2018
Reviews G×E research across psychiatric disorders and describes the shift from single candidate genes toward polygenic and genome-wide approaches.
| Multiple authors | Nicotine & Tobacco Research | 2017
Systematic review examines gene-by-environment research on smoking initiation, frequency, quantity, nicotine dependence, and cessation and highlights major methodological heterogeneity.
| Mary-Anne Enoch | Current Psychiatry Reports | 2012-04
Reviews how stress, childhood adversity, social context, and other environments may interact with genetic susceptibility to alcoholism and drug dependence.
| Danielle M. Dick & Kenneth S. Kendler | Alcohol Research | 2012
Explains several forms of G×E in alcohol-use disorders, including evidence that environments with stronger social controls can suppress expression of inherited risk.
| Kelly C. Young-Wolff, Mary-Anne Enoch & Carol A. Prescott | Clinical Psychology Review | 2011-07
Reviews twin, adoption, and molecular studies showing that social control, adversity, peer groups, cultural environments, and other factors can modify genetic influences on alcohol use.
| Joel Nigg et al. | Journal of the American Academy of Child & Adolescent Psychiatry | 2010
Reviews measured G×E studies of ADHD and finds more consistent evidence for interaction with psychosocial environments than with many prenatal or perinatal exposures.
| Cleo S. van der Zwaluw & Rutger C. M. E. Engels | Addiction | 2009
Reviews early molecular and twin evidence for G×E in alcohol use and dependence and emphasizes the need for better theory, larger longitudinal cohorts, and replication.
| Jim van Os, Bart P. F. Rutten & Richie Poulton | Schizophrenia Bulletin | 2008
Reviews epidemiological evidence that psychosis may emerge through interactions between genetic liability and cannabis use, urbanicity, trauma, migration, and related exposures.
Obesity, Body Weight, and Physical Activity
| Marthe de Roo et al. | International Journal of Obesity | 2026
Systematic review and meta-analysis examines polygenic indices, environmental exposures, and variation in BMI, bringing G×E research into the modern polygenic-score era.
| Cornelie Nienaber-Rousseau | Nutrition Reviews | 2025-02-01
Practical review of G×E in nutrition, with special attention to African populations, nutrigenetics, study design, reproducibility, environmental diversity, and future AI-assisted analysis.
| Multiple authors | Current Nutrition Reports | 2022
Reviews hundreds of loci reported to interact with diet, smoking, alcohol, sleep, and physical activity in GWAS of metabolic traits and assesses implications for precision nutrition.
| Lu Qi | Current Obesity Reports | 2017
Reviews gene–diet interactions in obesity and weight-loss responses and considers metabolomics, the microbiome, and genetic information in precision nutrition.
| Mariaelisa Graff et al. | PLOS Genetics | 2017
Genome-wide analysis of roughly 200,000 adults confirmed physical-activity interaction at FTO but showed how difficult it is to detect additional genome-wide interaction loci.
| Shafqat Ahmad et al. | Current Obesity Reports | 2015
Reviews developments in obesity G×E research and statistical methods while noting that many reported interactions remain inconclusive or poorly replicated.
| Paul W. Franks et al. | Obesity Reviews | 2013
Systematically evaluates evidence that genetic susceptibility interacts with diet and physical activity to influence obesity and concludes that larger standardized studies are needed.
| Tuomas O. Kilpeläinen et al. | PLOS Medicine | 2011-11-01
Meta-analysis of more than 218,000 adults reports that physical activity attenuated the BMI-raising effect of the FTO obesity-risk variant, an important replicated G×E example.
| Lu Qi & Young-Ho Cho | Nutrition Reviews | 2008
Reviews how dietary composition, physical inactivity, and other lifestyle factors may modify genetic predisposition to obesity and discusses implications for personalized prevention.
| Claude Bouchard & Tuomo Rankinen | Obesity | 2008
Reviews genetic differences in physiological and body-weight responses to exercise and physical activity and emphasizes substantial individual and familial variation.
Diabetes, Diet, and Metabolic Disease
| Multiple authors | Nutrients | 2026-07-26
Systematic review of observational studies and clinical trials finds numerous reported gene–diet interactions related to type 2 diabetes but substantial heterogeneity and weak replication.
| Multiple authors | International Journal of Molecular Sciences | 2025
Reviews gene–diet interactions in diabetes and evaluates the promise and limitations of using nutrigenetics and multi-omics to develop personalized dietary prevention.
| Multiple authors | Diabetic Medicine | 2021
Systematic review evaluates reported interactions between diabetes genes and diet, physical activity, and weight-loss interventions, finding promising signals but limited replication.
| Multiple authors | International Journal of Molecular Sciences | 2017
Reviews nutrient–gene relationships, nutrigenetics, nutrigenomics, epigenetics, and dietary modulation of genetic susceptibility to type 2 diabetes.
| Paul W. Franks | Diabetes Care | 2013-04-13
Discusses gene–environment and gene–treatment interactions in type 2 diabetes and how lifestyle intervention could potentially offset inherited susceptibility.
| Paul W. Franks et al. | Journal of Diabetes Research | 2013
Reviews the combined influence of inherited risk and obesogenic lifestyles on type 2 diabetes and distinguishes plausible interaction hypotheses from well-replicated evidence.
| Marilyn C. Cornelis & Frank B. Hu | Annual Review of Nutrition | 2012
Reviews interactions between diabetes-associated loci and physical activity, Western dietary patterns, and other lifestyle exposures while emphasizing replication and exposure-measurement problems.
| Multiple authors | Diabetes Care | 2010
Tests interactions between whole-grain intake and glucose- or insulin-related genetic loci, illustrating both attempted replication and difficulties reproducing candidate G×E findings.
| Andreas Fisher et al. | British Journal of Nutrition | 2009
Reports interaction between whole-grain intake and TCF7L2 rs7903146 in type 2 diabetes risk, providing a specific example of a proposed gene–diet effect.
| Multiple authors | Current Opinion in Lipidology | 2008
Reviews interactions among genes, dietary fat, alcohol, smoking, obesity, insulin resistance, dyslipidemia, hypertension, diabetes, and atherosclerosis.
Cardiovascular Disease, Lifestyle, and Air Pollution
| Multiple authors | npj Clean Air | 2026
UK Biobank research reports interactions between polygenic risk and a composite environment involving air pollution, road noise, and limited green space in cardiovascular and metabolic disease.
| Shafqat Ahmad & Gull Rukh | Nature Reviews Cardiology | 2025-11-07
Modern review examines how inherited susceptibility interacts with lifestyle and environmental factors in coronary and cardiovascular disease pathogenesis.
| Multiple authors | Current Atherosclerosis Reports | 2022
Reviews more recent cardiovascular G×E evidence involving smoking, diet, physical activity, lipid pathways, and genetic risk scores.
| Multiple authors | Genetic Epidemiology | 2022
UK Biobank analysis finds additive interactions between smoking exposure and coronary artery disease genetic risk, showing especially high absolute risk among genetically susceptible smokers.
| Zayne M. Roa-Díaz et al. | BMC Cardiovascular Disorders | 2022
Systematic review of 59 articles finds many reported gene–diet interactions in cardiovascular disease but concludes that evidence is weakened by small samples and limited replication.
| Multiple authors | Circulation: Genomic and Precision Medicine | 2021
Uses enhanced polygenic risk scores to examine interactions with combined lifestyle factors for coronary disease, atrial fibrillation, diabetes, and lipid traits.
| Multiple authors | Journal of Clinical Medicine | 2021
UK Biobank study examines cardiovascular outcomes and mortality across combinations of polygenic risk and smoking, diet, activity, obesity, sleep, and other lifestyle factors.
| Multiple authors | European Journal of Preventive Cardiology | 2012
Reviews theoretical and epidemiological foundations of G×E in cardiovascular disease and emphasizes interactions between inherited susceptibility and behavioral or environmental risks.
Systematic review examines genetic differences in cardiovascular responses to ambient air pollution and the role of oxidative-stress and inflammatory pathways.
| Philippa J. Talmud | Nutrition, Metabolism and Cardiovascular Diseases | 2007-02
Reviews how smoking, diet, and other environmental factors interact with genetic variants to influence coronary heart disease risk.
Asthma, Allergy, and Respiratory Disease
| Eric B. Brandt & Gurjit K. Khurana Hershey | Journal of Allergy and Clinical Immunology | 2019
Reviews interactions between genetic susceptibility and indoor or outdoor pollutants in asthma, including evidence involving DNA methylation and oxidative-stress pathways.
| Steve Turner | Frontiers in Pediatrics | 2017-05-22
Compares reported G×E findings for asthma and allergic disease and asks whether the same genetic-environmental mechanisms underlie both conditions.
| Multiple authors | Current Opinion in Allergy and Clinical Immunology | 2014
Reviews asthma G×E research after the emergence of GWAS, including interactions involving GSTP1, pollution, smoking, occupational allergens, endotoxin, and domestic exposures.
| Francine Kauffmann & Florence Demenais | Journal of Allergy and Clinical Immunology | 2012
Reviews G×E in asthma and allergy and discusses movement from candidate genes toward genome-wide, sequencing, and systems-biology approaches.
| Stephanie J. London & Isabelle Romieu | Annual Review of Public Health | 2009-04-21
Reviews interaction between asthma susceptibility genes and secondhand smoke, ambient pollution, endotoxin, and other environmental exposures.
| Multiple authors | International Journal of COPD | 2008
Reviews interaction between cigarette smoke, pollution, infections, and inherited susceptibility in chronic obstructive pulmonary disease.
| Stephanie J. London et al. | Proceedings of the American Thoracic Society | 2007
Reviews evidence that GSTM1, TNF, and other genes can modify respiratory responses to ozone, tobacco smoke, endotoxin, and related asthma exposures.
| Multiple authors | Occupational and Environmental Medicine | 2007
Reviews interactions involving occupational agents, tobacco smoke, pollution, oxidative-stress genes, immune genes, and airway-response genes in asthma.
| Multiple authors | Archives of Disease in Childhood | 2007
Reviews evidence for G×E in childhood asthma and highlights the difficulty of replicating interactions across populations with different exposures and phenotypes.
| Multiple authors | Annual Review of Medicine | 2005
Reviews genetic and environmental contributions to asthma, COPD, chronic bronchitis, and occupational lung disease and the challenges involved in identifying respiratory G×E mechanisms.
Cancer, Smoking, Diet, and Chemical Exposure
| Multiple authors | eBioMedicine | 2024
Large pooled genome-wide study investigates interactions between genetic variation and intake of fiber, fruit, and vegetables in colorectal cancer.
| Multiple authors | International Journal of Cancer | 2022
Examines interactions between smoking and bladder-cancer susceptibility variants and reports particularly strong interaction involving NAT2 and aggressive urothelial cancer.
| Anja Rudolph, Jenny Chang-Claude & Marjanka K. Schmidt | British Journal of Cancer | 2016-01-12
Reviews evidence for breast-cancer G×E involving established genetic loci and factors such as parity and BMI and discusses the large samples required to detect interactions.
| Multiple authors | PLOS Genetics | 2014
Genome-wide analysis identifies interaction between processed-meat intake and a variant near GATA3 in colorectal-cancer risk, illustrating large-scale gene–diet interaction testing.
| Multiple authors | Breast Cancer Research | 2014
Reviews candidate G×E research in breast cancer involving reproductive, lifestyle, and anthropometric exposures together with common susceptibility variants.
| Multiple authors | Carcinogenesis | 2008
Reviews G×E in tobacco-related cancers, focusing on carcinogen metabolism, DNA repair, smoking dose, biomarkers, and genetic variation influencing susceptibility.
| Multiple authors | Cancer Science | 2005
Reports interactions among alcohol consumption, ALDH2, ADH2, and other alcohol-metabolizing genes in esophageal-cancer risk.
| Multiple authors | Reproductive Toxicology | 2005
Broad toxicology review includes interactions involving pesticides, benzene, tobacco smoke, alcohol, folate, PON1, GST genes, MTHFR, CYP enzymes, and reproductive or developmental outcomes.
| J. Green et al. | British Journal of Cancer | 2000-07-04
Reviews NAT2 variation, smoking, occupational aromatic-amine exposure, and bladder-cancer risk—an early and influential example of carcinogen-related G×E research.
Autoimmunity, Rheumatoid Arthritis, IBD, and Celiac Disease
| Multiple authors | Review article | 2026
Reviews celiac disease as an interaction between HLA-DQ2/DQ8 susceptibility, gluten, infections, microbiota, early-life ecology, and intestinal epithelial responses.
| Multiple authors | Journal of Crohn's and Colitis | 2025
Systematic review identifies reported interactions in inflammatory bowel disease involving NOD2, smoking, diet, selenium, vitamin D, fatty acids, alcohol, and other exposures.
| Multiple authors | Current Opinion in Gastroenterology | 2015
Reviews gene–environment interactions in inflammatory bowel disease, emphasizing the emerging importance of host genome–microbiome relationships.
Reviews evidence that genetic susceptibility and environmental triggers interact across autoimmune diseases and discusses implications for prevention and personalized medicine.
| Multiple authors | Current Opinion in Rheumatology | 2014
Reviews genetics, environmental factors, and G×E across rheumatoid arthritis, lupus, and ankylosing spondylitis, including smoking, microbiome, metabolomics, and epigenetics.
| Multiple authors | Cellular & Molecular Immunology | 2011
Uses celiac disease as a model for studying how strong genetic susceptibility interacts with a clearly defined dietary environmental trigger—gluten.
| Elizabeth W. Karlson et al. | Annals of the Rheumatic Diseases | 2010-01
Shows that heavy cumulative smoking exposure interacts strongly with HLA-DRB1 shared-epitope genotype in seropositive rheumatoid arthritis.
| Emeli Lundström et al. | Arthritis & Rheumatism | 2009
Examines different HLA-DRB1 shared-epitope alleles and smoking in ACPA-positive rheumatoid arthritis, refining one of the best-known human G×E examples.
| Multiple authors | PLOS Medicine | 2007
Examines interactions among HLA-DRB1, PTPN22, and smoking across rheumatoid-arthritis cohorts and compares additive and multiplicative definitions of interaction.
| Leonid Padyukov et al. | Arthritis & Rheumatism | 2004
Landmark study reports a strong interaction between cigarette smoking and HLA-DR shared-epitope alleles in seropositive rheumatoid arthritis.
Neurological Disease, Development, Pregnancy, and Other G×E Examples
| Sumitaka Kobayashi et al. | Pediatric Research | 2026-03-02
Reviews interactions between maternal or fetal genetic polymorphisms and prenatal chemical exposures in determining fetal growth and other birth outcomes.
| Kimberly Keil-Stietz & Pamela J. Lein | Current Topics in Developmental Biology | 2023
Reviews how environmental chemicals may interact with autism-related genetic susceptibility during neurodevelopment and discusses experimental approaches for identifying mechanisms.
| Lucia Migliore & Fabio Coppedè | Nature Reviews Neurology | 2022-09-30
Reviews interactions among Alzheimer susceptibility genes, diet, smoking, alcohol, pollution, oxidative stress, and epigenetic modifications.
| Multiple authors | Nutrients | 2022
Systematic review examines interactions between genetic variation, sun exposure, season, and vitamin-D status and identifies important methodological limitations.
| João Xavier Santos, Célia Rasga & Astrid Moura Vicente | IntechOpen | 2021-02-03
Reviews autism G×E involving air pollutants, pesticides, heavy metals, pharmaceuticals, nutrients, and susceptibility genes including GSTM1, GSTP1, MET, MTHFR, CYP2R1, and VDR.
| Multiple authors | Journal of Alzheimer's Disease | 2019
Explores Alzheimer disease through combined genetic, lifestyle, pollution, pesticide, age, and sex risks and proposes a G×E framework for precision prevention.
| Multiple authors | Parkinsonism & Related Disorders | 2016
Reports a genome-wide analysis of genetic interactions with pesticide exposure in Parkinson disease and illustrates the statistical difficulty of discovering G×E with modest samples.
| Daniel Rossignol et al. | Translational Psychiatry | 2014
Systematic review examines toxicant exposures, biomarkers, and genetic variants involving PON1, GST genes, and other detoxification pathways in autism-spectrum disorder.
| Rhoshel K. Lenroot & Jay N. Giedd | Journal of Child Psychology and Psychiatry | 2011
Explains how G×E effects can change across childhood and adolescence as gene expression, epigenetics, brain development, and environmental selection change with age.
| Robert O. Wright | Current Opinion in Pediatrics | 2010
Reviews G×E in childhood health and development, emphasizing prospective exposure measurement and critical developmental windows.
Molecular Mechanisms, Gene Regulation, and Epigenetics
| Multiple authors | Frontiers in Genetics | 2026
Proposes that biological state—including infection, puberty, inflammation, hormonal transitions, insulin resistance, and aging—can determine when a genetic susceptibility becomes functionally important.
| Multiple authors | Nature Genetics | 2024
Reviews genotype-by-environment interactions in gene regulation and complex traits, emphasizing eQTLs, molecular mechanisms, latent environmental factors, and statistical methods for detecting context-dependent genetic effects.
| Multiple authors | Genome Research | 2022
Examines genetic effects on gene expression across diverse environmental perturbations and shows that some regulatory variants become detectable only after specific treatments.
| Multiple authors | American Journal of Human Genetics | 2021
Develops a framework for identifying environmental factors that modify genetic risk by integrating experimentally induced transcriptional responses with GWAS results.
| Multiple authors | PubMed-indexed review | 2019
Reviews DNA methylation as an interface between genetic variation and environmental exposure and discusses developmental programming and exposure-associated epigenetic changes.
| Multiple authors | Nature Communications | 2017
Shows that immune stimulation reveals hundreds of response eQTLs and that these context-dependent regulatory variants are enriched at autoimmune-disease susceptibility loci.
| Multiple authors | Genome Research | 2016
Tests allele-specific expression across 250 environmental conditions and identifies hundreds of genes whose regulatory effects depend on environmental exposure.
| Multiple authors | mSystems | 2016
Examines genetic and transcriptional responses to healthy gut microbiota and finds evidence that host genotype can alter cellular responses to microbial exposure.
| Vladislav Grishkevich and Itai Yanai | Trends in Genetics | 2013
Reviews genome-wide evidence that genotype-by-environment interactions in gene expression are widespread and influenced by promoter architecture, regulatory complexity, expression level, and upstream regulatory networks.
| Multiple authors | Cell | 2012
Uses systems genetics in macrophages exposed to inflammatory stimuli to demonstrate extensive genotype-dependent variation in immune gene expression.
Metals, Arsenic, Lead, Cadmium, and Endocrine Disruptors
| Multiple authors | PubMed-indexed study | 2025
Reports interactions among arsenic exposure, genetic susceptibility, and lifestyle in the deterioration of glucose-insulin homeostasis.
| Multiple authors | PubMed-indexed study | 2025
Examines lifetime arsenic exposure from drinking water together with GSTZ1, MTHFR, polygenic scores, and genome-wide variation in bladder-cancer risk.
| Deng et al. | PubMed-indexed study | 2025
Reports interactions between VEGFA variants and combined lead-cadmium exposure in relation to renal dysfunction among exposed workers.
| Multiple authors | PubMed-indexed study | 2023
Finds that genetic predisposition affecting arsenic metabolism can modify associations between inorganic arsenic exposure and type 2 diabetes.
| Multiple authors | Toxics | 2021
Reviews evidence that endocrine-disrupting chemicals can produce different biological effects according to genetic background and proposes improved experimental approaches for identifying susceptible populations.
| Multiple authors | PubMed-indexed study | 2018
Demonstrates a two-step omics strategy for detecting gene–arsenic interactions using genetic variants, gene expression, and DNA methylation.
| Multiple authors | PubMed-indexed study | 2017
Genome-wide interaction analysis of prenatal lead exposure identifies variation near UNC5D that may modify lead-associated effects on childhood neurodevelopment.
| Maria Grau-Perez et al. | Environment International | 2017
Finds that cadmium-associated albuminuria differs according to genetic variants involved in oxidative stress, cadmium transport, and metabolism.
| Multiple authors | Science of the Total Environment | 2012
Examines CDH1 genetic variation and arsenic exposure in West Bengal and finds evidence that inherited susceptibility can modify risk of arsenic-related skin lesions.
| Angeline S. Andrew et al. | Toxicology Letters | 2009
Reports interaction between arsenic exposure and DNA-repair variation in XRCC3 in relation to bladder-cancer susceptibility.
Air Pollution, Tobacco Smoke, Asthma, and Respiratory Health
| Yidan Meng et al. | European Respiratory Review | 2026
Synthesizes 48 human studies identifying genetic variants that modify respiratory effects of outdoor air pollution.
| Multiple authors | Genetic Epidemiology | 2025
Examines polygenic asthma risk and air pollution in the ethnically diverse Southern California Children's Health Study.
| Multiple authors | Scoping Review | 2025
Reviews genetic susceptibility to PM2.5, PM10, NO2, and other air pollutants, emphasizing inflammatory, oxidative-stress, DNA-repair, and epigenetic pathways.
| Xin Dai, Dinh S. Bui and Caroline Lodge | Current Allergy and Asthma Reports | 2021
Reviews glutathione S-transferase variants and interactions with tobacco smoke, pollution, and other exposures in asthma.
| Multiple authors | International Journal of Molecular Sciences | 2020
Reports that IL1RN polymorphisms modify associations between childhood environmental tobacco-smoke exposure and adult asthma susceptibility.
| Multiple authors | American Journal of Respiratory and Critical Care Medicine | 2017
Genome-wide interaction analysis identifies ADCY2, B4GALT5, and DLG2 as possible modifiers of childhood-asthma risk associated with traffic-related air pollution.
| Multiple authors | GABRIEL Consortium study | 2017
Conducts a genome-wide search for variants whose associations with adult-onset asthma differ according to active tobacco-smoking exposure.
| Multiple authors | Occupational and Environmental Medicine | 2011
Finds that variants in CD14 and other innate-immune genes modify respiratory responses to occupational endotoxin exposure among agricultural workers.
| Markus Ege et al. | Journal of Allergy and Clinical Immunology | 2011
Genome-wide interaction analysis investigates why growing up in farming environments protects some genetically susceptible children from asthma and atopy.
| Multiple authors | PubMed-indexed review | 2007
Reviews the replicated interaction between CD14 genetic variation, environmental endotoxin exposure, and asthma or allergic phenotypes.
Multiple Sclerosis and Immune-Mediated Disease
| Multiple authors | PubMed-indexed study | 2026
Reports that smoking-related multiple-sclerosis disability progression differs according to HLA-A*02:01 genotype.
| Multiple authors | Systematic Review and Meta-analysis | 2025
Finds that low sun exposure or low vitamin D combined with HLA-DRB1*15:01 produces substantially greater multiple-sclerosis risk than either factor alone.
| Multiple authors | PubMed-indexed study | 2020
Finds evidence that variants in nicotinic acetylcholine receptor genes CHRNA7 and CHRNA9 modify tobacco-smoke-related multiple-sclerosis susceptibility.
| Multiple authors | Arthritis & Rheumatology | 2020
Finds additive interaction between cigarette smoking and a genome-wide genetic risk score in systemic lupus erythematosus.
| Multiple authors | PubMed-indexed study | 2019
Shows that the smoking interaction with HLA-DRB1*15:01 depends partly on DQA1*01:01 status, demonstrating complex gene–gene–environment effects.
| Multiple authors | PubMed-indexed review | 2018
Reviews interactions involving HLA genetic risk with smoking, Epstein-Barr virus, adolescent obesity, vitamin D, sunlight, and other environmental factors in multiple sclerosis.
| Anna Karin Hedström et al. | European Journal of Epidemiology | 2017
Replicates a strong interaction among cigarette smoking, HLA-DRB1*15, and absence of HLA-A*02 in multiple-sclerosis susceptibility.
| Multiple authors | PubMed-indexed study | 2014
Reports that passive smoking interacts with HLA-DRB1*15 and absence of HLA-A*02 in multiple-sclerosis risk.
| Lahiru Handunnetthi, Sreeram V. Ramagopalan and George C. Ebers | Neurology | 2010
Reviews evidence linking vitamin D, ultraviolet exposure, and HLA-DRB1*15 to multiple-sclerosis risk.
| Kassandra Simon et al. | Multiple Sclerosis Journal | 2010
Examines vitamin-D-metabolism genes including VDR, CYP27B1, CYP24A1, CYP2R1, and DBP together with environmental and dietary vitamin D exposure.
Lupus, Eczema, Psoriasis, Endocrine Disruption, and UV Exposure
| Multiple authors | Allergy | 2025
Large multi-cohort analysis finds evidence that early-life dog exposure may modify an IL7R-related genetic effect on atopic eczema.
| Multiple authors | Current Environmental Health Reports | 2022
Reviews chemical, occupational, hormonal, smoking, ultraviolet, and other environmental exposures that may interact with inherited susceptibility to systemic lupus erythematosus.
| Multiple authors | PubMed-indexed study | 2020
Reports interaction between IL10 polymorphisms and cigarette smoking in susceptibility to systemic lupus erythematosus.
| Xuan Mo, Sarah Preston and M. Raza Zaidi | Advances in Cancer Research | 2019
Reviews interactions among ultraviolet radiation, melanoma susceptibility genes, melanocyte biology, pigmentation, inflammation, and the skin microenvironment.
| Multiple authors | Immunologic Research | 2017
Finds that ESR1 polymorphisms interact with smoking and alcohol exposure in systemic lupus erythematosus risk.
| Xiaona Huo et al. | International Journal of Environmental Research and Public Health | 2015
Reviews evidence that genetic differences may modify reproductive responses to bisphenol-A exposure and contribute to female infertility.
| Xian-yong Yin et al. | Journal of Dermatological Science | 2013
Reports interactions between psoriasis susceptibility loci and cigarette smoking or alcohol consumption.
| Multiple authors | Lupus | 2009
Reports substantially elevated lupus risk among smokers carrying the NAT2 slow-acetylator genotype.
| Glenn Merlino and Frances P. Noonan | Trends in Molecular Medicine | 2003
Discusses genetically tractable melanoma models as a way to understand how ultraviolet radiation interacts with inherited cancer susceptibility.
Discusses melanoma as a model of interaction between inherited pigmentation and cancer susceptibility and ultraviolet exposure.
Cancer Gene–Environment Interactions
| Claire E. Thomas et al. | Epidemiology | 2025
Finds additive interactions between colorectal-cancer genetic risk and heavy alcohol consumption, smoking, obesity, and high red-meat intake.
| Multiple authors | Cancer Epidemiology, Biomarkers & Prevention | 2023
Genome-wide analysis identifies variants near HAS2 and SMAD7 whose associations with colorectal cancer differ according to red- or processed-meat consumption.
| Multiple authors | Current Colorectal Cancer Reports | 2015
Reviews candidate-gene and genome-wide evidence for interactions between dietary exposures and genetic susceptibility to colorectal cancer.
| Multiple authors | Carcinogenesis | 2014
Performs a genome-wide gene-by-smoking interaction analysis for lung cancer in a Han Chinese population.
| Multiple authors | Journal of the National Cancer Institute | 2013
Large international study tests breast-cancer susceptibility loci against reproductive, hormonal, anthropometric, alcohol, smoking, and physical-activity exposures.
| Carolyn Hutter et al. | Cancer Epidemiology, Biomarkers & Prevention | 2012
Tests colorectal-cancer susceptibility loci against smoking, alcohol, BMI, aspirin use, fruit, vegetables, meat, fiber, calcium, and folate intake.
| Multiple authors | American Journal of Epidemiology | 2012
Examines whether lung-cancer variants at chromosome 15q25.1 act directly, through smoking behavior, or through genotype-by-smoking interaction.
| Multiple authors | Breast Journal | 2011
Examines whether alcohol consumption modifies breast-cancer risk associated with BRCA1 and BRCA2 mutations.
| Multiple authors | Cancer Research | 2001
Finds that cumulative cigarette exposure modifies associations between microsomal epoxide-hydrolase genotypes and particular lung-cancer subtypes.
| Multiple authors | Cancer Research | 1998
Reports gene–gene–smoking interactions involving NAT1 and NAT2 acetylation variants in bladder-cancer risk.
Pregnancy, Birth Outcomes, and Congenital Development
| Multiple authors | Birth Defects Research | 2021
Investigates interactions between air-pollution exposure during pregnancy and genetic variants in biotransformation enzymes in relation to structural birth defects.
| Multiple authors | Birth Defects Research | 2021
Reviews gene–environment interactions in neural-tube defects, including folate metabolism, maternal nutrition, environmental chemicals, and developmental susceptibility genes.
| Multiple authors | Pediatric Research | 2020
Reports interactions between maternal or fetal genetic variants and vaginal or urinary infections in different clinical forms of preterm birth.
| Rita Dias Pereira, Cornelius Rietveld and Hans van Kippersluis | medRxiv | 2020
Uses polygenic scores to test whether offspring genetic predisposition modifies the effect of maternal smoking during pregnancy on birth weight.
| Tao Wu et al. | Birth Defects Research | 2012
Finds evidence that RUNX2 variants interact with environmental tobacco-smoke exposure in risk of cleft lip with or without cleft palate.
| Luis M. Gómez et al. | American Journal of Obstetrics and Gynecology | 2010
Finds that bacterial vaginosis modifies genetic susceptibility to spontaneous preterm birth in inflammatory-response genes.
| Multiple authors | Human Molecular Genetics | 2008
Experimental work shows that folate deficiency markedly increases neural-tube-defect susceptibility in embryos carrying impaired Pax3 function.
| Multiple authors | American Journal of Epidemiology | 2007
Finds that maternal CYP1A1 and EPHX1 genotypes modify the association between passive cigarette-smoke exposure and infant birth weight.
| Joanna S. Zeiger, Terri H. Beaty and Kung-Yee Liang | Cleft Palate-Craniofacial Journal | 2005
Meta-analysis evaluates interaction between maternal cigarette smoking and infant TGFA genotype in nonsyndromic oral clefts.
| G. M. Shaw et al. | American Journal of Human Genetics | 1996
Reports increased orofacial-cleft risk associated with maternal smoking, particularly among infants carrying a susceptible TGFA variant.
Social Environment, Cognitive Development, and Behavioral G×E
| Multiple authors | Economics & Human Biology | 2023
Finds that associations between education-related polygenic scores and educational attainment are weaker in environments with greater educational mobility.
| Multiple authors | Nature Human Behaviour | 2022
Shows how geographic clustering of socioeconomic environments can produce gene–environment correlations that affect genome-wide association results.
| Meng-Jung Lin | Social Science Research | 2020
Examines interactions among educational polygenic scores, parental education, and historical educational expansion.
| Multiple authors | Perspectives on Psychological Science | 2015
Reviews genetic, epigenetic, environmental, and social influences on loneliness and discusses possible gene-by-social-environment mechanisms.
| Multiple authors | American Journal of Geriatric Psychiatry | 2014
Finds that CRHR1 variation modifies the association between poor social contact with children and loneliness among older adults.
| Multiple authors | Development and Psychopathology | 2013
Reviews mechanisms through which genes and social environments can moderate each other's effects on behavioral and developmental outcomes.
| Michael J. Meaney | Child Development | 2010
Reviews epigenetic mechanisms through which early-life environments can alter long-term gene regulation and developmental phenotypes.
| Sophie van der Sluis et al. | Behavior Genetics | 2008
Examines whether educational, residential, and socioeconomic environments modify genetic influences on adult intelligence.
| Avshalom Caspi et al. | Proceedings of the National Academy of Sciences | 2007
Reports that FADS2 variation modifies the association between breastfeeding and childhood IQ, linking fatty-acid metabolism genes to an early nutritional environment.
| David Reiss and Leslie D. Leve | Development and Psychopathology | 2007
Explores how family and social relationships can moderate expression of genetic influences and how genetically influenced behavior can reshape the social environment.
Sleep, Diet, Hypertension, Vitamin D, and Lifestyle
| Multiple authors | Genome-wide interaction study | 2025
Uses satellite-derived ultraviolet-B exposure and nearly 339,000 UK Biobank participants to identify 162 previously unreported vitamin-D-associated variants and extensive genotype-by-UV effects.
| Multiple authors | Nutrients | 2018
Examines interaction between GNB3 genetic variation and dietary sodium consumption in the development of hypertension.
| Mohanraj Krishnan et al. | Sleep Medicine | 2017
Reports interactions of CLOCK, PEMT, and GHRELIN variants with sleep duration in relation to childhood obesity traits.
| Multiple authors | Journal of Molecular Neuroscience | 2017
Examines whether ADORA2A and CYP1A2 variants modify the protective association between coffee consumption and Parkinson disease.
| Nathaniel F. Watson et al. | Sleep | 2012
Twin study finds that genetic influences on BMI are considerably stronger among short sleepers than among people with long sleep duration.
| Multiple authors | Hypertension Research | 2009
Examines ADH1B and ALDH2 variants, drinking behavior, and genotype-dependent sensitivity to the blood-pressure effects of alcohol.
| Multiple authors | Journal of Human Hypertension | 2007
Reports that the effect of high salt intake on hypertension differs according to ACE insertion-deletion genotype and is further influenced by obesity.
| Multiple authors | Hypertension | 2007
Finds gene–gene–environment interactions involving CYP3A5, ABCB1, sodium excretion, blood pressure, renal sodium handling, and response to antihypertensive treatment.
| Multiple authors | American Journal of Hypertension | 2006
Finds that high dietary salt intake modifies the association between an endothelial nitric-oxide-synthase polymorphism and hypertension.
| Multiple authors | American Journal of Hypertension | 1998
Reports that APOE phenotype modifies the association between alcohol consumption and blood pressure in middle-aged men.
Infection, Microbiome, Aging, and Host Genetic Susceptibility
| Multiple authors | Nature Communications | 2026
Single-cell analysis of COVID-19 patients finds widespread genotype-dependent regulation of immune responses that appears specifically during active SARS-CoV-2 infection.
| Multiple authors | PubMed-indexed cohort study | 2026
Uses more than 264,000 UK Biobank participants to examine additive and multiplicative interactions between APOE genotype and vascular risk-factor burden in dementia and Alzheimer's disease.
| Multiple authors | PubMed-indexed GWAS | 2022
Finds interactions involving host genetic variation, HIV infection, smoking, alcohol, and obesity in subclinical atherosclerosis among young people living with HIV.
| Multiple authors | Science | 2020
Reviews ways in which human genetic adaptation to diet, climate, and pathogen exposure may have interacted with the evolution and composition of the microbiome.
| Multiple authors | Current Diabetes Reports | 2019
Reviews how type 1 diabetes risk alleles may alter host antiviral responses to enteroviruses and influence progression toward autoimmune diabetes.
| Multiple authors | Journal of Autoimmunity | 2017
Reviews interactions among inherited autoimmune susceptibility, microbiome composition, epigenetic regulation, mucosal immunity, and environmental exposures.
| Multiple authors | Nature Reviews Genetics | 2015
Reviews how HLA, CCR5, other host genetic factors, viral characteristics, and environmental conditions combine to determine susceptibility and outcomes after HIV-1 infection.
| T. Luck et al. | Psychological Medicine | 2014
Examines whether physical activity modifies dementia and Alzheimer-disease risk associated with the APOE ε4 allele in late life.
| Multiple authors | Best Practice & Research Clinical Obstetrics & Gynaecology | 2007
Reviews interactions between maternal inflammatory-response genes and bacterial vaginosis or altered vaginal flora in spontaneous preterm birth.
| Elena L. Grigorenko | Journals of Gerontology Series B | 2005
Discusses conceptual and methodological complexities of studying gene–environment interactions across aging, health, cognition, and social environments.
