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PubMed2025

Genomic prediction of agronomic traits in perennial ryegrass (Lolium perenne L.) and genotype x environment interactions at the limit of the species distribution.

KEY MESSAGE: Perennial ryegrass shows extensive genotype x environment interactions at the limit of its ecological niche. Accounting for GxE may improve prediction even when environmental and genetic samples are highly diverse. BACKGROUND: In breeding the aim is to identify and accumulate beneficial variants. However, detection of these variants may be challenging in the presence of extensive genotype x environment interactions (GxE). METHODS: The study assesses the performance of 264 diploid perennial ryegrass accessions in a multi-environment field trial. We investigate the extent of GxE, for yield (total dry matter) and persistence traits under environmental conditions experienced in Nordic and Baltic regions at the limit of the species distribution. Two different approaches to modelling GxE were tested and validated under three different breeding scenarios. RESULTS: Our analysis documented the presence of significant GxE for all traits. Validation showed improvements in prediction accuracy when accounting for GxE: up to 4% for yield when predicting in unobserved environments, and up to 22% and 9% for spring cover and winter kill, respectively, when predicting unobserved germplasm. Genome-wide-association-studies (GWAS) were utilized to detect genetic variants with marginal effects (environment-independent effect) and conditional effects (environment-dependent effects). Results showed the presence of large-effect genetic variants with marginal effects, in addition to few Quantitative Trait Loci (QTL) whose effects were adaptive under specific environmental conditions while neutral or deleterious under different environmental conditions. CONCLUSION: This study demonstrates the usefulness and limitations of genomic prediction models for predicting GxE in highly diverse samples and describes the extent of GxE at the limit of species distribution for perennial ryegrass. Our study points towards adaptive variation which may enhance persistence of perennial ryegrass populations in Nordic and Baltic growing conditions.

Lolium↗

PubMed2025

Experimental Validation of Genome-Environment Associations in Arabidopsis.

Identifying the genetic basis of local adaptation is a key goal in evolutionary biology. Allele frequency clines along environmental gradients, known as genotype-environment associations (GEA), are often used to detect potential loci causing local adaptation but are rarely followed by experimental validation. Here, we tested loci identified in three moisture-related GEA studies on Arabidopsis. We studied 42 GEA-identified genes using t-DNA knockout lines under drought and tested effects on flowering time, an adaptive trait, and genotype-by-environment (GxE) interactions for performance and fitness. In total, 16/42 genes had significant effects on traits involved in local adaptation or performance responses to the environment. We found that wrky38 mutants had significant GxE effects for fitness; lsd1 plants had a significant GxE effect for flowering time, and 11 genes showed flowering time effects with no drought interaction. However, most GEA candidates did not exhibit GxE. In the follow-up experiments, wrky38 caused decreased stomatal conductance and specific leaf area under drought, indicating potentially adaptive drought avoidance. Additionally, GEA identified natural putative LoF variants of WRKY38 associated with dry environments, as well as alleles associated with variation in LSD1 expression. While only a few GEA-identified genes were validated for GxE interactions for fitness, we likely overlooked some genes because experiments might not well represent natural environments and t-DNA insertions might not well represent natural alleles. Nevertheless, GEAs apparently identified some genes contributing to local adaptation. GEA and follow-up experiments are straightforward to implement in model systems and demonstrate prospects for GEA discovery of new local adaptations.

Arabidopsis↗

PubMed2026

Integrating biological pathway polygenic scores and trauma in psychosis: findings from the EU-GEI study.

Psychotic disorders are complex, multifactorial conditions influenced by both genetic liability and early environmental adversity. Polygenic risk scores (PRSs) derived from genome-wide association studies have shown utility in capturing genetic predisposition, but their biological interpretability remains limited. In this study, we evaluated whether biologically informed pathway-specific polygenic scores (pPGSs) for psychosis, restricted to neurotransmitter-related pathways, could help clarify gene-environment interplay. Using data from 1 192 individuals in the EU-GEI multi-site case-control study, we constructed pPGSs for dopamine, glutamate, GABA, and serotonin systems. We investigated associations between pPGSs and childhood trauma (rGE), their interactions on psychosis risk (GxE), and the influence of the genome-wide psychosis PRS on these relationships. Serotonin, dopamine, and glutamate pPGSs were positively associated with a composite trauma exposure (i.e., abuse and neglect), suggesting shared genetic factors contributing to both psychosis liability and early adversity. Significant negative GxE effects were observed for both dopamine and serotonin pPGSs, indicating that higher trauma exposure diminished the relative influence of genetic liability on psychosis risk. Adjustment for the genome-wide psychosis PRS attenuated most effects, but serotonergic and dopaminergic associations remained robust, supporting pathway-specific contributions beyond general polygenic risk. These findings provide proof-of-concept for the utility of pPGSs in psychiatric research, suggesting both genetic contributions to trauma exposure and GxE effects on psychosis risk. Further research incorporating epigenetic data and longitudinal designs may enhance mechanistic insight and translational potential.

Adult↗

PubMed2026

Gene by environment interaction effects on the metabolic subtype of Polycystic Ovary Syndrome in Hispanic Community Health Study/Study of Latinos.

Polycystic Ovary Syndrome (PCOS) is a common polygenic endocrine disorder that is heterogenous in clinical presentation across genetic ancestry groups. PCOS is characterized by an array of symptoms such as hyperandrogenism, impaired mental health, and metabolic dysregulation. Studying the interaction of environmental factors (such as diet, physical activity, anxiety, and depression) with genetic variants on PCOS and its subtypes in populations with high cardiometabolic burden, e.g., Hispanic/Latinas, could aid in unraveling pathophysiological and genetic pathways through which PCOS functions. We sought to study gene by environment interactions with PCOS and its metabolic subtype (mPCOS) in a sample of US Hispanic/Latina female adults from the Hispanic Community Heath Study/Study of Latinos. In this large community-based study, we derived PCOS using self-reported condition and menstrual cycle information. We classified females with PCOS as having mPCOS if they had high metabolic impairment (fasting glucose, fasting insulin, or body mass index higher than the 75th percentile). There were 451 individuals with PCOS and 221 of them had mPCOS in our sample. We found that PCOS and mPCOS were significantly associated with hyperglycemia and high triglycerides in this population. While a polygenic risk score derived in European ancestry did not generalize to Hispanic/Latina females with PCOS, we identified the best proxy genetic variants in this population in known PCOS regions and investigated their interactions with four environment variables (diet, physical activity, anxiety and depression). Associations with known PCOS loci were generalized in our study at STAG3L4 and CACNA1G genomic regions. We observed GxE interactions between variants in/near three genes and physical activity on PCOS and mPCOS, including FGGY, FAT1, and PTHLH. Additionally, we noted interactions between diet and a variant in FANCC on PCOS, and diet and a variant near CMAS on both PCOS and mPCOS. We also detected GxE interactions between anxiety and depression and a variant in FGGY on PCOS, and depression and a variant near FBP1 on mPCOS. Our results point to potential protective effects of physical activity in females with PCOS and could inform future research on the mitigating effects of lifestyle management on PCOS genetic risk in Hispanic/Latino populations.

GxE↗

PubMed2026

A cross-sectional study of oxidative stress pathway genotypes and their interactions with environmental pollutant levels identifies associations with gene expression and lung function.

BACKGROUND: Asthma is a heterogeneous disease influenced by genetic and environmental factors. Fine particulate matter (PM2.5) exacerbates asthma, likely through oxidative stress pathways, but whether genetic variation modifies this effect remains unclear. METHODS: We analysed data on 948 adults with asthma from the Severe Asthma Research Program (SARP), linking ZIP-code-level PM2.5 exposure with whole-genome sequencing data. We tested 4337 single nucleotide polymorphisms (SNPs) in 120 oxidative stress pathway genes for gene-environment (GxE) interactions with PM2.5 on lung function (forced expiratory volume in 1 s [FEV1] % predicted) using weighted linear regression. Gene expression data from bronchial epithelial cells (n = 170) were used to assess cis-expression quantitative trait loci (eQTLs). FINDINGS: Higher PM2.5 exposure was associated with lower FEV1% predicted (β per μg/m3 = -0.7, p = 0.01). We identified 20 SNPs across seven genes (OXSR1, PXDN, TPO, LRRK2, APP, MSRA, MSRB2) with significant GxE interactions after multiple-testing correction. Five SNPs were also eQTLs, linking PM2.5-modified gene expression to lung function. Minor alleles in OXSR1 and PXDN were associated with reduced gene expression and worsened FEV1% under high PM2.5 exposure. Conversely, TPO variants were associated with higher baseline expression and lower lung function, but under increasing PM2.5 exposure, minor allele carriers showed suppressed TPO expression and improved FEV1%. INTERPRETATION: This study identified 20 SNPs in oxidative stress pathway genes that modify the effect of PM2.5 on lung function in asthma. These findings highlight the importance of integrating environmental context in genetic studies and suggest potential therapeutic targets for pollution-sensitive asthma phenotypes. FUNDING: Supported by NIH grants.

Cross-Sectional Studies↗

PubMed2025

Genetic Susceptibility to the Environment Moderates the Impact of Childhood Experiences on Psychotic, Depressive, and Anxiety Dimensions.

BACKGROUND AND HYPOTHESIS: Gene-by-environment (GxE) studies in psychosis have exclusively focused on negative exposures. However, evidence supports the resilience-enhancing effect of positive factors on psychosis outcome. The Differential Susceptibility (DS) model proposes that common genetic variants may confer not only disproportionate responsiveness to negative environments, but also greater sensitivity to positive, resilience-enhancing conditions. This study is the first to apply the DS model to the expression of subclinical psychosis, employing polygenic risk scores of environmental sensitivity (PRS-ES). PRS-ES were hypothesized to moderate, in a DS manner, associations between childhood adversity and psychosis, affective, and anxiety dimensions in young adults. An exploratory goal examined whether PRS for psychotic-like experiences (PRS-PLE) also showed DS patterns. STUDY DESIGN: PRS, schizotypy, PLE, depression, anxiety, and childhood adversity ratings were obtained for 197 nonclinical young adults. LEGIT software for testing competitive-confirmatory GxE models was employed. STUDY RESULTS: Results largely supported DS: Individuals high on PRS-ES showed increased subclinical psychosis, depression, and anxiety if they had experienced elevated childhood adversity, and lower symptoms if exposed to low levels of adversity as compared with those with low PRS-ES. Similarly, PRS-PLE moderated the effect of adversity on PLE, positive schizotypy, and depression following the DS model, but only PRS-ES moderation on PLE survived statistical correction. CONCLUSIONS: Our results suggest that genetic DS to the environment is relevant to psychosis, depression, and anxiety. Current debates on reconceptualization of genetic "risk" and resilience may benefit from this insight that support optimistic views on preventative efforts for early detection and intervention.

Humans↗

PubMed2025

Dynamic neuro-immune regulation of psychiatric risk loci in human neurons.

The prenatal environment influences neurodevelopment and subsequent clinical trajectories for psychiatric outcomes in childhood and adolescence. Yet it remains unclear if the impact of maternal and fetal immune activation varies with distinct polygenic risk profiles. Therefore, here we catalogue genotype and environment (GxE) interactions, contrasting allele-specific regulatory activity between inflammatory contexts. We report a cue-specific neuronal massively parallel reporter assay (MPRA) of 220 loci from genome-wide association study (GWAS) linked to ten brain traits/disorders, empirically dissecting the impact of interleukin-6 (IL-6) and interferon-alpha (IFNα) on transcriptional activity. Of 1,469 active candidate regulatory risk elements (MPRA-active CRSs) across three conditions, we identify 316 with dynamic variant-specific effects (MPRA-QTLs) in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons. Broadly, across hundreds of variants, neuronal immune-mediated regulatory activity is driven by differences in transcription factor binding and chromatin accessibility, the gene targets of which show pleiotropic enrichments for brain, metabolic, and immune disorders. Dynamic genetic regulation mediates immune effects, informing our understanding of mechanisms governing pleiotropy and variable penetrance. Understanding neurodevelopmental GxE interactions will inform mental health trajectories and resolve mechanisms mediating prenatal risk.

dynamic expression quantitative trait loci↗

PubMed2025

Genetic risk factors modulate the association between physical activity and colorectal cancer.

BACKGROUND: Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-PA interaction analysis. METHODS: Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. RESULTS: PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81-0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10- 8). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75-0.85), but no significant PA-CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10- 8). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72-0.82). CONCLUSIONS: In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

GWAS↗

PubMed2025

Compensatory evolution to DNA replication stress is robust to nutrient availability.

Evolutionary repair refers to the compensatory evolution that follows perturbations in cellular processes. While evolutionary trajectories are often reproducible, other studies suggest they are shaped by genotype-by-environment (GxE) interactions. Here, we test the predictability of evolutionary repair in response to DNA replication stress-a severe perturbation impairing the conserved mechanisms of DNA synthesis, resulting in genetic instability. We conducted high-throughput experimental evolution on Saccharomyces cerevisiae experiencing constitutive replication stress, grown under different glucose availability. We found that glucose levels impact the physiology and adaptation rate of replication stress mutants. However, the genetics of adaptation show remarkable robustness across environments. Recurrent mutations collectively recapitulated the fitness of evolved lines and are advantageous across macronutrient availability. We also identified a novel role of the mediator complex of RNA polymerase II in adaptation to replicative stress. Our results highlight the robustness and predictability of evolutionary repair mechanisms to DNA replication stress and provide new insights into the evolutionary aspects of genome stability, with potential implications for understanding cancer development.

DNA Replication↗

PubMed2026

Quantifying the Evolutionary Potential for Delta Smelt Persistence in a Warming Habitat.

Long-term persistence of managed species will depend, in part, on whether the species harbors the physiological or genetic potential to adjust to warming temperatures, and whether relevant genetic variation is modified by management practices. The critically endangered Delta Smelt (Hypomesus transpacificus) is intensively managed, but little is known about the presence of genetic variation for resistance to elevated temperature. Using a pedigree and whole genome sequencing data, we characterized the genetic basis of CTMax (as a metric of upper thermal tolerance) across control and elevated rearing temperatures, alongside covarying traits (body size and degree of hatchery ancestry). Warmer rearing temperatures increased CTMax through acclimation but also resulted in reduced additive genetic variation for the trait. We observed modest heritability for CTMax at rearing temperatures of 15°C and 18°C (0.26 and 0.16, respectively), but only a limited number of loci were identified that had consistent effects on CTMax across rearing temperatures. Instead, the genomic basis of thermal tolerance was highly dependent on rearing temperature (i.e., many loci detected with a GxE effect). This temperature-dependent genomic architecture is consistent with our finding that additive genetic variation for CTMax was reduced under warmer rearing conditions, indicating a potential constraint on adaptive evolutionary change. The influence of domestication selection was indicated by changes in allele frequency, and divergence in upper thermal tolerance and plasticity, between low and high hatchery ancestry groups. Minimal overlap between loci associated with domestication and CTMax suggests that these traits possess separate genetic underpinnings. Knowledge of genetic variation supporting ecologically relevant physiological variation may be useful for captive management and may inform supplementation of fish to the wild in an ever-warming environment.

conservation physiology↗

PubMed2026

Divergent Biological Consequences of APOE Isoforms Across Industrialized and Non-Industrial Environments.

The apolipoprotein ε4 (APOE ε4) isoform directly alters cholesterol and immune biology and is associated with an increased risk of neurodegenerative and cardiometabolic disease in industrialized settings; nevertheless, APOE ε4-which is ancestral in humans-has persisted over evolutionary time. One potential explanation is that the costs and benefits of APOE ε4 were significantly different in the environments in which humans evolved compared to those we experience today. In support, previous work has suggested that living in a high pathogen environment, engaging in high levels of physical activity, or eating a low fat diet can dampen the detrimental effects of APOE ε4, and has revealed positive effects for fertility. However, direct tests of whether APOE isoforms are associated with different biological outcomes in non-industrial versus industrialized contexts are lacking. Working with the Turkana of Kenya and the Orang Asli of Peninsular Malaysia-two Indigenous groups in which individuals of shared ancestry span a continuum of subsistence, non-industrial to urban, industrialized lifestyles-we investigated how APOE genotypes impact cholesterol, immunological, and reproductive traits and tested for genotype x environment (GxE) interactions. First, we confirmed established genotype effects across lifestyles, showing that more APOE ε4 alleles are associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol. Second, we tested for lifestyle interactions, finding lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli but not Turkana. Finally, we show that more APOE ε4 alleles are correlated with an extended reproductive lifespan, however this effect is relatively weak, is not consistent across populations, and does not correspond with a higher reproductive output. Together, our study provides evidence that industrialized environments can modify the biology of APOE ε4; however, we find that APOE ε4 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits.

Journal Article↗

PubMed2026

Quantifying the evolutionary potential for Delta Smelt persistence in a warming habitat.

Long-term persistence of managed species will depend, in part, on whether the species harbors the physiological or genetic potential to adjust to warming temperatures, and whether relevant genetic variation is modified by management practices. The critically endangered Delta Smelt (Hypomesus transpacificus) is intensively managed, but little is known about the presence of genetic variation for resistance to elevated temperature, which will be important to maintain for their persistence in a rapidly warming future. Using a pedigree and whole genome sequencing data, we characterized the genetic variation and genomic architecture for CTMax (as a metric of upper thermal tolerance) across control and elevated rearing temperatures, alongside covarying traits (body size, degree of hatchery ancestry). Warmer rearing temperatures increased CTMax through acclimation but also resulted in reduced additive genetic variation for the trait, which could constrain adaptation under thermal stress. We found that larger fish had reduced CTMax, although this effect was diminished at elevated temperatures. We observed modest heritability for CTMax at rearing temperatures of 15°C and 18°C (0.26 and 0.16, respectively), but only a limited number of loci were identified that had consistent effects on CTMax across rearing temperatures. Instead, the genomic basis of thermal tolerance was highly dependent on rearing temperature (many loci detected with a GxE effect). The influence of domestication selection was indicated by changes in allele frequency, and divergence in upper thermal tolerance and plasticity, between low and high hatchery ancestry groups. Minimal overlap between loci associated with domestication and CTMax suggests that these traits possess separate genetic underpinnings. Knowledge of genetic variation supporting ecologically relevant physiological variation may be useful for refuge management and may inform supplementation in an ever-warming environment.

conservation physiology↗

PubMed2026

Perceived partner substance use, genetic predispositions, and their associations with problematic alcohol use, emotional well-being, and relationship quality.

BACKGROUND: Romantic relationships are important contexts for substance use and emotional well-being. We tested the hypotheses that (i) genetic predispositions for alcohol consumption would be positively associated with partner substance use, (ii) partner substance use would moderate genetic influences on one's own alcohol outcomes, and (iii) partner discordance in substance use would be associated with lower emotional well-being and relationship quality. METHODS: Analyses included 2,357 participants (Mage = 51.4, 58.2% female) from the Collaborative Studies on the Genetics of Alcoholism. Focal measures included participants' reports of their own and their current partner's past-year substance use (frequencies of alcohol use, heavy drinking, drunkenness, cannabis use, and nicotine use), emotional well-being, and relationship quality. Participants' genetic predispositions were indexed with genome-wide polygenic scores for alcohol consumption (PGSAlc). Participant-partner substance use discordance was calculated as the difference between the participant's and their partner's use for each substance use measure, separately. RESULTS: Participant PGSAlc was not significantly associated with partners' perceived substance use. Frequent perceived partner alcohol use and heavy drinking significantly amplified the association between PGSAlc and alcohol use or drunkenness. Frequent perceived partner drunkenness and cannabis use significantly attenuated the association between PGSAlc and heavy drinking or frequency of alcohol use. Participant-partner discordance for several substance use measures was significantly associated with lower emotional well-being and relationship quality, controlling for participant and partner substance use main effects. CONCLUSIONS: The results highlight the importance of partner substance use in etiological models of alcohol use, emotional health outcomes, and relationship quality.

Humans↗