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PubMed2026

Gene-environment interaction between perinatal oxytocin exposure and Pten mutation shapes epigenetic reprogramming of oxytocin signaling and behavior in mice.

Synthetic oxytocin (Pitocin) is the most commonly used pharmacologic agent for induction and augmentation of labor. Beyond its uterotonic effects, oxytocin plays a critical role in neurodevelopment and social behavior. Dysregulated oxytocin signaling has been implicated in autism spectrum disorder (ASD), raising concern that perinatal exposure to exogenous oxytocin may have lasting neurodevelopmental consequences. This study aimed to determine whether offspring harboring a genetic predisposition for ASD are differentially impacted by perinatal oxytocin exposures, with a focus on long-term oxytocin signaling and autism-like behavior. Pregnant mice carrying offspring with heterozygous mutations in phosphatase and tensin homolog deleted on chromosome ten (Pten), a well-established monogenic risk factor for ASD, received continuous oxytocin versus phosphate-buffered saline (PBS) control via micro-osmotic pumps during late gestation. Wild-type (WT) offspring exposed to each treatment served as a secondary control. Adult offspring were assessed for oxytocin receptor (Oxtr) methylation in the frontal cortex and hippocampus, oxytocin expression in the hypothalamus, serum oxytocin levels, and were subject to a battery of social and anxiety-related behavior tests. Perinatal oxytocin exposure produced genotype-dependent effects in offspring. Epigenetic analyses revealed bidirectional remodeling of Oxtr methylation in the frontal cortex and hippocampus, with increased exon 1 methylation in WT mice and decreased methylation in Pten-mutant mice, resulting in significant genotype-treatment interactions. Hypothalamic oxytocin expression increased following treatment regardless of genotype, though baseline levels were higher in Pten-mutant mice. Neither oxytocin treatment nor genotype impacted long-term serum oxytocin levels. Behavioral outcomes were modest but context-specific: repetitive behaviors and cognition performance were unchanged, but oxytocin-treated Pten-mutant mice exhibited increased anxiety-like behavior alongside improved social memory. In contrast, oxytocin-treated WT mice showed reduced social novelty preference. Exploratory analyses suggested potential sex-dependent trends. Our findings support a model in which genetic susceptibility shapes the epigenetic encoding of early-life hormonal signals, thereby recalibrating oxytocin system function and downstream behavioral outcomes. Together, these data highlight the context-dependent effects of perinatal oxytocin exposure and argue against uniformly beneficial or detrimental effects, emphasizing the importance of gene-environment interactions in neurodevelopmental trajectories.

Animals↗

PubMed2026

Variance Polygenic Scores (vPGS) as a Tool for Studying Gene-Environment Interactions Associated With Refractive Error.

PURPOSE: Conventional polygenic scores predict an individual's phenotype based on their genetics. By contrast, variance polygenic scores (vPGS) quantify genetic predisposition to phenotypic variance. We tested the hypothesis that a vPGS for refractive error can identify individuals with increased susceptibility to environmental risk factors for myopia. METHODS: Six vPGS construction strategies were evaluated in UK Biobank participants: three variance heterogeneity genome-wide association study (vGWAS) methods and two reweighting schemes. vPGS performance was assessed using two metrics: (i) "Diff"-difference in phenotypic variance in vPGS decile ten versus one; (ii) Spearman correlation of phenotypic variance versus vPGS decile. The optimal vPGS was used to test for vPGS × time spent reading or vPGS × time spent outdoors interactions in children aged 15 years (ALSPAC cohort; n = 3471). RESULTS: Of the vGWAS methods, conditional quantile regression outperformed SCAMPI and Levene's Test. Of the re-weighting schemes, LDpred2 outperformed pruning and thresholding. In an independent sample of UK Biobank participants (n = 19,470), the top-performing vPGS successfully stratified individuals into groups with increasing variance in refractive error, even after adjusting for a conventional PGS (Diff: 2.55, 95% confidence interval [CI], 1.64-3.47; Spearman correlation = 0.87; 95% CI, 0.43-0.93). However, in ALSPAC participants, there was minimal support for vPGS interactions with time reading (P = 0.80) or time outdoors (P = 0.89). CONCLUSIONS: A novel vPGS successfully stratified individuals into groups with relatively high or low genetic susceptibility to refractive error variance. However, the vPGS could not identify individuals at enhanced risk from lifestyle risk factors for myopia.

Humans↗

PubMed2026

MMP-2 rs243865 Polymorphism as a Risk Modifier of Hepatocellular Carcinoma in Taiwanese Males, Smokers and Alcohol Consumers.

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Matrix metalloproteinase-2 (MMP-2) plays an important role in extracellular matrix remodeling and HCC progression. This study investigated the associations of two functional MMP-2 promoter polymorphisms, rs243865 and rs2285053, with HCC susceptibility in a Taiwanese population and explored their potential interactions with environmental risk factors. MATERIALS AND METHODS: A hospital-based case-control study was conducted at China Medical University Hospital (Taichung, Taiwan), involving 298 HCC patients and 889 age- and sex-matched cancer-free controls recruited in Taiwan. MMP-2 rs243865 and rs2285053 genotypes were determined utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Stratified analyses were used to explore their potential interactions between MMP-2 genotypes and environmental factors including sex, smoking and alcohol drinking status. RESULTS: No significant association was observed between HCC susceptibility and either rs243865 (CT+TT versus CC: odds ratio (OR)=1.20, 95% confidence interval (CI)=0.87-1.66, p=0.2944] or rs2285053 (CT+TT versus CC: OR=1.12, 95% CI=0.86-1.46, p=0.4219). Similarly, allelic analyses revealed no significant effects. Interestingly, stratified analyses demonstrated significant gene-environment interactions for rs243865. Male carriers of the TT genotype exhibited an increased HCC risk (OR=3.24, 95% CI=1.12-9.37, p=0.0488). Among smokers, the TT genotype was associated with a markedly elevated risk (OR=6.46, 95% CI=1.65-25.29, p=0.0055), while alcohol drinkers carrying the TT genotype showed the highest susceptibility (OR=9.69, 95% CI=1.99-47.13, p=0.0022). No significant association was found for rs2285053 genotype in any genetic variant and subgroup. CONCLUSION: Although MMP-2 rs243865 and rs2285053 do not independently determine HCC susceptibility, rs243865 T allele may serve as a genetic biomarker for identifying Taiwanese males, smokers, and alcohol drinkers at elevated risk of HCC. These findings highlight the importance of gene-environment interactions in hepatocarcinogenesis and support the incorporation of genetic information into personalized HCC risk assessment and prediction strategies.

Humans↗

PubMed2026

Genetic risk scores, perceived neighborhood disorder, and sleep duration.

STUDY OBJECTIVES: Most studies of neighborhood context and sleep health emphasize direct effects and fail to account for the role of genetics. In this paper, we draw on the socioecological model to examine the interplay of genetics, neighborhood context, and sleep health. We specifically examine the independent and joint effects of genetic risk scores (GRS) and perceived neighborhood disorder on sleep duration. METHODS: We combine genomic and cross-sectional survey data from the All of Us Research Program, a non-probability sample of 22 575 adults of European ancestry living in the United States. We use the sleep duration-increasing risk allele count for 78 genome-wide single nucleotide polymorphisms (SNPs) to construct weighted genetic risk scores. Our analyses include an index of perceived neighborhood disorder and an objective measure of sleep duration based on wrist actigraphy. RESULTS: Genetic risk scores are inversely associated with neighborhood disorder, positively associated with continuous sleep duration, and inversely associated with the odds of short sleep. Neighborhood disorder is inversely associated with continuous sleep duration and positively associated with the odds of short and long sleep. The association between genetic risk scores and sleep duration (continuous and categorical) is invariant across levels of neighborhood disorder. CONCLUSIONS: Our analyses confirm the independent direct effects of genetic risk scores and neighborhood disorder on sleep duration. Our findings extend the socioecological model by assessing the role of genetics in the study of neighborhood context and sleep health. Although we observed a gene-environment correlation between genetic risk scores and perceived neighborhood disorder, there was little indication of genetic confounding and no evidence of gene-environment interaction.

Humans↗

PubMed2026

Heterokairic Genes and the Eco-Evo-Devo of Timing.

Concepts of developmental timing have traditionally been framed under heterochrony as evolved (genetically based) differences in timing, while environmentally induced shifts in timing within genotypes have been treated more loosely. In this article, heterokairy is presented as plasticity in the timing of developmental events, and the term "heterokairic genes" is proposed for environmentally modulated heterochronic genes that underlie this plasticity. Evidence from nematodes, insects, plants, and vertebrates is assembled, with emphasis placed on systems where environmental cues are relayed through endocrine or metabolic pathways to known timing modules/genes. On this basis, a distinction is drawn between validated heterokairic genes, supported by direct mechanistic data, and a broader set of candidates inferred from gene-environment interactions in developmental timing. The eco-evolutionary consequences of such genes are considered, and experimental and genomic strategies for their identification are outlined. It is argued that heterokairic genes provide a useful bridge between environmental variation, developmental mechanisms, and evolutionary change in timing.

Animals↗

PubMed2026

Shielding the First 24 Postnatal Months of Life: A Proposal for a Prospective Cohort Study of Early-Life Electromagnetic Exposure and Autism Risk.

BACKGROUND: Autism Spectrum Disorder (ASD) involves Mirror Neuron System (MNS) dysfunction, driving core social and imitative impairments. Systemic physiological alterations such as autonomic dysregulation, mitochondrial dysfunction and neuroinflammation are known to impair synchronization and plasticity of neuronal clusters. A less-evident environmental cofactor, coinciding with rising ASD prevalence, is the considerable world-wide increase in electromagnetic radiation (EMR) overall exposure among children. Experimental evidence shows how low-intensity EMR influences cellular processes, via voltage-gated calcium channels (VGCCs), oxidative stress, and mitochondrial metabolism. The Resonant Convergence framework, allow to predict how chronic EMR exposure during the first 24 postnatal months of life can act as a factor in ASD pathogenesis. The best candidate mechanism is chronic Ion Cyclotron Resonance (ICR) detuning the Ca2+-calmodulin pathway, thus disrupting MNS synchronization. METHODS AND ANALYSIS: A prospective observational pilot cohort study (24-month follow-up) proposes to enroll 1000 full-term newborns into two arms: an EMR-reduced cohort (n = 500, rest and sleep-phase Faraday shielding) and a standard exposure cohort (n = 500). Exposure is quantified via radiofrequency (RF)/extremely low frequency(ELF) measurements, proximity analysis, device inventories and wearable dosimetry. The primary endpoint is a continuous neurodevelopmental trajectory score (joint attention, language, electroencephalogram (EEG) mu-rhythm); binary ASD diagnosis (Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), Autism Diagnostic Interview-Revised (ADI-R)) is a secondary, exploratory endpoint. Moreover, an optional genomic screening will evaluate gene-environment interactions within extremely low-frequency electromagnetic field (ELF-EMF) vulnerable pathways, including ASD-associated genes upregulated by RF via bromodomain and extraterminal protein (BET)-mediated epigenetic mechanisms. Analyses will employ risk ratios, Fisher's exact tests and logistic regression adjusted for confounders; mixed-effects and Bayesian modeling will evaluate longitudinal outcomes and exposure reduction effects. Given a 2-3% baseline prevalence, approximately 20-30 ASD cases are expected. The study is therefore powered for exploratory signal detection rather than definitive causal inference, providing the critical baseline data required to justify and design future confirmatory trials. Sex-stratified modeling will address the 4:1 male-to-female prevalence ratio. ETHICS AND DISSEMINATION: Ethics committee approval is not yet sought; full protocol review and approval will be obtained prior to the study initiation, in strict accordance with the Declaration of Helsinki. Written parental informed consent will be mandatory for all participants prior to enrollment. Study findings and methodological milestones will be disseminated through peer-reviewed international scientific publications. This protocol provides a structured methodological framework for the first prospective investigation of sleep-phase EMR reduction as a potential modulator of ASD incidence during early neurodevelopment. Results will inform adequately powered confirmatory trials in electromagnetic neurodevelopmental epidemiology.

autism spectrum disorder↗

PubMed2026

Nonuniform Association of Genetic Risk Scores for Intraocular Pressure.

IMPORTANCE: Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma, and genetic risk scores hold promise as a tool for screening for ocular hypertension. However, genetic risk scores for IOP have a nonuniform association across the range of IOP, which reduces their accuracy. OBJECTIVE: To test the hypothesis that nonuniform behavior of genetic risk scores for IOP is associated with a specific type of genetic interaction. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, post hoc genetic association studies were performed using linear and quantile regression in a sample of UK Biobank participants. Data were analyzed from January to September 2025. EXPOSURES: Ninety-eight genetic variants associated with IOP. MAIN OUTCOMES AND MEASURES: Tests were carried out for 98 genetic variants associated with IOP (P < 5.0 ×10-8) to examine (1) dominant or recessive genetic effects, (2) genotype × genotype interactions, (3) genotype × age interactions, and (4) genotype × sex interactions. RESULTS: A total of 98 235 participants (mean [SD] age, 58.1 [7.9] years; 52 168 female [53.1%]) were included in this analysis. More variants exhibited genotype × age interactions than expected by chance (14 of the 98 variants associated with IOP had at least nominal evidence of an interaction with age; P = 3.76 ×10-4). For 12 of these 14 variants, age increased rather than decreased the magnitude of the IOP vs genotype association. However, integrating age interactions into the genetic risk score construction process did not yield improved accuracy (incremental noninteraction model, R2 = 4.05; 95% CI, 3.82-4.31 and interaction model, R2 = 4.04; 95% CI, 3.80-4.27). There was little support for other types of genetic interaction. CONCLUSIONS AND RELEVANCE: In the current work, findings show minimal evidence that nonadditive allelic effects, genotype × genotype interactions, and genotype × sex interactions contributed to the nonuniform association of genetic variants with IOP across quantiles of IOP. Although a genetic risk score for IOP was more accurate in older vs younger individuals, efforts to account for genotype × age interactions in genetic risk score construction did not improve accuracy. These findings suggest other factors, such as gene-environment interactions, contribute to the nonuniform relationship of genetic variants with IOP.

Humans↗

PubMed2026

Partitioned blood pressure polygenic risk reveals differential genetic effects of tissue-specific enhancers and their interactions on cardiovascular disease.

Polygenic risk scores (PRS) compress genome-wide associations into a single predictor, but this aggregation obscures the distinct biological mechanisms through which genetic variation shapes complex traits. Here we introduce a framework that additively decomposes a trait's PRS, without loss of SNP heritability, into independent components defined by the tissue-specific and tissue-agnostic cis-regulatory elements (CREs) in which its variants act. Applied to blood pressure (BP) using ~0.5 million CREs across four BP-relevant tissues (adrenal gland, artery, heart, kidney), the framework reveals that regulatory effects are globally additive across tissues yet locally non-additive, and that the resulting partitioned scores carry pronounced, reproducible heterogeneity in their effects on BP and cardiovascular outcomes. We show this heterogeneity reflects gene-environment interactions, and trace one example to its mechanism: a kidney-CRE-partitioned score is protective against coronary artery disease and myocardial infarction through an interaction between ATP2B1 and antihypertensive medication. Explicitly modeling these interactions improves prediction and transferability, and tissue-focused partitioning increases power to resolve causal genes and reveals genes such as ADAMTS8 with antagonistic effects across BP components. Validated in an independent All of Us cohort, these findings recast the PRS from a blunt aggregate predictor into a mechanistic probe of context-dependent genetic architecture.

Journal Article↗

PubMed2026

Novel epigenetic loci identified from an epigenome-wide association study underlying brain structural changes in bipolar disorder.

BACKGROUND: DNA methylation influences gene-environment interactions and brain development in bipolar disorder (BD). We aimed to identify BD-associated epigenetic loci and examine their associations with brain structural variation. METHODS: We conducted an epigenome-wide association study (BD group, n = 90; healthy controls group, n = 161) to identify BD-associated DNA methylation loci, and we additionally performed copy number alteration and functional enrichment analyses. The correlations between epigenetic loci and cortical thickness (CT) were assessed using Pearson's partial correlation analysis, and the co-methylation effect of the epigenetic loci identified in the neuroimaging-epigenetic analysis was investigated. FINDINGS: A total of 156 differentially methylated positions (DMPs) and 7 differentially methylated regions were identified, and the genes associated with them were observed to be enriched in biological processes related to muscle hypertrophy and neuronal activity. Significant correlations between the methylation levels of 13 DMPs associated with three genes (miR886, PLEC1, and ICAM5) and the CT of the right postcentral gyrus and inferior frontal gyrus were identified. Specifically, 10 DMPs associated with the CpG island in the upstream region of the miR886 gene showed negative correlations with the right postcentral gyrus CT, implicating miR886-associated CpG-island methylation in regional cortical thinning. CONCLUSION: Epigenetic changes might play an important role in brain structural changes in BD. These multimodal findings nominate miR886-related methylation as a candidate molecular correlate of cortical thinning and warrant replication and mechanistic follow-up in larger, state-diverse cohorts.

Humans↗

PubMed2026

UHRF1 deficiency exacerbates intestinal inflammation by epigenetic modulation of NPY1R gene methylation.

Epigenetic modifications play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) by mediating gene-environment interactions. We previously showed that UHRF1, a central regulator of DNA methylation, contributes to cancer progression; however, its function in IBD remains poorly understood. Here, we revealed that UHRF1 was frequently reduced in inflamed tissues of patients with IBD and that its deficiency exacerbated intestinal epithelial cell (IEC) damage. Through a multilevel approach incorporating human cell models and an intestinal epithelial-specific Uhrf1-KO mouse model, we established UHRF1 as a key mitigator of IBD progression. Mechanistically, UHRF1 bound to the NPY1R promoter, promoted its methylation, and led to transcriptional suppression. The NPY1R upregulation resulting from UHRF1 deficiency attenuated cAMP/PKA/CREB signaling in IECs, thereby enhancing NF-κB activation and subsequent proinflammatory responses, which compromised intestinal epithelial barrier integrity. Furthermore, we identified miR-141 as a negative regulator of NPY1R, highlighting its potential as a therapeutic agent. Collectively, our results identified the UHRF1/NPY1R regulatory axis as a critical epigenetic mechanism in intestinal inflammation and underscored its dual promise for IBD diagnostics and therapy.

Animals↗

PubMed2026

Recent Advances in Multi-Omics of Systemic Lupus Erythematosus.

This comprehensive narrative review examines recent advances in multi-omics research for Systemic Lupus Erythematosus (SLE), emphasizing integrated approaches over single-omics studies. The review critically evaluates technological advancements, methodological innovations, and clinical applications while identifying current limitations and future research directions. We conducted a comprehensive narrative review following SANRA guidelines, searching PubMed, Web of Science, Scopus, and Embase, covering publications from January 2018 to June 2025. The review focuses on studies integrating two or more omics layers in SLE research, with emphasis on computational methods, biomarker validation, and clinical applications. Multi-omics integration has revealed critical insights into SLE pathogenesis, including immune cell heterogeneity, gene-environment interactions, and metabolic dysregulation. However, significant challenges remain in data integration methodologies, small sample sizes, and biomarker reproducibility. Current computational approaches include early integration (concatenation), intermediate integration (joint dimensionality reduction), and late integration (ensemble methods). While multi-omics approaches offer unprecedented insights into SLE complexity, standardized integration protocols and robust validation frameworks are urgently needed. Small sample sizes and heterogeneity issues limit reproducibility, particularly affecting biomarker discovery and clinical translation. Multi-omics integration represents a paradigm shift toward precision medicine in SLE, but realizing this potential requires addressing current methodological limitations, standardizing validation processes, and developing robust computational frameworks for reliable clinical applications.

Humans↗

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↗

PubMed2026

Complex genotype-phenotype relationships in neurodevelopmental disorders.

With the advent of sequencing technologies in recent years, hundreds of high-confidence risk genes have been implicated in neurodevelopmental disorders (NDDs). However, individuals carrying pathogenic variants in the same gene frequently exhibit diverse clinical presentations, including varied symptoms and diagnoses. We propose that this heterogeneity arises from different interacting factors that modulate the phenotypic outcomes of pathogenic variants, including variant-level features, modifying variation across the genome, prenatal and early-life environmental exposures, and developmental noise. Resolving these factors requires integrative approaches that combine population-scale genetics and functional genomics with environmental monitoring and quantitative assessments of stochastic developmental variation. Advancing our understanding of these factors is critical to elucidating the etiology of NDDs and improving diagnostic and personalized therapeutic strategies.

Humans↗

PubMed2025

Polygenic scores capture genetic modification of the adiposity-cardiometabolic risk factor relationship.

Polygenic scores (PGSs) that can predict response to interventions can facilitate precision medicine and are detectable in observational datasets as PGS-by-exposure (PGS×E) interactions. PGSs based on interactions (iPGSs) or variance effects (vPGSs) may be more powerful than standard PGSs for detecting PGS×E, but these have yet to be systematically compared. We describe a generalized pipeline for developing and comparing these PGS types and apply it to detect genetic modification of the relationship between adiposity (measured by BMI) and a broad set of cardiometabolic risk factors. Our applied analysis in the UK Biobank identified significant PGS×BMI for 16/20 risk factors, most consistently for the iPGS approach. Many interactions replicated in All of Us (AoU); for example, we observed a 72% larger BMI-alanine aminotransferase association in the top iPGS decile in AoU. Our study provides a framework for the comparison of PGS×E strategies and informs efforts toward clinically useful response-focused PGSs.

Humans↗

PubMed2026

Integrating Genetics and Environment to Find Causal Mechanisms for Multiple Sclerosis.

Genome-wide association studies (GWAS) have identified hundreds of risk loci for multiple sclerosis (MS), but we have limited knowledge of the mechanisms through which genetic variants mediate risk. Similarly, epidemiological studies implicate numerous environmental risk factors in MS risk, but these cannot identify specific causal mechanisms. We review our current knowledge of genetic mechanisms in MS, including the critical role of expression quantitative trait locus (eQTL) mapping in translating genetic risk loci into causal mechanisms. Molecular and functional context has emerged as an important missing component of these studies, and we discuss how environmental risk factors can be modelled in a quantitative genetic context to identify disease mechanisms. In parallel, we highlight recent advances in which quantitative genetic methods establish a causal role for low vitamin D and obesity in MS, and to dissect the mechanisms through which these operate. As genetic, transcriptional, and epigenetic studies continue to expand, further mechanistic insights for MS are likely to come from the integration of genetic and environmental data.

Humans↗

PubMed2026

Genetic and Environmental Influences on Caffeine Intake in Korean Twins.

Caffeine intake may be influenced by both genetic and environmental factors. This study aimed to examine the genetic contribution to variation in coffee and tea drinking, as well as total caffeine intake. A total of 1,106 Korean twins, comprising 456 monozygotic and 97 dizygotic twin pairs aged 30 years or older, from the Healthy Twin Study were included. Structural equation models were used to assess heritability estimates and their 95% confidence intervals (CIs). Heritability (95% CI) was estimated at 0.29 (0.21, 0.37) for coffee drinking, 0.11 (0.02, 0.20) for tea drinking, and 0.27 (0.16, 0.38) for total caffeine intake, with the remaining variance in each trait attributed to unique environmental factors. The unique environmental factors contributed more substantially to coffee drinking than genetic factors during early adulthood, while the genetic contribution to tea drinking remained consistently low across all ages. In conclusion, coffee drinking, tea drinking, and total caffeine intake were partly heritable, with unique environmental factors playing a predominant role.

Humans↗

PubMed2026

Humanizing acidic mammalian chitinase variants establish lung immune conditioning and control environmentally driven inflammation and fibrosis.

Chitin, a widespread environmental particle constituent, triggers lung inflammation but is degraded by chitinases. In humans, single-nucleotide polymorphisms (SNPs) in CHIA (acidic mammalian chitinase; AMCase) are associated with lung disease, suggesting that chitinase variants influence responses to airborne particles. Here, we edit the mouse Chia1 locus to generate humanized (hChia) mice harboring common human SNPs. Compared with controls expressing disease-protective SNPs, hChia mice lack robust chitinase activity and fail to degrade natural chitin substrates. Lung-resident lymphocytes and macrophages are spontaneously primed and sensitive to inflammatory triggering by environmental chitin. Immune cell infiltration correlates with airway chitin following challenge, and hChia mice exhibit exacerbated inflammatory and fibrotic lung disease. In humans with acute respiratory failure, alveolar hemorrhage coincides with environmentally derived chitin particles that are susceptible to chitinase degradation, attenuating inflammatory cell responses. Thus, environmental chitin and chitinase activity are crucial determinants of lung immune conditioning with potential therapeutic applications.

AMCase↗

PubMed2026

Genetic heterogeneity affects the risk of incident depression, comorbidity, and response to environment: A prospective trajectory study.

BACKGROUND: Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored. METHODS: First, depression risk loci from a large-scale genome-wide meta-analysis were annotated to Gene Ontology (GO) terms by functional enrichment. GO-based polygenic risk scores (GO-PRS) were then calculated for individuals in the UK Biobank. Principal component analysis (PCA) was applied for dimensionality reduction, followed by cluster analysis to identify genetic subtypes of depression. Multistate models were applied to assess the impact of genetic patterns on the trajectory from healthy status to incident depression, and depression to 26 subsequent diseases, as well as the associations between environmental factors and disease trajectories across genetic subtypes. RESULTS: Participants were categorized into three genetic subtypes: immune-dominant, neuro-dominant, and comprehensive-risk. Significant differences in risk of depression and subsequent diseases, and susceptibility to environmental factors were observed across subtypes. Comprehensive-risk subtype showed higher risks of depression compared to immune-dominant (HR: 1.10, 95% CI: 1.05-1.15) and neuro-dominant subtype (HR: 1.12, 95% CI: 1.08-1.16). Comprehensive-risk subtype exhibited higher risks of transition from depression to subsequent diseases, such as anemia compared to immune-dominant subtype, and diseases of the digestive system compared to neuro-dominant subtype. Environmental factors were more strongly associated with the transition from depression to subsequent diseases in immune-dominant and comprehensive-risk subtypes, including cardiovascular, respiratory, and metabolic diseases. CONCLUSIONS: Our findings highlight the genetic heterogeneity of depression and comorbidities, and shed light on how genetic components modulate responses to environmental factors.

Humans↗