Gene‒Environment Interaction Between CAST Gene and Eye-Rubbing in the Chinese Keratoconus Cohort Study: A Case-Only Study.

Purpose: Keratoconus (KC), characterized by progressive corneal protrusion and thinning, is a complex disease influenced by the combination of genetic and environmental factors. The purpose of this study was to explore potential gene‒environment interaction between the calpastatin (CAST) gene and eye-rubbing in KC. Methods: A case-only study including 930 patients (676 patients with eye-rubbing and 254 patients without eye-rubbing) from the Chinese Keratoconus (CKC) cohort study was performed in the present study. Genotyping of single nucleotide polymorphism (SNP) was conducted using the Illumina Infinium Human Asian Screening Array (ASA) Beadchip. The gene‒environment interactions between CAST gene and eye-rubbing were analyzed using PLINK version 1.90. The interactions between CAST genotypes and eye-rubbing were analyzed by logistic regression models. The SNP-SNP-environment interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). Results: Three SNPs in CAST gene, namely, rs26515, rs27991, and rs9314177, reached the significance threshold for interactions (defined as P < 2.272 × 10-3). Notably, the minor alleles of these three SNPs exhibited negative interactions with eye-rubbing in KC. The results of logistic regression models revealed that the minor allele homozygotes and heterozygotes of rs26515, rs27991, and rs9314177 also exhibited negative interactions with eye-rubbing. Furthermore, GMDR analysis revealed the significant SNP-SNP-environment interactions among rs26515, rs27991, rs9314177, and eye-rubbing in KC. Conclusions: This study identified rs26515, rs27991, and rs9314177 in CAST gene existed gene-environment interactions with eye-rubbing in KC, which is highly important for understanding the underlying biological mechanisms of KC and guiding precision prevention and proper management.

Systematic discovery of gene-environment interactions underlying the human plasma proteome in UK Biobank.

Understanding how gene-environment interactions (GEIs) influence the circulating proteome could aid in biomarker discovery and validation. The presence of GEIs can be inferred from single nucleotide polymorphisms that associate with phenotypic variability - termed variance quantitative trait loci (vQTLs). Here, vQTL association studies are performed on plasma levels of 1463 proteins in 52,363 UK Biobank participants. A set of 677 independent vQTLs are identified across 568 proteins. They include 67 variants that lack conventional additive main effects on protein levels. Over 1100 GEIs are identified between 101 proteins and 153 environmental exposures. GEI analyses uncover possible mechanisms that explain why 13/67 vQTL-only sites lack corresponding main effects. Additional analyses also highlight how age, sex, epistatic interactions and statistical artefacts may underscore associations between genetic variation and variance heterogeneity. This study establishes the most comprehensive database yet of vQTLs and GEIs for the human proteome.

Factor analytic selection tools and environmental feature-integration enable holistic decision-making in Eucalyptus breeding.

Understanding the genotype-by-environment interaction (GEI) and considering it in the selection process is a sine qua non condition for the expansion of Brazilian eucalyptus silviculture. This study's objective is to select high-performance and stable eucalyptus clones based on a novel selection index that considers the Factor Analytic Selection Tools (FAST) and the clone's reliability. The investigation explores the nuances interplay of GEI and extends its insights by scrutinizing the relationship between latent factors and real environmental features. The analysis, conducted across seven trials in five Brazilian states involving 78 clones, employs FAST. The clonal selection was performed using an extended FAST index weighted by the clone's reliability. Further insights about GEI emerge from the integration of factor loadings with 25 environmental features through a principal component analysis. Ten clones, distinguished by high performance, stability, and reliability, have been selected across the target population of environments. The environmental features most closely associated with factor loadings, encompassing air temperature, radiation, and soil characteristics, emerge as pivotal drivers of GEI within this dataset. This study contributes insights to eucalyptus breeders, equipping them to enhance decision-making by harnessing a holistic understanding-from the genotypes under evaluation to the diverse environments anticipated in commercial plantations.

Assessing genetic and environmental components for pterygium: a nationwide study in Taiwan.

This study aims to estimate the familial risks of pterygium and assess its relative contributions to environmental and genetic factors using the 2000-2017 Taiwan National Health Insurance Research Database. The marginal Cox's model and the polygenic liability model were made. In Taiwan, the prevalence rate of pterygium in 2017 was 1.64% for individuals with affected first-degree relatives, higher than the general population (1.34%). The adjusted relative risk (RR) for pterygium was highest for twins of the same sex (15.54), followed by siblings of the same sex (4.69), offsprings (3.39), siblings of the different sex (2.88), spouse (2.12), parents (1.86), twins of the different sex (1.57), respectively. The phenotypic variance of pterygium was 21.6% from additive genetic variance, 24.3% from common environmental factors shared by family members, and 54.1% from non-shared environmental factors, respectively. Sensitivity analysis by restricting those with surgical pterygium reveals that aRRs and the three components were similar to those of the overall pterygium. In summary, the prevalence rate of pterygium was higher for individuals with affected first-degree relatives than for the general population. The non-shared environmental factors account for half of the phenotypic variance of pterygium; genetic and shared environmental factors explain the rest.

Genetic and environmental impact on variation in the palatal dimensions in permanent dentition: a twin study.

The objective of this study was to assess the relative contributions of genetic and environmental factors to variation in palatal parameters in twins with completed maxillary growth. The subjects of this study comprised digital dental casts of 50 monozygotic and 35 dizygotic twin pairs. The subjects' average age was 17.95 ± 2.83 years. Zygosity determination was carried out using 15 specific DNA markers and an amel fragment of the amelogenin gene. The interdental distances were measured between selected dental landmarks at the occlusal and gingival planes. The palatal height, surface area and volume were measured between the gingival plane and the midpalate suture. High heritability estimates were observed for all transverse intra-arch measurements. The palate height (a2 = 0.8), dental arch width in the molar area (a2 = 0.86), palatal surface area (a2 = 0.61) and palate volume (a2 = 0.69) were under strong additive genetic control. Moderate genetic dominance was observed for dental arch widths at the gingival line in the canine (d2 = 0.5) and premolar regions (d2 = 0.78-0.81). Sexual dimorphism was shown, with males exhibiting a greater arch width, palate surface area and volume than females (p < 0.01). The majority of palate parameters variation in twins was controlled by genetic effects, and most were highly heritable.

Spatial distribution of residential environment, genetic susceptibility, and psoriasis: A prospective cohort study.

Background: Genetic and environmental factors contribute to psoriasis, but the impact of residential environments on this condition remains uncertain. We aimed to investigate the association of residential environments with psoriasis risk and explore its interaction with genes. Methods: We retrieved data on the spatial distribution of residential environments at 300 and 1000 m buffer zones from the UK Biobank, including the proportions of natural environments, domestic gardens, green spaces, and blue spaces within these zones. We then used Cox hazard models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between residential environments and psoriasis risk. Lastly, we constructed polygenic risk scores to determine genetic susceptibility and further analyse the interaction with residential environments. Results: Overall, 3755 incident cases of psoriasis were documented during a median follow-up of 12.45 years. Compared with the lowest exposure quantile (Q1), Q4 exposure to natural environments (1000 m buffer: HR = 1.16, 95% CI = 1.05-1.29; 300 m buffer: HR = 1.12, 95% CI = 1.02-1.24) and green spaces (1000 m buffer: HR = 1.16, 95% CI = 1.04-1.28; 300m buffer: HR = 1.10, 95% CI = 1.00-1.21) increased the risk of psoriasis, while Q4 exposure to domestic gardens (1000 m buffer: HR = 0.85, 95% CI = 0.77-0.93; 300m buffer: HR = 0.91, 95% CI = 0.83-1.00) and Q3 exposure to blue spaces (1000 m buffer: HR = 0.89, 95% CI = 0.81-0.98) were negatively associated with psoriasis risk. Among participants with a high genetic risk, those exposed to high levels of natural environments (1000 m buffer: HR = 1.49, 95% CI = 1.15-1.93; 300 m buffer: HR = 1.39, 95% CI = 1.10-1.77) and green spaces (300 m buffer: HR = 1.30, 95% CI = 1.04-1.64) had a higher risk of psoriasis, while those exposed to blue spaces (1000 m buffer: HR = 0.78, 95% CI = 0.63-0.98) had a lower risk of psoriasis. We also observed joint effects of genetic risk and residential environments and an antagonistic additive interaction between blue spaces and genetic risk (P = 0.011). Conclusions: We observed that residing in natural environments and green areas increased the risk of psoriasis in our sample, while proximity to blue spaces and domestic gardens was associated to reduced risks. The association of residential environments with psoriasis risk was modified by genetic susceptibility.

A framework for simulating genotype-by-environment interaction using multiplicative models.

KEY MESSAGE: The simulation of genotype-by-environment interaction using multiplicative models provides a general and scalable framework to generate realistic multi-environment datasets and model plant breeding programmes. Plant breeding has been historically shaped by genotype-by-environment interaction (GEI). Despite its importance, however, many current simulations do not adequately capture the complexity of GEI inherent to plant breeding. The framework developed in this paper simulates GEI with desirable structure using multiplicative models. The framework can be used to simulate a hypothetical target population of environments (TPE), from which many different multi-environment trial (MET) datasets can be sampled. Measures of variance explained and expected accuracy are developed to tune the simulation of non-crossover and crossover GEI and quantify the MET-TPE alignment. The framework has been implemented within the R package FieldSimR, and is demonstrated here using two working examples supported by R code. The first example embeds the framework into a linear mixed model to generate MET datasets with low, moderate and high GEI, which are used to compare several popular statistical models applied to plant breeding. The prediction accuracy generally increases as the level of GEI decreases or the number of environments sampled in the MET increases. The second example integrates the framework into a breeding programme simulation to compare genomic and phenotypic selection strategies over time. Genomic selection outperforms phenotypic selection by ∼ 50-70% in the TPE, depending on the level of GEI. These examples demonstrate how the new framework can be used to generate realistic MET datasets and model plant breeding programmes that better reflect the complexity of real-world settings, making it a valuable tool for optimising a wide range of breeding methodologies.

A Systematic Review of the Gene-Lifestyle Interactions on Metabolic Disease-Related Outcomes in Arab Populations.

The increased prevalence of metabolic diseases in the Arab countries is mainly associated with genetic susceptibility, lifestyle behaviours, such as physical inactivity, and an unhealthy diet. The objective of this review was to investigate and summarise the findings of the gene-lifestyle interaction studies on metabolic diseases such as obesity and type 2 diabetes in Arab populations. Relevant articles were retrieved from a literature search on PubMed, Web of Science, and Google Scholar starting at the earliest indexing date through to January 2024. Articles that reported an interaction between gene variants and diet or physical activity were included and excluded if no interaction was investigated or if they were conducted among a non-Arab population. In total, five articles were included in this review. To date, among three out of twenty-two Arab populations, fourteen interactions have been found between the FTO rs9939609, TCF7L2 rs7903146, MC4R rs17782313, and MTHFR rs1801133 polymorphisms and diet or physical activity on obesity and type 2 diabetes outcomes. The majority of the reported gene-diet/ gene-physical activity interactions (twelve) appeared only once in the review. Consequently, replication, comparisons, and generalisation of the findings are limited due to the sample size, study designs, dietary assessment tools, statistical analysis, and genetic heterogeneity of the studied sample.

THE JEREMIAH METZGER LECTURE: ENVIRONMENTAL INFLUENCES ON COLORECTAL CANCER.

Gene-environmental interactions create risk profiles for sporadic cancer development in patients with colorectal cancer (CRC). For instance, a person's socioeconomic status over their lifetime can affect their level of physical activity and type of diet, and their exposure to tobacco and alcohol may affect their gut microbiome and ultimate risk for developing CRC. Metabolic disease can independently or further change the gut microbiome and alter the typical timing of CRC development, such as is observed and linked with early-onset disease. Patients with microsatellite unstable tumors where DNA mismatch repair is defective have altered immune environments as a result of tumor hypermutability and neoantigen generation, allowing for immune checkpoint inhibitor susceptibility; in such cases, the genetics of the tumor changed the environment. The environment can also change the genetics, where interleukin-6-generated inflammation can inactivate MSH3 protein function that is associated with CRCs which are more metastatic, and patients show poor outcomes. Some specific aspects of the local microbial environment that may be influenced by diet and metabolism are associated with CRC risk, such as Fusobacterium nucleatum infection, and may affect the initiation, perpetuation, and spread of CRC. Overall, both the macro- and microenvironments associated with a person play a major role in CRC formation, progression, and metastases.

Interaction between angiotensin-converting enzyme gene rs4343 polymorphism, environment factors, and angiotensin II level on susceptibility to knee osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is a complex multifactorial disease. The association of knee OA risk with ACE gene rs4343 polymorphism, gene environment synergistic effect, and angiotensin II serum level has not been previously examined. Therefore, we investigate the ACE gene rs4343 polymorphism in knee OA, and its association with severity of knee OA, and angiotensin II serum level. METHODS: Using a case-control design, we recruited 200 subjects (100 cases and 100 controls) and all were subjected to genotyping of rs4343 SNP by real-time polymerase chain reaction and assay of serum angiotensin II level by ELISA. RESULTS: G containing genotypes (AG and GG) and G allele frequencies of the ACE rs4343 polymorphism were significantly higher in the case group than that in the control group. There was significant association between ACE rs4343 genotypes and risk of knee OA under the following genetic inheritance models: GG vs. AA (P=0.003), AA vs. GG/AG (P=0.014), AG/AA vs. GG (P=0.037), and G vs. A (P<0.001). Stratified analyses showed ACE rs4343 polymorphism was evidently associated with a significantly increased risk of knee OA among those had BMI≥25% (adjusted OR=3.016; 95% CI 1.052-8.648; P=0.040). Additionally, knee OA patients with GG genotype had greater knee specific WOMAC index, Kellgren score, and serum angiotensin II level than those with AA or GA genotypes. CONCLUSION: The investigated polymorphism in the ACE gene rs4343 may reflect the risk and severity of knee OA in the Egyptian population, particularly with the GG genotype. The interaction between ACE gene rs4343 polymorphism and obesity further increased the risk of knee OA. Moreover, the higher angiotensin II level may be involved in the pathogenesis of knee OA.

Cracking the type 1 diabetes code: Genes, microbes, immunity, and the early life environment.

Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin-secreting pancreatic ß cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non-HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying ß cell-directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in ß-cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies.

Polycyclic aromatic hydrocarbon and its adducts in peripheral blood: Gene and environment interaction among Chinese population.

BACKGROUND: Benzo(a)pyrene (B[a]P) is the most widely concerned polycyclic aromatic hydrocarbons (PAHs), which metabolizes benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) in vivo to produce carcinogenic effect on the body. Currently, there is limited research on the role of the variation of metabolic enzymes in this process. METHODS: We carried out a study including 752 participants, measured the concentrations of 16 kinds PAHs in both particle and gaseous phases, urinary PAHs metabolites, leukocyte BPDE-DNA adduct and serum BPDE- Albumin (BPDE-Alb) adduct, and calculated daily intake dose (DID) to assess the cumulative exposure of PAHs. We conducted single nucleotide polymorphism sites (SNPs) of metabolic enzymes, explored the exposure-response relationship between the levels of exposure and BPDE adducts using multiple linear regression models. RESULT: Our results indicated that an interquartile range (IQR) increase in B[a]P, PAHs, BaPeq, 1-hydroxypyrene (1-OHP), 1-hydroxynaphthalene (1-OHNap) and 2-hydroxynaphthalene (2-OHNap) were associated with 26.53 %, 24.24 %, 28.15 %, 39.15 %, 12.85 % and 14.09 % increase in leukocyte BPDE-DNA adduct (all P < 0.05). However, there was no significant correlation between exposure with serum BPDE-Alb adduct (P > 0.05). Besides, we also found the polymorphism of CYP1A1(Gly45Asp), CYP2C9 (Ile359Leu), and UGT1A1(downstream) may affect BPDE adducts level. CONCLUSION: Our results indicated that leukocyte BPDE-DNA adduct could better reflect the exposure to PAHs. Furthermore, the polymorphism of CYP1A1, CYP2C9 and UGT1A1affected the content of BPDE adducts.

DNA damage and its association with early-life exposome: Gene-environment analysis in Colombian children under five years old.

Environmental exposures and gene-exposure interactions are the major causes of some diseases. Early-life exposome studies are needed to elucidate the role of environmental exposures and their complex interactions with biological mechanisms involved in childhood health. This study aimed to determine the contribution of early-life exposome to DNA damage and the modifying effect of genetic polymorphisms involved in air pollutants metabolism, antioxidant defense, and DNA repair. We conducted a cohort study in 416 Colombian children under five years. Blood samples at baseline were collected to measure DNA damage by the Comet assay and to determine GSTT1, GSTM1, CYP1A1, H2AX, OGG1, and SOD2 genetic polymorphisms. The exposome was estimated using geographic information systems, remote sensing, LUR models, and questionnaires. The association exposome-DNA damage was estimated using the Elastic Net linear regression with log link. Our results suggest that exposure to PM2.5 one year before the blood draw (BBD) (0.83, 95 %CI: 0.76; 0.91), soft drinks consumption (0.94, 0.89; 0.98), and GSTM1 null genotype (0.05, 0.01; 0.36) diminished the DNA damage, whereas exposure to PM2.5 one-week BBD (1.18, 1.06; 1.32), NO2 lag-5 days BBD (1.27, 1.18; 1.36), in-house cockroaches (1.10, 1.00; 1.21) at the recruitment, crowding at home (1.34, 1.08; 1.67) at the recruitment, cereal consumption (1.11, 1.04; 1.19) and H2AX (AG/GG vs. AA) (1.44, 1.11; 1.88) increased the DNA damage. The interactions between H2AX (AG/GG vs. AA) genotypes with crowding and PM2.5 one week BBD, GSTM1 (null vs. present) with humidity at the first year of life, and OGG1 (SC/CC vs. SS) with walkability at the first year of life were significant. The early-life exposome contributes to elucidating the effect of environmental exposures on DNA damage in Colombian children under five years old. The exposome-DNA damage effect appears to be modulated by genetic variants in DNA repair and antioxidant defense enzymes.

Systemic sclerosis and environment: an intriguing and still debated association.

Systemic sclerosis (SSc) is characterised by a heterogeneous clinical expression probably reflecting the different genetic background of each patient. Progress has been made in the definition of the principal pathogenetic events of the disease that can be summarised in endothelial damage and dysfunction, inflammation with activation of immune system and fibrosis. The aetiology of the disease still remains to be clarified and probably the first events are attributable to the repeated action of environmental stimuli in genetically predisposed subjects.The aim of the present manuscript is to review the most recent and relevant data regarding the association of SSc with environmental factors.

Differential interactions between gene expressions and stressors across the lifespan in major depressive disorder.

BACKGROUND: Both genetic predispositions and exposures to stressors have collectively contributed to the development of major depressive disorder (MDD). To deep dive into their roles in MDD, our study aimed to examine which susceptible gene expression interacts with various dimensions of stressors in the MDD risk among a large population cohort. METHODS: Data analyzed were from a longitudinal community-based cohort from Southwest Montreal, Canada (N = 1083). Latent profile models were used to identify distinct patterns of stressors for the study cohort. A transcriptome-wide association study (TWAS) method was performed to examine the interactive effects of three dimensions of stressors (threat, deprivation, and cumulative lifetime stress) and gene expression on the MDD risk in a total of 48 tissues from GTEx. Additional analyses were also conducted to further explore and specify these associations including colocalization, and fine-mapping analyses, in addition to enrichment analysis investigations based on TWAS. RESULTS: We identified 3321 genes linked to MDD at the nominal p-value <0.05 and found that different patterns of stressors can amplify the genetic susceptibility to MDD. We also observed specific genes and pathways that interacted with deprivation and cumulative lifetime stressors, particularly in specific brain tissues including basal ganglia, prefrontal cortex, brain amygdala, brain cerebellum, brain cortex, and the whole blood. Colocalization analysis also identified these genes as having a high probability of sharing MDD causal variants. LIMITATIONS: The study cohort was composed exclusively of individuals of Caucasians, which restricts the generalizability of the findings to other ethnic population groups. CONCLUSIONS: The findings of the study unveiled significant interactions between potential tissue-specific gene expression × stressors in the MDD risk and shed light on the intricate etiological attributes of gene expression and specific stressors across the lifespan in MDD. These genetic and environmental attributes in MDD corroborate the vulnerability-stress theory and direct future stress research to have a closer examination of genetic predisposition and potential involvements of omics studies to specify the intricate relationships between genes and stressful environments.

Exploring the effects of family and life events on genetic and environmental architecture of schizotypal and hypomanic dimensions: Insights from a twin study.

BACKGROUND: Strategies of prevention for psychiatric disorders need a deep understanding of the aetiological factors involved in the psychopathological processes. Our twin study aims at disentangling the contributions of genes and environment to schizotypal and hypomanic dimensions, considering the role of stressful life events (LEs) and the quality of family relationships. METHODS: The Magical Ideation Scale (MIS) and Perceptual Aberration Scale (PAS) were used to assess positive schizotypy, while Hypomanic Personality Scale (HPS) and its sub-scales were used to investigate proneness to affective disorders. 268 twins (54.5 % female; aged 18.0 ± 6.68) were included. Participants filled out a questionnaire on LEs and their parents provided an evaluation of intra-family relationship (Relationship Quality Index, RQI). Classic univariate twin models for quantitative traits were fitted for scales, and the effects of covariates (LEs and RQI) were assessed. RESULTS: For MIS, HPS and its sub-scales, significant common and unique environmental effects were detected, with genetic factors affecting only HPS Social Vitality sub-scale. Unique environment was the only source of variance of PAS score. The number of recent LEs influenced MIS and PAS models, while RQI score affected MIS model. LIMITATIONS: The main limitation of the study is the small sample size, which reduces statistical power and may potentially lead to an underestimation of heritability. Additionally, the cross-sectional design limits the possibility to draw causal considerations. CONCLUSIONS: Findings provide preliminary evidence for a significant environmental role in modulating states of vulnerability. Moreover, the expression of positive schizotypy resulted influenced by recent stressors and intra-family relationships.

Across-environment seed protein stability and genetic architecture of seed components in soybean.

The recent surge in the plant-based protein market has resulted in high demands for soybean genotypes with improved grain yield, seed protein and oil content, and essential amino acids (EAAs). Given the quantitative nature of these traits, complex interactions among seed components, as well as between seed components and environmental factors and management practices, add complexity to the development of desired genotypes. In this study, the across-environment seed protein stability of 449 genetically diverse plant introductions was assessed, revealing that genotypes may display varying sensitivities to such environmental stimuli. The EAAs valine, phenylalanine, and threonine showed the highest variable importance toward the variation in stability, while both seed protein and oil contents were among the explanatory variables with the lowest importance. In addition, 56 single nucleotide polymorphism (SNP) markers were significantly associated with various seed components. Despite the strong phenotypic Pearson's correlation observed among most seed components, many independent genomic regions associated with one or few seed components were identified. These findings provide insights for improving the seed concentration of specific EAAs and reducing the negative correlation between seed protein and oil contents.

Genotypic variation in the promoter region of the CRH-248 gene interacts with early rearing experiences to disrupt the development of the HPA axis in infant rhesus macaques (Macaca mulatta).

Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of conditions such as depression, anxiety disorders, and post-traumatic stress disorder. Early-life adversity and genetic variation can interaction to disrupt HPA axis regulation, potentially contributing to certain forms of psychopathology. This study employs a rhesus macaque model to investigate how early parental neglect interacts with a single nucleotide polymorphism within the promoter region of the corticotropin-releasing hormone (CRH-248) gene, impacting the development of the HPA axis. For the initial six months of life, 307 rhesus monkey infants (n = 146 females, n = 161 males) were either reared with their mothers (MR) in conditions emulating the natural environment (control group) or raised without maternal care in groups with constant or 3-hours daily access to same-aged peers (NR). Blood samples collected on days 30, 60, 90, and 120 of life under stressful conditions were assayed for plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations. Findings revealed that NR subjects exhibited a significant blunting of both ACTH and cortisol concentrations. Notably, there was a gene-by-environment interaction observed for ACTH and cortisol levels, with NR subjects with the polymorphism displaying higher ACTH concentrations and lower cortisol concentrations. To the extent that these results generalize to humans, they suggest that early parental neglect may render individuals vulnerable to HPA axis dysfunction, a susceptibility that is modulated by CRH-248 genotype-a gene-by-environment interaction that leaves a lasting developmental signature.

Genetic Polymorphisms in Cardiovascular Disease: Effects Across Three Generations Exposed to Radiation from the Semipalatinsk Nuclear Test Site.

The population in the areas neighboring the Semipalatinsk Nuclear Test Site (SNTS) in the eastern region of Kazakhstan faces increased cardiovascular disease (CVD) risk. Previous research has not explored gene polymorphisms related to CVD in this population. Therefore, the present study examines the prevalence of six CVD-associated genotypes in three generations exposed to SNTS radiation. The genotyping of ApoE Leu28 → Pro, AGT Met174 → Thr, AGT Met235 → Thr, eNOS T786 → C, PON1 Gln192 → Arg, and EDN 1 Lys198 → Asn was performed using real-time polymerase chain reaction. The present study encompassed a cohort of 218 participants with a familial history of arterial hypertension and/or carotid artery disease spanning at least three generations. The analysis unveiled significant disparities in the prevalence of ApoE Leu28 → Pro, eNOS T786 → C, and PON1 Gln192 → Arg genotypes across different generations. Furthermore, a substantial variation in the distribution of the eNOS T786 → C genotype was observed between individuals of Kazakh and Russian ethnicities. Nevertheless, no significant discrepancies were detected in the frequencies of the investigated genotypes between genders. Further research in this area is warranted to enhance the understanding of the genetic factors contributing to CVD in the population exposed to radiation from the SNTS. Specifically, future studies should broaden the scope of genetic polymorphisms investigated and include representatives of healthy individuals who have not been exposed to radiation as controls.

BHAFT: Bayesian heredity-constrained accelerated failure time models for detecting gene-environment interactions in survival analysis.

In addition to considering the main effects, understanding gene-environment (G × E) interactions is imperative for determining the etiology of diseases and the factors that affect their prognosis. In the existing statistical framework for censored survival outcomes, there are several challenges in detecting G × E interactions, such as handling high-dimensional omics data, diverse environmental factors, and algorithmic complications in survival analysis. The effect heredity principle has widely been used in studies involving interaction identification because it incorporates the dependence of the main and interaction effects. However, Bayesian survival models that incorporate the assumption of this principle have not been developed. Therefore, we propose Bayesian heredity-constrained accelerated failure time (BHAFT) models for identifying main and interaction (M-I) effects with novel spike-and-slab or regularized horseshoe priors to incorporate the assumption of effect heredity principle. The R package rstan was used to fit the proposed models. Extensive simulations demonstrated that BHAFT models had outperformed other existing models in terms of signal identification, coefficient estimation, and prognosis prediction. Biologically plausible G × E interactions associated with the prognosis of lung adenocarcinoma were identified using our proposed model. Notably, BHAFT models incorporating the effect heredity principle could identify both main and interaction effects, which are highly useful in exploring G × E interactions in high-dimensional survival analysis. The code and data used in our paper are available at https://github.com/SunNa-bayesian/BHAFT.