Gene-environment Interaction Studies Research Articles

Exploring the role of genetic variability and exposure to bisphenols and parabens on excess body weight in Spanish children

Gene-environment interaction studies are emerging as a promising tool to shed light on the reasons for the rapid increase in excess body weight (overweight and obesity). We aimed to investigate the influence of several polymorphisms on excess weight in Spanish children according to a short- and long-term exposure to bisphenols and parabens, combining individual approach with the joint effect of them. This case-control study included 144 controls and 98 cases children aged 3-12 years. Thirty SNPs in genes involved in obesity-related pathways, xenobiotic metabolism and hormone systems were genotyped using the GSA microchip technology and qPCRs with Taqman® probes. Levels of bisphenols and parabens in urine and hair were used to assess short- and long-term exposure, respectively, via UHPLC-MS/MS system. LEPR rs9436303 was identified as a relevant risk variant for excess weight (ORDom:AAvsAG+GG=2.65, p<0.001), and this effect persisted across exposure-stratified models. For long-term exposure, GPX1 rs1050450 was associated with increased excess weight at low single paraben exposure (ORGvsA=2.00, p=0.028, p-interaction=0.016), whereas LEPR rs1137101 exhibited a protective function at high co-exposure (ORDom:AAvsAG+GG=0.17, p=0.007, p-interaction=0.043). ESR2 rs3020450 (ORDom:GGvsAG+AA=5.17, p=0.020, p-interaction=0.028) and CYP2C19 rs4244285 (ORDom:GGvsAG+AA=3.54, p=0.039, p-interaction=0.285) were identified as predisposing variants at low and high co-exposure, respectively. In short-term exposure, higher odds were observed for INSIG2 rs7566605 at high bisphenol exposure (ORCvsG=2.97, p=0.035, p-interaction=0.017) and for GSTP1 rs1695 at low levels (ORDom:AAvsAG+GG=5.38, p=0.016, p-interaction=0.016). At low and medium co-exposure, SH2B1 rs7498665 (ORAvsG=0.17, p=0.015, p-interaction=0.085) and MC4R rs17782313 (ORAvsG=0.10, p=0.023, p-interaction=0.045) displayed a protective effect, whereas ESR2 rs3020450 maintained its contributing role (ORGvsA=3.12, p=0.030, p-interaction=0.010). Our findings demonstrate for the first time that understanding the genetic variation in excess weight and how the level of exposure to bisphenols and parabens might interact with it, is crucial for a more in-depth comprehension of the complex polygenic and multifactorial aetiology of overweight and obesity.

Long-term effects of arsenic on glucose-insulin homeostasis: A gene-environment interaction study

Abstract Background Arsenic exposure and genetic factors are associated with an increased risk of type 2 diabetes, yet study of environment-gene interaction on glucose-insulin homeostasis remains scarce. We aimed to investigate the associations and interactions of urinary total arsenic (UTAs) and genetic susceptibility with glucose-insulin homeostasis through a longitudinal epidemiological study. Methods A total of 6136 observations (3063 participants) from the baseline, 3-year follow-up, and 6-year follow-up of the Wuhan-Zhuhai cohort were included in this study. In each study period, we repeatedly measured UTAs, fasting plasma glucose (FPG), fasting plasma insulin (FPI), and homeostasis model-assessed insulin resistance (HOMA-IR) and β-cell function (HOMA-β). Polygenic risk scores (PRSs) specific for all traits were constructed by corresponding genome-wide association summary statistics. Linear mixed models were used to assess associations and interactions of UTAs and PRSs with four indicators of glucose-insulin homeostasis. Results After adjustment for all covariates, the βs (95% CIs) for the annual growth rates of FPG, FPI, and HOMA-IR were 0.020 (0.008, 0.032), 0.007 (0.002, 0.013), and 0.011 (0.004, 0.017), respectively, associated with each ln-unit increase in UTAs. Compared to subjects with the first-quartile PRS and low UTAs, participants with the fourth-quartile PRS and high UTAs had a 0.029 (0.012, 0.047) or 0.032 (0.012, 0.051) ln-unit increase in the annual growth rate of FPI or HOMA-IR, respectively. UTAs and PRS had significant interactions on the longitudinal progressive increases of FPI and HOMA-IR (P interaction &amp;lt; 0.05). Conclusions Arsenic exposure and genetic variants are significantly synergistic risk factors for dysregulation and progressive deterioration of glucose-insulin homeostasis. Our findings emphasize the importance of reducing arsenic exposure to maintain normal glucose-insulin metabolism, especially for those at higher genetic risk. Key messages • Arsenic exposure was associated with annual increased rates of FPG, FPI, and HOMA-IR. • Arsenic exposure and trait-specific PRSs are synergistic risk factors for glucose-insulin homeostasis impairment.

Case of familial interstitial lung disease attributedto ATP-binding cassette transporter 3 gene mutationin identical twins.

Mutations in ABCA3 can result in surfactant deficiency, leading to respiratory distress syndrome in term neonates, and interstitial lung disease (ILD) in children. Here, we report an extremely rare case of ILD in an identical twin with novel ABCA3 germline mutations. Interestingly, they showed mostly similar, but slightly different, clinical features. Our cases suggest that, in addition to genetic factors, non-genetic factors are involved in the severity of the disease and its clinical course. Studies of gene-environment interactions, especially with twins, are needed, as they may contribute to the understanding of the clinical heterogeneity of ILD and its association with various underlying conditions as well as rare variant mutations.

Genetic predisposition to impaired beta-cell function modifies the association between serum pyrethroid levels and the risk of type 2 diabetes: A gene-environment interaction study

Previous studies suggested that pyrethroid exposure was associated with elevated type 2 diabetes (T2D) risk, while it remains uncertain whether genetic predisposition modifies this association. A nested case-control study within the prospective Dongfeng-Tongji cohort comprised 1832 T2D cases, age- (±5 years) and sex-matched controls with qualified genotyping data. Serum pyrethroids were measured by gas chromatography-tandem mass spectrometry. Overall diabetes-related genetic risk score (GRS) or pathway-specific GRS, including unweighted GRSs (uGRS) and weighted GRSs (wGRS), was developed by genetic variants identified in Asian populations. Higher overall diabetes-related GRS and GRS specific to the pathway of impaired beta cell function (Beta-cell GRS) were associated with a higher incident T2D risk. Beta-cell uGRS significantly modified the association of serum permethrin (Pinteraction=0.04) and deltamethrin (Pinteraction=0.01) with T2D. Specifically, for each doubling increase in serum deltamethrin, the odds ratios (ORs) (95 % confidence intervals [CIs]) for T2D were 1.23 (0.98–1.56) and 0.91 (0.77–1.07) in the highest and lowest Beta-cell uGRS group, as well as 1.23 (1.02–1.47) and 0.95 (0.78–1.15) for Beta-cell wGRS group, respectively. When considering jointly, those with the highest deltamethrin levels and highest Beta-cell GRS had a substantially higher T2D risk, compared with the reference group (OR for uGRS: 3.79 [95 % CI: 2.03–7.07], Pinteraction=0.03 and 3.23 [95 % CI: 1.78–5.87], Pinteraction=0.05 for wGRS). Our findings suggested that genetic susceptibility to impaired beta-cell function should be considered for T2D prevention targeting pyrethroid exposure, particularly deltamethrin.

Acacia seeds: compositional variation based on species, growing locations and harvest years

SummaryThree different Acacia seeds (A. retinodes, A. provincialis and A. tenuissima) harvested from different locations and in different years were analysed for their variations in proximate and mineral composition. Results showed no one species had the highest content across all proximate and mineral analyses, for example, A. retinodes Harmans 2020 had the highest ash (3.7%), A. retinodes Harmans 2022 had the highest protein content (31.3%), A. tenuissima Hindmarsh 2020 had the highest fat content (18.5%) and A. provincialis Tarrington 2022 had the highest magnesium content (469 mg/100 g). Principle component analysis was carried out to determine the effect of species, harvest locations and years on the chemical composition. A biplot of the first two principal components with a total of 60.5% variation showed clustering based on harvest years. The compositions of the Acacia seeds were determined to be affected by species, harvest location and year differences. However, a complete gene–environment interaction study is needed to validate this.

Styrene and ethylbenzene exposure and type 2 diabetes mellitus: A longitudinal gene–environment interaction study

Styrene and ethylbenzene (S/EB) are identified as hazardous air contaminants that raise significant concerns. The association between S/EB exposure and the incidence of type 2 diabetes mellitus (T2DM), and the interaction between genes and environment, remains poorly understood. Our study consisted of 2,219 Chinese adults who were part of the Wuhan-Zhuhai cohort. A follow-up assessment was conducted after six years. Exposure to S/EB was quantified by determining the concentrations of urinary biomarkers of exposure to S/EB (UBE-S/EB; urinary phenylglyoxylic acid level plus urinary mandelic acid level). Logistic regression models were constructed to investigate the relations of UBE-S/EB and genetic risk score (GRS) with T2DM prevalence and incidence. The interaction effects of UBE-S/EB and GRS on T2DM were investigated on multiplicative and additive scales. UBE-S/EB was dose-dependently and positively related to T2DM prevalence and incidence. Participants with high levels of UBE-S/EB [relative risk (RR) ​= ​1.930, 95% confidence interval (CI): 1.157–3.309] or GRS (1.943, 1.110–3.462) demonstrated the highest risk of incident T2DM, in comparison to those with low levels of UBE-S/EB or GRS. Significant additive interaction between UBE-S/EB and GRS on T2DM incidence was discovered with relative excess risk due to interaction (95% CI) of 0.178 (0.065–0.292). The RR (95% CI) of T2DM incidence was 2.602 (1.238–6.140) for individuals with high UBE-S/EB and high GRS, compared to those with low UBE-S/EB and low GRS. This study presented the initial evidence that S/EB exposure was significantly related to increased risk of T2DM incidence, and the relationship was interactively aggravated by genetic predisposition.

401. Gene-Environment Interaction Study on the Correlates for Psychotic Experiences in the UK Biobank

401. Gene-Environment Interaction Study on the Correlates for Psychotic Experiences in the UK Biobank

Lysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use

Parkinson’s disease (PD), the second most common neurodegenerative disorder, develops sporadically, likely through a combination of polygenic and environmental factors. Previous studies associate pesticide exposure and genes involved in lysosomal function with PD risk. We evaluated the frequency of variants in lysosomal function genes among patients from the Parkinson’s, Environment, and Genes (PEG) study with ambient pesticide exposure from agricultural sources. 757 PD patients, primarily of White European/non-Hispanic ancestry (75%), were screened for variants in 85 genes using a custom amplicon panel. Variant enrichment was calculated against the Genome Aggregation Database (gnomAD). Enriched exonic variants were prioritized by exposure to a cluster of pesticides used on cotton and severity of disease progression in a subset of 386 patients subdivided by race/ethnicity. Gene enrichment analysis identified 36 variants in 26 genes in PEG PD patients. Twelve of the identified genes (12/26, 46%) had multiple enriched variants and/or a single enriched variant present in multiple individuals, representing 61% (22/36) of the observed variation in the cohort. The majority of enriched variants (26/36, 72%) were found in genes contributing to lysosomal function, particularly autophagy, and were bioinformatically deemed functionally deleterious (31/36, 86%). We conclude that, in this study, variants in genes associated with lysosomal function, notably autophagy, were enriched in PD patients exposed to agricultural pesticides suggesting that altered lysosomal function may generate an underlying susceptibility for developing PD with pesticide exposure. Further study of gene-environment interactions targeting lysosomal function may improve understanding of PD risk in individuals exposed to pesticides.

Abstract 6140: Gene-environment interactions for lifetime water arsenic exposure and bladder cancer risk in the New England Bladder Cancer study

Abstract Environmental arsenic and genetic susceptibility have both been shown to increase bladder cancer risk, yet little is known about their respective interaction. We conducted a gene-environment interaction (GxE) study to characterize lifetime arsenic exposure from drinking water, inherited susceptibility, and bladder cancer risk in the New England Bladder Cancer Study. Exposures were estimated from arsenic measured in water samples collected at home and workplace. We evaluated common single-nucleotide polymorphisms (SNPs) i) from the latest bladder cancer genome-wide association study (n= 28), ii) from candidate gene studies of arsenic or bladder cancer (n= 16 SNPs), and iii) SNPs from a large genome-wide association study of arsenic metabolism (n = 4 SNPs) as potential effect modifiers of the arsenic-bladder cancer relationship. We coded SNPs as the absence or presence of a risk/effect allele for bladder cancer or arsenic metabolism in 2,019 adults (928 bladder cancer cases and 1,091 controls) and arsenic exposures as tertiles. Odds ratios (OR) with 95% confidence intervals (CI) adjusted for age, sex, smoking status, high-risk occupation, and principal components of genetic ancestry were estimated using logistic regression models. P-values for multiplicative interaction were calculated. Out of 48 SNPs, we found evidence of interaction for 7 SNPs at the statistical significance level of P&amp;lt;0.05. Most SNPs involved in GxE interactions are mapped to genomic regions known or suspected to function in arsenic metabolism. For the association between cumulative lifetime water arsenic (mg) and bladder cancer, the strongest evidence of an interaction was with rs1046428 (near GSTZ1 on 14q23); among those with one or two copies of the T risk allele, ORT2vsT1: 1.52, CI: 1.11 - 2.07; ORT3 vsT1: 1.44, CI: 1.05 - 1.98, Pinteraction = 0.01; among those with no risk allele copy, ORT2vsT1: 0.91, CI: 0.62 - 1.35; ORT3 vsT1: 0.97, CI: 0.65 - 1.44. For average daily water arsenic (µg/day), we found evidence of interaction among those with risk allele for rs1801133 (A/A, A/G; MTHFR on 1p36) ORT2 vsT1: 1.70, CI: 1.18 - 2.44; ORT3 vsT1: 1.53, CI: 1.06 - 2.23, Pinteraction = 0.02, in those with no copies of risk allele ORT2vsT1: 0.85, CI: 0.61 - 1.17; ORT3 vsT1: 1.11, CI: 0.79 - 1.54; and rs1801131 (G/G; G/T; MTHFR ) ORT2 vsT1: 1.59, CI: 1.14 - 2.22; ORT3 vsT1: 1.63, CI: 1.16 - 2.29, Pinteraction = 0.01, whereas in those with no risk allele ORT2vsT1: 0.84, CI: 0.59 - 1.19; ORT3 vsT1: 1, CI: 0.69 - 1.44. For 40-year lagged cumulative lifetime water arsenic (mg) and average daily water arsenic (µg/day), we found suggestive interactions with rs2234636 (SLC39A2 on 14q11), and rs1495741 (NAT2 on 8p22). Our study provides evidence of interactions between lifetime arsenic exposure and genetic variants that function in xenobiotic metabolism on bladder cancer occurrence. Citation Format: Hugo Pomares-Millan, Stella Koutros, Nathaniel Rothman, Dalsu Baris, Molly Schwenn, Alison Johnson, Debra T. Silverman, Margaret R. Karagas, Michael N. Passarelli. Gene-environment interactions for lifetime water arsenic exposure and bladder cancer risk in the New England Bladder Cancer study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6140.

Associations between disturbed sleep and attenuated psychotic experiences in people at clinical high risk for psychosis.

Pre-diagnostic stages of psychotic illnesses, including 'clinical high risk' (CHR), are marked by sleep disturbances. These sleep disturbances appear to represent a key aspect in the etiology and maintenance of psychotic disorders. We aimed to examine the relationship between self-reported sleep dysfunction and attenuated psychotic symptoms (APS) on a day-to-day basis. Seventy-six CHR young people completed the Experience Sampling Methodology (ESM) component of the European Union Gene-Environment Interaction Study, collected through PsyMate® devices, prompting sleep and symptom questionnaires 10 times daily for 6 days. Bayesian multilevel mixed linear regression analyses were performed on time-variant ESM data using the brms package in R. We investigated the day-to-day associations between sleep and psychotic experiences bidirectionally on an item level. Sleep items included sleep onset latency, fragmentation, and quality. Psychosis items assessed a range of perceptual, cognitive, and bizarre thought content common in the CHR population. Two of the seven psychosis variables were unidirectionally predicted by previous night's number of awakenings: every unit increase in number of nightly awakenings predicted a 0.27 and 0.28 unit increase in feeling unreal or paranoid the next day, respectively. No other sleep variables credibly predicted next-day psychotic symptoms or vice-versa. In this study, the relationship between sleep disturbance and APS appears specific to the item in question. However, some APS, including perceptual disturbances, had low levels of endorsement amongst this sample. Nonetheless, these results provide evidence for a unidirectional relationship between sleep and some APS in this population.

Understanding and applying gene-environment interactions: a guide for nutrition professionals with an emphasis on integration in African research settings.

Noncommunicable diseases (NCDs) are influenced by the interplay between genetics and environmental exposures, particularly diet. However, many healthcare professionals, including nutritionists and dietitians, have limited genetic background and, therefore, they may lack understanding of gene-environment interactions (GxEs) studies. Even researchers deeply involved in nutrition studies, but with a focus elsewhere, can struggle to interpret, evaluate, and conduct GxE studies. There is an urgent need to study African populations that bear a heavy burden of NCDs, demonstrate unique genetic variability, and have cultural practices resulting in distinctive environmental exposures compared with Europeans or Americans, who are studied more. Although diverse and rapidly changing environments, as well as the high genetic variability of Africans and difference in linkage disequilibrium (ie, certain gene variants are inherited together more often than expected by chance), provide unparalleled potential to investigate the omics fields, only a small percentage of studies come from Africa. Furthermore, research evidence lags behind the practices of companies offering genetic testing for personalized medicine and nutrition. We need to generate more evidence on GxEs that also considers continental African populations to be able to prevent unethical practices and enable tailored treatments. This review aims to introduce nutrition professionals to genetics terms and valid methods to investigate GxEs and their challenges, and proposes ways to improve quality and reproducibility. The review also provides insight into the potential contributions of nutrigenetics and nutrigenomics to the healthcare sphere, addresses direct-to-consumer genetic testing, and concludes by offering insights into the field's future, including advanced technologies like artificial intelligence and machine learning.

The Promise and Potential of Brain Organoids.

Brain organoids are 3D in vitro culture systems derived from human pluripotent stem cells that self-organize to model features of the (developing) human brain. This review examines the techniques behind organoid generation, their current and potential applications, and future directions for the field. Brain organoids possess complex architecture containing various neural cell types, synapses, and myelination. They have been utilized for toxicology testing, disease modeling, infection studies, personalized medicine, and gene-environment interaction studies. An emerging concept termed Organoid Intelligence (OI) combines organoids with artificial intelligence systems to generate learning and memory, with the goals of modeling cognition and enabling biological computing applications. Brain organoids allow neuroscience studies not previously achievable with traditional techniques, and have the potential to transform disease modeling, drug development, and the understanding of human brain development and disorders. The aspirational vision of OI parallels the origins of artificial intelligence, and efforts are underway to map a roadmap toward its realization. In summary, brain organoids constitute a disruptive technology that is rapidly advancing and gaining traction across multiple disciplines.

A Kpna1-deficient psychotropic drug-induced schizophrenia model mouse for studying gene–environment interactions

KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De novo mutations in Kpna1 have been identified using genome-wide association studies in humans with schizophrenia; however, it remains unclear how KPNA1 contributes to schizophrenia pathogenesis. Recent studies have suggested a complex combination of genetic and environmental factors that are closely related to psychiatric disorders. Here, we found that subchronic administration of phencyclidine, a psychotropic drug, induced vulnerability and behavioral abnormalities consistent with the symptoms of schizophrenia in Kpna1-deficient mice. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.

Re-analysis and meta-analysis of summary statistics from gene-environment interaction studies.

statistics from genome-wide association studies enable many valuable downstream analyses that are more efficient than individual-level data analysis while also reducing privacy concerns. As growing sample sizes enable better-powered analysis of gene-environment interactions, there is a need for gene-environment interaction-specific methods that manipulate and use summary statistics. We introduce two tools to facilitate such analysis, with a focus on statistical models containing multiple gene-exposure and/or gene-covariate interaction terms. REGEM (RE-analysis of GEM summary statistics) uses summary statistics from a single, multi-exposure genome-wide interaction study to derive analogous sets of summary statistics with arbitrary sets of exposures and interaction covariate adjustments. METAGEM (META-analysis of GEM summary statistics) extends current fixed-effects meta-analysis models to incorporate multiple exposures from multiple studies. We demonstrate the value and efficiency of these tools by exploring alternative methods of accounting for ancestry-related population stratification in genome-wide interaction study in the UK Biobank as well as by conducting a multi-exposure genome-wide interaction study meta-analysis in cohorts from the diabetes-focused ProDiGY consortium. These programs help to maximize the value of summary statistics from diverse and complex gene-environment interaction studies. REGEM and METAGEM are open-source projects freely available at https://github.com/large-scale-gxe-methods/REGEM and https://github.com/large-scale-gxe-methods/METAGEM.

Genetics and Epigenetics of Nonsuicidal Self-Injury: a Narrative Review

Nonsuicidal self-injury (NSSI), or self-harm is widely spread, especially among the young people. However, despite the problem’s relevance, NSSI was investigated mainly from the psychological and social perspective, while a fairly small number of biological studies of NSSI have been published to date. The aim of this narrative review was to analyze all the currently available publications on the genetics and epigenetics of NSSI – one of the most promising areas in biological research. We discussed and analyzed all stages of genetic research of NSSI: from twin studies and studies of self-harm in the framework of hereditary diseases to candidate genes, genome-wide, epigenetic and gene-environment interactions studies. We demonstrated data indicating significant contribution of genetic and epigenetic factors to the development of NSSI, discussed advantages and limitations of analyzed studies, outlined prospects for further research in this area.

Association of polygenic scores for depression and neuroticism with perceived stress in daily life during a long-lasting stress period.

Genetic factors contribute significantly to interindividual differences in the susceptibility to stress-related disorders. As stress can also be conceptualized as environmental exposure, controlled gene-environment interaction (GxE) studies with an in-depth phenotyping may help to unravel mechanisms underlying the interplay between genetic factors and stress. In a prospective-longitudinal quasi-experimental study, we investigated whether polygenic scores (PGS) for depression (DEP-PGS) and neuroticism (NEU-PGS), respectively, were associated with responses to chronic stress in daily life. We examined law students (n = 432) over 13 months. Participants in the stress group experienced a long-lasting stress phase, namely the preparation for the first state examination for law students. The control group consisted of law students without particular stress exposure. In the present manuscript, we analyzed perceived stress levels assessed at high frequency and in an ecologically valid manner by ambulatory assessments as well as depression symptoms and two parameters of the cortisol awakening response. The latter was only assessed in a subsample (n = 196). No associations between the DEP-PGS and stress-related variables were found. However, for the NEU-PGS we found a significant GxE effect. Only in individuals experiencing academic stress a higher PGS for neuroticism predicted stronger increases of perceived stress levels until the exam. At baseline, a higher NEU-PGS was associated with higher perceived stress levels in both groups. Despite the small sample size, we provide preliminary evidence that the genetic disposition for neuroticism is associated with stress level increases in daily life during a long-lasting stress period.

Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation.

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.

A Case-Only Genome-Wide Interaction Study of Smoking and Bladder Cancer Risk: Results from the COBLAnCE Cohort.

Bladder cancer (BC) is the 6th most common cancer worldwide, with tobacco smoking considered as its main risk factor. Accumulating evidence has found associations between genetic variants and the risk of BC. Candidate gene-environment interaction studies have suggested interactions between cigarette smoking and NAT2/GSTM1 gene variants. Our objective was to perform a genome-wide association case-only study using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr), focusing on smoking behavior. The COBLAnCE cohort comprises 1800 BC patients enrolled between 2012 and 2018. Peripheral blood samples collected at enrolment were genotyped using the Illumina Global Screening Array with a Multi-Disease drop-in panel. Genotyping data (9,719,614 single nucleotide polymorphisms (SNP)) of 1674, 1283, and 1342 patients were analyzed for smoking status, average tobacco consumption, and age at smoking initiation, respectively. A genome-wide association study (GWAS) was conducted adjusting for gender, age, and genetic principal components. The results suggest new candidate loci (4q22.1, 12p13.1, 16p13.3) interacting with smoking behavior for the risk of BC. Our results need to be validated in other case-control or cohort studies.

Socioeconomic status and risk for child psychopathology: exploring gene-environment interaction in the presence of gene-environment correlation using extended families in the Norwegian Mother, Father and Child Birth Cohort Study.

Low socioeconomic status (SES) is associated with increased risk for emotional and behavioural problems among children. Evidence from twin studies has shown that family SES moderates genetic and environmental influences on child mental health. However, it is also known that SES is itself under genetic influence and previous gene-environment interaction (G×E) studies have not incorporated the potential genetic overlap between child mental health and family SES into G×E analyses. We applied a novel approach using extended family data to investigate the moderation of aetiological influences on child emotional and behavioural problems by parental socioeconomic status in the presence of modelled gene-environment correlation. The sample comprised >28,100 children in extended-family units drawn from the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers reported children's emotional and behavioural symptoms. Parents' income and educational attainment were obtained through linkage to administrative register data. Bivariate moderation Multiple-Children-of-Twins-and-Siblings (MCoTS) models were used to analyse relationships between offspring outcomes (emotional and behavioural symptom scores) and parental socioeconomic moderators (income rank and educational attainment). The aetiology of child emotional symptoms was moderated by maternal and paternal educational attainment. Shared environmental influences on child emotional symptoms were greater at lower levels of parents' education. The aetiology of child behavioural symptoms was moderated by maternal, but not paternal, socioeconomic factors. Genetic factors shared between maternal income and child behavioural symptoms were greater in families with lower levels maternal income. Nonshared environmental influences on child behavioural symptoms were greater in families with higher maternal income and education. Parental socioeconomic indicators moderated familial influences and nonshared environmental influences on child emotional and behavioural outcomes. Maternal SES and child mental health share aetiological overlap such that shared genetic influence was greater at the lower end of the socioeconomic distribution. Our findings collectively highlight the role that family socioeconomic factors play in shaping the origins of child emotional and behavioural problems.

The Relationship Between Antisocial Personality Disorder and Criminology: Acquired Factors and Genetic Influences

This study looks at the interaction of internal and external factors in the process of antisocial personality disorder (ASPD) and criminal conduct. It reveals the major contributions of both genetic and acquired factors using data from longitudinal twin studies, neuroimaging research, and gene-environment interaction studies. Environmental variables, such as bad childhood experiences, community hardship, and exposure to violence, also play important roles in antisocial behavior variance. The complicated interaction between genetic predispositions and environmental conditions emphasizes the need of understanding these components' dynamic character throughout an individual's development. With further knowledge, it will be feasible to build complete, individualized therapies that target both genetic and environmental aspects in the emergence and maintenance of antisocial behavior. Furthermore, this review emphasizes the importance of early intervention and prevention strategies that take an individual's unique genetic and environmental risk factors into account, ultimately contributing to a more effective approach in reducing the prevalence of ASPD and criminal behavior in society.