Gene X Environment Interactions Research Articles

From genes to fields: Environmental compatibility of herbicide tolerant transgenic cotton

IntroductionThere are several enticing reasons to use genetic engineering to develop transgenic cotton plants with economically relevant new traits. The use of transgenic cotton to protect crops from biotic stressors like weeds may prove to be a cost-effective solution. ObjectivesThe development of herbicide-resistant cotton variants is the primary motivation for gene transfer in this crop. In the current study, we conducted a battery of experiments on the herbicide-tolerant cotton variety MNH-786 to investigate its expression patterns and environmental adaptation. Material and methodsThe 35S promoter controls the expression of the codon-optimized Cp4-EPSPS gene that is present in this variety. Several different molecular approaches, such as polymerase chain reaction (PCR), Florescent In-Situ Hybridization analysis, and enzyme-linked immunosorbent assay (ELISA), are used to confirm the presence of transgenic cotton plants. The glyphosate spray assay was performed using molecular analysis, employing a dosage of 2000 ml per acre. The suitability of transgenic and non-transgenic cotton plants in four unique environments—the Multan, Vehari, Bahawalpur, and Faisalabad Districts of Punjab province, Pakistan was assessed using a comparative comparison. A gene x environment interaction (GEI) biplot was used to analyze the correlation between genes and their environments. ResultsTransgenic cotton plants screened using PCR to target 1.467 kb regions showed effective integration into cotton genomes. Results showed that Cp4-EPSPS proteins fluctuated and associated with environmental variables across all three generations (T0, T1, and T2). In the herbicide spray assay, all transgenic cotton plants survived, but non-transgenic cotton and all weeds died. According to the "which-won-where" polygon, transgenic cotton plant Events 3, 4, 5, 6, and 7 performed better in three settings, except Faisalabad. According to correlation and heat-map yield research, transgenic cotton variety MNH-786 Events 4, 5 and 6 have a higher consistency and influence in Vehari district's natural habitats. Multan and Bahawalpur also show encouraging results. In Faisalabad, no transgenic events perform well. ConclusionWe conclude that Events 4 and 5 show a substantial abundance of genetic potential that is robust over a wide range of environments thanks to our thorough study of the outcomes obtained under these conditions. SignificanceOur study emphasises the importance of transgenic cotton, its performance, and its exposure to appropriate agroecological zones. This knowledge can be advantageous for farmers in attaining optimal conditions to maximize productivity.

NR3C1 and NR3C2 Genes Increase the Risk of Suicide Attempt in Psychiatric Disorder Patients with History of Childhood Trauma.

Hypothalamic-pituitary-adrenal axis gene variants and childhood trauma (CT) are considered risk factors for suicide attempt (SA). The aim of the present study was analyzed gene x environment (GxE) interaction of NR3C1, NR3C2, and CT, and NR3C1 and NR3C2 gene expression in the development of SA with CT. A total of 516 psychiatric Mexican patients from Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. Among them, 274 had SA at least once and 242 had not SA. Genetic variants of NR3C1 and NR3C2 were genotyped in all the patients, of which were obtained the CT information from medical records. Additionally, the gene expression of NR3C1 and NR3C2 was also analyzed for a subsample of 96 patients, obtaining the TC information from Childhood Trauma Questionnaire (CTQ). The analysis showed a GxE interaction of NR3C1, NR3C2, and CT (OR=2.8, 95% CI [1.9-3.9], p<0.0001). Interactions were also observed with neglect (OR=2.1, 95% CI [1.4-3.1], p<0.0001), emotional abuse (OR=2.1, 95% CI [1.5-3], p<0.0001), and sexual abuse (OR=2.4, 95% CI [1.4-2.9], p<0.0001) in the prediction of SA. The analysis of gene expression identified an overexpression of NR3C1 in SA patients with high scores for physical and sexual abuse (p<0.0001; p<0.0006, respectively) and emotional neglect (p=0.014). An underexpression was observed of NR3C2, associated with high scores of trauma subtypes (p<0.0001) except physical neglect. Additionally, we observed an overexpression of NR3C1 gene in patients with SA carriers of A allele of rs6191 (p=0.0015). Also, overexpression of NR3C1 gene in carriers of G allele of rs6198 and underexpression of NR3C2 gene in carriers of G allele of rs5522 (p<0.0001). Our findings suggest that genetic variants of NR3C1 and NR3C2 differentially affect expression levels, increasing the susceptibility to SA in psychiatric patients with a history of CT.

Genetic Background in the Rat Impacts Metabolic Outcomes of Post‐wean BPF Exposure

Bisphenol F (BPF) is a common substitute for bisphenol A (BPA), an endocrine disruptor associated with cardiometabolic disease, and is found in polycarbonates and consumer products. BPF is a potent endocrine disruptor with effects on thyroid, reproductive health, and neuroendocrine functions. Interindividual variation in human bisphenol levels suggests that gene x environment (GxE) interactions influence cardiometabolic disease risk from bisphenol exposure. Traditional in vivo toxicity studies are performed in isogenic or genetically undefined outbred rodents, leading to conflicting results possibly due to GxE interactions. This limitation can be avoided by studying the N/NIH Heterogeneous Stock (HS) rats, an outbred population derived from 8 founder inbred strains that are readily amenable to genetic study.Our overall study hypothesis is that BPF‐induced cardiometabolic disease has underlying genetic risk, which can be identified using the HS rat and its founding inbred strains. We previously demonstrated that 5 weeks of post‐wean BPF exposure significantly impacts body growth and adiposity in male HS rats. The goal of this project was to evaluate the metabolic impact of post‐wean BPF exposure in a subset of HS founding inbred strains. Weanling littermate pairs of male and female ACI/EurMcwi (ACI), BN/NHsdMcwi (BN), F344/Stm (F344), and WKY/NCrl (WKY) rats were randomly exposed to either vehicle (0.1% EtOH) or 1.125 mg BPF/L in 0.1% EtOH for 10 weeks in drinking water. Cardiometabolic measures, tissues, urine, and feces were taken.FemalesFeeding efficiency was significantly increased in BPF ACI females compared to vehicle ACI females. BN, F344, and WKY females showed no impact from BPF exposure.MalesDigestive efficiency was decreased in BPF ACI males compared to all other males. BPF F344 males showed a trend in decreased body length compared to vehicle F344 males. Preliminary metabolic rate measures indicate that BPF ACI and F344 males have decreased metabolic rates compared to vehicle exposed males of the same strain. BPF‐exposed male endocrine glands were affected compared to vehicle males of the same strain: ACI males had increased thyroid gland mass, BN males showed a trend in increased pituitary gland and testes mass, and WKY males had increased adrenal gland mass. Analysis of pituitary‐secreted hormones suggests disruption of the hypothalamic‐pituitary‐gonadal (HPG) and ‐adrenal (HPA) axis in BPF WKY males and the HPG axis in BPF ACI males compared to vehicle males of the same strain.Our preliminary data suggest that post‐wean BPF exposure has numerous effects on the endocrine system and metabolic rate depending on genetic background. The unique outcomes seen in these strains exemplifies that HS rat founding inbred strains possess diverse bisphenol‐exposure risk alleles influencing metabolic health. This work supports BPF exposure as a cardiometabolic disease risk factor and indicates that the HS rat will be a useful model for dissecting GxBPF interactions on metabolic health.

Novel GxE effects and resilience: A case:control longitudinal study of psychosocial stress with war-affected youth.

Responses to early life adversity differ greatly across individuals. Elucidating which factors underlie this variation can help us better understand how to improve health trajectories. Here we used a case:control study of refugee and non-refugee youth, differentially exposed to war-related trauma, to investigate the effects of genetics and psychosocial environment on response to trauma. We investigated genetic variants in two genes (serotonin transporter, 5-HTT, and catechol-O-methyltransferase, COMT) that have been implicated in response to trauma. We collected buccal samples and survey data from 417 Syrian refugee and 306 Jordanian non-refugee youth who were enrolled in a randomized controlled trial to evaluate a mental health-focused intervention. Measures of lifetime trauma exposure, resilience, and six mental health and psychosocial stress outcomes were collected at three time points: baseline, ~13 weeks, and ~48 weeks. We used multilevel models to identify gene x environment (GxE) interactions and direct effects of the genetic variants in association with the six outcome measures over time. We did not identify any interactions with trauma exposure, but we did identify GxE interactions with both genes and resilience; 1) individuals with high expression (HE) variants of 5-HTTLPR and high levels of resilience had the lowest levels of perceived stress and 2) individuals homozygous for the Val variant of COMT with high levels of resilience showed stable levels of post-traumatic stress symptoms. We also identified a direct protective effect of 5-HTTLPR HE homozygotes on perceived insecurity. Our results point to novel interactions between the protective effects of genetic variants and resilience, lending support to ideas of differential susceptibility and altered stress reactivity in a cohort of war-affected adolescents.

Review on Effect of Genotype x Environment Interaction and Yield Stability Among Sorghum (&amp;lt;i&amp;gt;Sorghum bicolor (L.) &amp;lt;/i&amp;gt;Moench.) Genotypes

Sorghum is a prominent cereal crop, particularly in the world's semi-arid tropics. It is grown in over 105 countries across Africa, Asia, Oceania, and the Americas on 40 million hectares. Sorghum is an important indigenous food crop, second only to teff in terms of production of injera (leavened native flat bread). The majority of sorghum varieties are recommended for various agro ecological zones (AEZs), and no single variety is appropriate for all of Ethiopia's circumstances (GxE). GxE affects grain yield, nutritional quality and content, as well as physicochemical and malting quality. The interaction of an organism's genetic composition with its environment results in phenotype, which is a physical trait. The presence of GEI complicates the selection of yield and yield-related traits. GEI can inhibit progress in the selection process and is a key driver of genotype-to-genotype yield stability differences. Plant breeders should investigate GEI in order to better understand crop development in relation to biophysical conditions. In different agro-ecologies, locales, and seasons, genotypes will respond differently. Agronomic/dynamic stability refers to a genotype's ability to adapt to changes in the environment. Breeders should encourage the development of varieties/hybrids that can adapt to a wide range of environments. Crossover and non-crossover gene x environment interactions (GEI) are the two forms of GEI. When there is a disparity in genotypic performance between individuals. Statistical analysis of yield studies can help agronomists, breeders, and other agricultural specialists make faster progress. G x E Interaction and Stability Analysis permits genotypes' relative performance and stability for yield and yield-related variables to be assessed. Therefore the objective of this review study is to assess the role of G x E on yield stability of sorghum.

Abstract P177: Sex- And Strain- Specific Metabolic Effects Of Postnatal Bpf Exposure In Heterogeneous Stock Rat Founding Inbred Strains

Bisphenol F (BPF) is increasing substituting bisphenol A (BPA), an endocrine disruptor associated with cardiometabolic disease, in manufacturing polycarbonates and consumer products. Interindividual variation in bisphenol levels suggests that gene x environment (GxE) interactions influence cardiometabolic disease risk from bisphenol exposure. Studies show that BPF is a potent endocrine disruptor with effects on thyroid, reproductive health, and neuroendocrine functions. Traditional in vivo toxicity studies are performed in isogenic or genetically undefined outbred rodents, leading to conflicting results possibly due to GxE interactions. The N/NIH Heterogeneous Stock (HS) rats are a genetically heterogeneous population amenable to genetic study. Our overall study hypothesis is that BPF-induced cardiometabolic disease has underlying genetic risk, which can be identified using the HS rat and its founding inbred strains. We previously demonstrated that five weeks of postnatal BPF exposure significantly impacts body growth and adiposity in male HS rats. The goal of this project was to evaluate the metabolic health impact of postnatal BPF exposure in HS founding inbred strains. Weanling littermate pairs of male and female ACI/EurMcwi (ACI), BN/NHsdMcwi (BN), F344/Stm (F344), and WKY/NCrl (WKY) rats were randomly exposed to either vehicle (0.1% EtOH) or 1.125 mg BPF/L in 0.1% EtOH for ten weeks in drinking water. Cardiometabolic measures, tissues, urine, and feces were taken. Our studies determined BPF exposure in ACI female rats significantly increased feeding efficiency (0.54 ± 0.07 vs 0.62 ± 0.06 vs, p=0.04), suggesting a possible decrease in metabolic rate. BPF exposure impacted males more often than females, with ACI males showing significantly increased thyroid mass (0.045 ± 0.004 mg/g vs 0.051 ± 0.003 mg/g, p&lt;0.01), BN males showing a trend in increased pituitary mass (0.026 ± 0.003 mg/g vs 0.029 ± 0.001 mg/g, p=0.07), and WKY males showing increased adrenal mass (0.164 ± 0.010 mg/g vs 0.176 ± 0.005 mg/g, p&lt;0.01). Our preliminary data suggests that the ACI strain and male BN and WKY are susceptible to metabolic effects of BPF exposure. This work indicates that the HS rat will be a useful model for dissecting GxBPF interactions on metabolic health.

Abstract P121: Metabolic Influences Of Bisphenol F Exposure In Population-based Heterogeneous Stock Rats

Bisphenol F (BPF) is marketed as a ‘safe’ substitute for bisphenol A (BPA), an endocrine disruptor associated with obesity and heart disease (i.e. cardiometabolic disease), in manufacturing polycarbonates and common consumer products. BPF’s environmental presence is growing and is detected in 66.5% of U.S. adults. Evidence of individual variation in bisphenol levels suggests that gene x environment (GxE) interactions influence cardiometabolic disease risk from bisphenol exposure. Few studies of BPF exposure in either humans or animals have been performed, thus health risks associated with BPF exposure are unknown. Traditional in vivo toxicity studies are performed in isogenic or genetically undefined outbred rodents, leading to conflicting results possibly due to GxE interactions. The N/NIH Heterogeneous Stock (HS) rats are a genetically heterogeneous population amenable to genetic study. Our overall study hypothesis is that BPF-induced cardiometabolic disease has underlying genetic risk, which can be identified using the HS rat model. The goal of this pilot project was to determine if BPF exposure affects growth and adiposity in HS rats. Weanling littermate pairs of male HS rats were randomly exposed to either vehicle (0.1% EtOH) or 1.125 mg BPF/L in 0.1% EtOH for five weeks in drinking water. Cardiometabolic measures, tissues, urine, and feces were taken. Our studies determined BPF exposure in HS rats significantly increases body growth (154.2 ± 3.0 g vs 160.9 ± 3.2 g, p=0.03). BPF exposure alters body composition seen in nuclear magnetic resonance measurements by increasing %fat (7.8 ± 0.3 % vs 8.4 ± 0.3 %; p=0.06), mirroring the significant increase in gonadal white adipose tissue (GWAT) mass (7.58 ± 0.29 mg/g vs 8.37 ± 0.34 mg/g, p=0.01) and perirenal white adipose tissue mass (10.6 ± 0.5 mg/g vs 12.2 ± 0.5 mg/g, p&lt;0.01) in BPF-exposed males. Linear regressions of liver Ugt1a9 expression, an enzyme implicated in BPF metabolism, and %fat or GWAT mass were significantly different between exposure groups (%fat p=0.02, GWAT p=0.02), suggesting that Ugt1a9 expression is related to adiposity phenotype development in BPF-exposed rats. Our data suggest that BPF exposure increases body growth and adiposity, which are risk factors for cardiometabolic disease.

Metabolic Effects of Maternal Bisphenol F Exposure in Population‐based Heterogeneous Stock Rats

Bisphenol F (BPF) is marketed as a ‘safe’ substitute for bisphenol A (BPA), a risk factor for obesity and heart disease, in manufacturing polycarbonates and in common consumer products. BPF’s environmental presence is growing rapidly and is detected in 66.5% of U.S. adults. There is evidence of individual variation in bisphenol levels, suggesting that gene x environment (GxE) interactions influence risk of cardiometabolic disease from bisphenol exposure. Few studies of BPF exposure in either humans or animals have been performed, thus their associated health risks are mostly unknown. Traditional in vivo toxicity studies are performed in genetically undefined outbred rats or genetically homogeneous inbred mice, leading to conflicting results possibly due to GxE interactions. The N/NIH Heterogeneous Stock (HS) rats are outbred rats that better model humans yet are amenable to genetic study. Our overall hypothesis is that BPF exposure is a cardiometabolic disease risk factor based on underlying genetic susceptibility, which can be identified using the HS rat model.We previously demonstrated that five weeks of post‐wean BPF exposure significantly impacts body growth and adiposity in male HS rats. The goal of this project was to determine if maternal BPF exposure also influences growth and adiposity in HS rats, since maternal exposure to BPA is known to impact the metabolic health of both the mother and offspring. HS female breeders were randomly selected for exposure to either vehicle (0.1% Ethanol), 0.1125 mg/L BPF in 0.1% Ethanol (Low Dose), or 1.125 mg/L BPF in 0.1% Ethanol (High Dose) in drinking water during gestation and lactation (~6 weeks total exposure time). One pup of each sex was weaned at 3 weeks of age with no additional exposure. Tissues were taken from dams. Weight and adiposity measures were obtained from weanlings until 8 weeks of age.Our study determined that dams exposed to High Dose showed significantly increased gonadal white adipose tissue (GWAT) mass and trended increased brown adipose tissue (BAT) mass (Table 1). Maternal High Dose exposure impacted weanling body composition at 7 weeks of age as measured by nuclear magnetic resonance (NMR), with the female weanlings significantly increasing %fat mass and trending decreased %lean mass. Maternal BPF exposure also impacted weanling BAT mass, with High Dose female weanlings trending increased BAT mass. No differences were found in male offspring. Our preliminary data suggest that maternal BPF exposure alters adiposity of both the HS dams and female offspring. This work supports BPF exposure as a cardiometabolic disease risk factor and indicates that the HS rat will be a useful model for dissecting GxBPF interactions on metabolic health.Support or Funding InformationNIH P30 ES005605, National Institutes of Health Predoctoral Training Grant T32GM008629 Subject Phenotype Vehicle Low Dose High Dose Dam % BAT (mg) 313 ± 14 343 ± 20 370 ± 31 GWAT (g) 5.7 ± 0.4 5.3 ± 0.5 7.9 ± 0.8 * Female Weanling # Fat % 9.9 ± 1.1 14.0 ± 2.9 17.0 ± 2.0 * Lean % 73.0 ± 1.1 69.3 ± 2.6 66.4 ± 1.7 BAT (mg) 175 ± 9 180 ± 10 213.8 ± 23 Values: mean ± SEM %Vehicle n = 10, Low Dose n = 9, High Dose n = 5 #Vehicle n = 10, Low Dose n = 10, High Dose n = 8 (NMR Vehicle n = 8, Low Dose n = 6, High Dose n = 4) *p &lt; 0.05 High Dose vs Vehicle (linear mixed model regression, Likelihood Ratio Test)

The role of CACNA1C gene and childhood trauma interaction on bipolar disorder

Studies on gene x environment interaction (GxE) have provided vital information for uncovering the origins of complex diseases. When considering the etiology of bipolar disorder (BD), the role of such interactions is unknown. Here, we tested whether trauma during childhood could modify the effect of two polymorphisms in the CACNA1C gene (rs1006737 and rs4765913) in terms of susceptibility to BD. The study enrolled 878 Caucasian young adults in a cross-sectional population-based survey. BD diagnosis was performed using a clinical interview MINI 5.0, and trauma was assessed with the childhood trauma questionnaire (CTQ). Binary logistic regression models were employed to test the main effects of polymorphisms, haplotypes, and GxE interactions using sex as a confounder. We did not observe an association between the polymorphisms and diagnosis of BD. However, we noted that childhood trauma modified the effect of the rs4765913 polymorphism (p = .018) and the AA haplotype (rs1006737 - rs4765913) (p = .018) on BD susceptibility. A allele carriers of the rs4765913 polymorphism or the AA haplotype exposed to childhood trauma are more likely to develop BD compared to the individuals without a genetic risk. Thus, this study showed that the risk of developing BD in individuals exposed to childhood trauma was influenced by the individual's genetic background, varying according to the CACNA1C genotypes.

Mesothelioma developing in carriers of inherited genetic mutations.

Malignant mesothelioma is associated with the exposure to asbestos fibers. Recent discovery of the BAP1 cancer syndrome, a Mendelian disorder with high-penetrance autosomal dominant inheritance fostered the genotyping for nucleotide-level or larger structural alteration of germline DNA. Inherited heterozygous mutations of the BAP1 gene increase the susceptibility to carcinogenic fibers, leading to a concept of gene x environment interaction (GxE) as a pathogenetic mechanism of mesothelioma. Several studies on cohorts of unselected patients with mesothelioma or on familial/early-onset cohorts of mesothelioma cases converged on BAP1 as the more frequent germline mutated gene, followed by other genes involved in DNA repair and homologous recombination. Evidence has been emerging that patients with mesothelioma carrying germline mutations of BAP1 and of other genes, such as those involved in DNA repair and tumor suppressor genes, have better prognosis and higher chemosensitivity when compared with patients with germline wildtype Bap1. We report here a germline genomic analysis targeted 22 genes in a cohort of 101 Japanese patients irrespective of asbestos exposure, age at diagnosis, or personal or family history of cancer. By comparing the results with the Human Genetic Variation Database (HGVD) and the Genome Aggregation Database (gnomAD) we selected rare germline variants with a Combined Annotation Dependent Depletion (CADD) >20. We show here that 31 of 101 subjects were carrying 25 rare variants in 14 genes, neither reported in the HGVD nor in the gnomAD database for 14/25 variants. Besides pathogenic variants of BAP1, rare missense variants were found in genes encoding lysine-specific histone methyltransferase SETD2 and SETDB1 and genes encoding subunits of the mSWI/SNF chromatin remodeling complex. The complete scenario of the genetic background consisting of pathogenic germline variants required for the predisposition and GxE for pathogenesis of mesothelioma appears complex, and further large-scale studies are warranted.

Metabolic Influences of Bisphenol F Exposure in Population‐based Heterogeneous Stock Rats

Bisphenol F (BPF) is marketed as a ‘safe’ substitute for bisphenol A (BPA), an endocrine disruptor associated with obesity and heart disease (i.e. cardiometabolic disease), in manufacturing polycarbonates and in common consumer products (e.g. food packaging). BPF's environmental presence is growing rapidly and is detected in over 85% of U.S. adults and children. There is evidence of individual variation in bisphenol levels, suggesting that genetic variation or gene x environment (GxE) interactions influence risk of cardiometabolic disease due to bisphenol exposure.Characterizing the cardiometabolic effects of BPF in either humans or an animal model has not been performed, and the health risks associated with BPF exposure are vastly unknown. Traditional in vivo toxicity studies are performed in genetically undefined, outbred rats or genetically homogeneous, inbred mice, leading to conflicting results possibly due to GxE interactions. The N/NIH Heterogeneous Stock (HS) rats are a genetically heterogeneous rat population that is amenable to genetic study. The overall hypothesis of this project is that BPF‐induced cardiometabolic disease is based on underlying genetic susceptibility which can be identified using the HS rat model.The goal of this pilot project was to determine if BPF exposure influences growth and adiposity in HS rats. Weanling littermate pairs of male HS rats were randomly selected for exposure to either vehicle (0.1% Ethanol) or 1.125 mg/L BPF in 0.1% Ethanol (average dose 154 μg BPF/kg body weight/day) for five weeks in drinking water. Cardiometabolic measures, tissues, urine, and feces were taken.Our studies determined BPF treatment in HS rats significantly increases body growth (Table 1). Heritability estimates of gain in body weight at eight weeks of age were 0.90±0.13 for vehicle‐treated males and 0.67±0.25 for BPF‐treated males (median±SEM). BPF treatment alters body composition seen in nuclear magnetic resonance (NMR) measurements by increasing % fat and decreasing % lean, mirroring the increase in gonadal white adipose tissue (GWAT) mass and the significant increase in perirenal white adipose tissue (PWAT) mass in BPF‐treated males at eight weeks of age (Table 1). Our data suggest that BPF treatment increases body growth and adiposity, which are risk factors for cardiometabolic disease. Future studies will determine if the response to BPF is genetically regulated.Support or Funding InformationUniversity of Iowa Environmental Health Sciences Research Center (NIH P30 ES005605); National Institutes of Health Predoctoral Training Grant T32GM008629, PI Daniel Eberl.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations.

Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin’s chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P<0.05). Association for SNP rs6983267 in the CCAT2 gene only was noteworthy after multiple test correction (P = 0.001). Site-specific analysis showed association between SNPs rs1799853 and rs2302615 with reduced colon cancer risk only (P = 0.01 and P = 0.004, respectively), however neither reached significance threshold following multiple test correction. Meta-analysis of SNPs rs2070959 and rs1105879 in UGT1A6 gene showed interaction between aspirin use and CRC risk (Pinteraction = 0.01 and 0.02, respectively); stratification by aspirin use showed an association for decreased CRC risk for aspirin users having a wild-type genotype (rs2070959 OR = 0.77, 95% CI = 0.68–0.86; rs1105879 OR = 0.77 95% CI = 0.69–0.86) compared to variant allele cariers. The direction of the interaction however is in contrast to that published in studies on colorectal adenomas. Both SNPs showed potential site-specific interaction with aspirin use and colon cancer risk only (Pinteraction = 0.006 and 0.008, respectively), with the direction of association similar to that observed for CRC. Additionally, they showed interaction between any non-steroidal anti-inflammatory drugs (including aspirin) use and CRC risk (Pinteraction = 0.01 for both). All gene x environment (GxE) interactions however were not significant after multiple test correction. Candidate gene investigation indicated no evidence of GxE interaction between genetic variants in genes involved in aspirin pathways, regular aspirin use and colorectal cancer risk.

Institutionalization and indiscriminate social behavior: Differential-susceptibility versus diathesis-stress models for the 5-HTTLPR and BDNF genotypes

Institutionalization adversely impacts children's emotional functioning, proving related to attachment disorders, perhaps most notably that involving indiscriminate behavior, the subject of this report. In seeking to extend work in this area, this research on gene X environment (GXE) interplay investigated whether the serotonin transporter (5-HTTLPR) and val66met Brain-Derived Neurotrophic Factor (BDNF) polymorphisms moderated the effect of institutional care on indiscriminate behavior in preschoolers. Eighty-five institutionalized and 135 home-reared Portuguese children were assessed using Disturbances of Attachment Interview (DAI). GXE results indicated that s/s homozygotes of the 5-HTTLPR gene displayed significantly higher levels of indiscriminate behavior than all other children if institutionalized, something not true of such children when family reared. These findings proved consistent with the diathesis-stress rather than differential-susceptibility model of person×environment interaction. BDNF proved unrelated to indiscriminate behavior. Results are discussed in relation to previous work on this subject of indiscriminate behavior, institutionalization and GXE interaction.

New perspectives in behavioural development: adaptive shaping of behaviour over a lifetime?

The last years have seen an explosion of publications on consistent, i.e. repeatable, behavioural differences among individuals and their potential adaptive significance and evolutionary origin. Stable, repeatable traits imply reduced plasticity and this is particularly interesting in the case of behaviour, which is the most flexible trait of an animal in its interaction with the biotic and abiotic environment. While the importance of consistent individual differences has been widely acknowledged, the lifetime development of these differences and their potentially adaptive or maladaptive consequences for individuals only recently came into the focus of research [1,2]. As a result, widespread evidence for the existence of changes in behaviour and behavioural plasticity over the lifetime of individuals begins to accumulate [3]. This has raised novel questions concerning the overwhelming importance of ontogenetic and trans-generational influences on the development and fitness of behavioural phenotypes and the mechanisms influencing changes during an individual’s lifetime. Much theoretical work has been published on the importance of and limits to individual plasticity, mostly in the framework of the reaction norm. Less empirical work has actually studied, how the reaction norm comes about in an individual’s lifetime and how or whether it may change over the lifetime [4]. This raises important questions about the adaptivity of the phenotypic plasticity of behaviour and the question when within a lifetime such plasticity might be particularly relevant. Do particular windows of plasticity exist, and if so why are they where they are within the lifetime of an organism? The potential lifetime plasticity also raises the question about the evolution of the reaction norm and, more recently, about the evolution of its plasticity, questions that so far have received but little attention. In these fields of investigation theory has moved far ahead of empirical studies. Often, if not always, individuals face uncertain environmental conditions throughout their life, forcing them to adapt plastically in order to maximise fitness. Under such uncertain conditions we expect natural selection to favour plasticity. However, plastic responses to the environment can only be adaptive, if informative environmental cues exist that allow prediction of future conditions with reasonably high probability [5]. Depending on the cues available and the ontogenetic stage of an individual we expect differential effects of such predictive cues: Early in life highly informative cues, whether derived from maternal influences or perceived directly, may potentially act in an organisational manner, whereas less informative cues or cues perceived at a later age may lead to more immediate plasticity (see [4] for a definition of different types of plasticity). This may lead to developmental influences on plasticity, i.e. early environments may particularly influence the reaction norm. This idea of plasticity of the reaction norm as a trait that develops and thereby influences the reaction norm expressed during the lifetime of an individual is rather novel [6]. However, it follows directly from Gene x Environment interactions (GxE) influencing the reaction norm. Along the developmental axis Gene x Age (GxA) and Individual x Age (IxA) interactions will then determine the expression of the developing reaction norm in interaction with the environments encountered by an individual (see [7]). As pointed out earlier [2] genes themselves provide an environment for other genes so that even more complex interactions are to be expected. As these interactions may change with the state and the age of an individual it becomes clear why ontogenetic processes are of prime * Correspondence: fritz.trillmich@uni-bielefeld.de Animal Behaviour, Bielefeld University, Morgenbreede 45, 33615 Bielefeld, Germany Full list of author information is available at the end of the article Trillmich et al. Frontiers in Zoology 2015, 12(Suppl 1):S1 http://www.frontiersinzoology.com/content/12/S1/S1

Implications of genomic signatures in the differential vulnerability to fetal alcohol exposure in C57BL/6 and DBA/2 mice.

Maternal alcohol consumption inflicts a multitude of phenotypic consequences that range from undetectable changes to severe dysmorphology. Using tightly controlled murine studies that deliver precise amounts of alcohol at discrete developmental stages, our group and other labs demonstrated in prior studies that the C57BL/6 and DBA/2 inbred mouse strains display differential susceptibility to the teratogenic effects of alcohol. Since the phenotypic diversity extends beyond the amount, dosage and timing of alcohol exposure, it is likely that an individual's genetic background contributes to the phenotypic spectrum. To identify the genomic signatures associated with these observed differences in alcohol-induced dysmorphology, we conducted a microarray-based transcriptome study that also interrogated the genomic signatures between these two lines based on genetic background and alcohol exposure. This approach is called a gene x environment (GxE) analysis; one example of a GxE interaction would be a gene whose expression level increases in C57BL/6, but decreases in DBA/2 embryos, following alcohol exposure. We identified 35 candidate genes exhibiting GxE interactions. To identify cis-acting factors that mediated these interactions, we interrogated the proximal promoters of these 35 candidates and found 241 single nucleotide variants (SNVs) in 16 promoters. Further investigation indicated that 186 SNVs (15 promoters) are predicted to alter transcription factor binding. In addition, 62 SNVs created, removed or altered the placement of a CpG dinucleotide in 13 of the proximal promoters, 53 of which overlapped putative transcription factor binding sites. These 53 SNVs are also our top candidates for future studies aimed at examining the effects of alcohol on epigenetic gene regulation.

Gene X Environment Interactions in Schizophrenia and Bipolar Disorder: Evidence from Neuroimaging

Introduction: Schizophrenia (SZ) and Bipolar disorder (BD) are considered as severe multifactorial diseases, stemming from genetic and environmental influences. Growing evidence supports gene x environment (GxE) interactions in these disorders and neuroimaging studies can help us to understand how those factors mechanistically interact. No reviews synthesized the existing data of neuroimaging studies in these issues.Methods: We conduct a systematic review on the neuroimaging studies exploring GxE interactions relative to SZ or BD in PubMed.Results: First results of the influence of genetic and environmental risks on brain structures came from monozygotic twin pairs concordant and discordant for SZ or BD. Few structural magnetic resonance imaging (sMRI) studies have explored the GxE interactions. No other imaging methods were found. Two main GxE interactions on brain volumes have arisen. First, an interaction between genetic liability to SZ and obstetric complications on gray matter, cerebrospinal fluid, and hippocampal volumes. Second, cannabis use and genetic liability interaction effects on cortical thickness and white matter volumes.Conclusion: Combining GxE interactions and neuroimaging domains is a promising approach. Genetic risk and environmental exposures such as cannabis or obstetrical complications seem to interact leading to specific neuroimaging cerebral alterations in SZ. They are suggestive of GxE interactions that confer phenotypic abnormalities in SZ and possibly BD. We need further, larger neuroimaging studies of GxE interactions for which we may propose a framework focusing on GxE interactions data already known to have a clinical effect such as infections, early stress, urbanicity, and substance abuse.

Youth Appraisals of Inter-parental Conflict and Genetic and Environmental Contributions to Attention-Deficit Hyperactivity Disorder: Examination of GxE Effects in a Twin Sample

Identification of gene x environment interactions (GxE) for attention-deficit hyperactivity disorder (ADHD) is a crucial component to understanding the mechanisms underpinning the disorder, as prior work indicates large genetic influences and numerous environmental risk factors. Building on prior research, children's appraisals of self-blame were examined as a psychosocial moderator of latent etiological influences on ADHD via biometric twin models, which provide an omnibus test of GxE while managing the potential confound of gene-environment correlation. Participants were 246 twin pairs (total n = 492) ages 6-16 years. ADHD behaviors were assessed via mother report on the Child Behavior Checklist. To assess level of self-blame, each twin completed the Children's Perception of Inter-parental Conflict scale. Two biometric GxE models were fit to the data. The first model revealed a significant decrease in genetic effects and a significant increase in unique environmental influences on ADHD with increasing levels of self-blame. These results generally persisted even after controlling for confounding effects due to gene-environment correlation in the second model. Results suggest that appraisals of self-blame in relation to inter-parental conflict may act as a key moderator of etiological contributions to ADHD.

Genetics of body weight in the LXS recombinant inbred mouse strains

This is the first phenotypic analysis of 75 new recombinant inbred (RI) strains derived from ILS and ISS progenitors. We analyzed body weight in two independent cohorts of female mice at various ages and in males at 60 days. Body weight is a complex trait which has been mapped in numerous crosses in rodents. The LXS RI strains displayed a large range of weights, transgressing those of the inbred progenitors, supporting the utility of this large panel for mapping traits not selected in the progenitors. Numerous QTLs for body weight mapped in single- and multilocus scans. We assessed replication between these and previously reported QTLs based on overlapping confidence intervals of published QTLs for body weight at 60 days and used meta-analyses to determine combined p values for three QTL regions located on Chromosomes 4, 5, and 11. Strain distribution patterns of microsatellite marker genotypes, weight, and other phenotypes are available on WebQTL (http://www.webqtl.org/search.html ) and allow genetic mapping of any heritable quantitative phenotype measured in these strains. We report one such analysis, correlating brain and body weights. Large reference panels of RI strains, such as the LXS, are invaluable for identifying genetic correlations, GXE (Gene X Environment) interactions, and replicating previously identified QTLs.

Biosocial models of deviant behavior

This article describes biological influences on criminality. It presents illustrative data suggesting a biological sex difference in criminality and heritable differences in this trait among individuals. Next, methods of isolating environmental influences are described, including shared environmental effects, genex environment interactions, and nonshared environmental effects. Using research designs that include just one level of genetic relatedness (e.g., full siblings) is scientifically a poor choice. Using environment-friendly behavior genetic research designs is both proper and would offer many avenues for environmental analysis.