Evaluation of genomic factors and early childhood stimulation on intelligence in children from a Brazilian birth cohort: The primary role of independent factors.

BACKGROUND: Childhood cognitive abilities are a predictor of health outcomes and adult income potential. Identifying factors associated with childhood intelligence and their interactions is essential in behavioral research. We assessed the impact of genetic variants and early child stimulation (ECS) on child intelligence and examined their possible interaction as potential modifiers of IQ in a population-based longitudinal study. METHODS: Participants of the 2004 Pelotas Birth Cohort study (N = 4231) underwent intelligent quotient (IQ) by WISC-III assessment at 6 years of age. At 24 and 48-months, mothers answered five ECS marker questions, whose sum was used to create a score. The polygenic score for intelligence (IQ-PGS) was constructed from the GWAS-weighted estimate of cognition. Association was assessed using multiple linear regression models adjusted for maternal, family, and child confounding variables. To explore the possible influence of skin color and ethnoracial classification, the regression models were stratified according to the skin color variable, as a sensitivity analysis. RESULTS: In the adjusted analysis, IQ-PGS (ß = 0.79, 95% confidence interval [95% CI] 0.26;1.31) as well as ECS (ß = 2.34; 95% CI: 1.76;2.92) were associated with IQ in this sample. The association between IQ-PGS and IQ was significant only in the white Brazilian group in the sensitivity analysis. However, there was no interaction between IQ-PGS and ECS on IQ (p(IQ-PGS x ECS) = 0.46). CONCLUSIONS: ECS did not modify the impact of genetic potential on intellectual development during childhood, suggesting that genetic factors and ECS exert independent effects on the IQ levels of children.

Individual and Combined Effect of MAO-A/MAO-B Gene Variants and Adverse Childhood Experiences on the Severity of Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is a mood disorder with a high prevalence worldwide that causes disability and, in some cases, suicide. Although environmental factors play a crucial role in this disease, other biological factors may predispose individuals to MDD. Genetic and environmental factors influence mental disorders; therefore, a potential combined effect of MAO-A/MAO-B gene variants may be a target for the study of susceptibility to MDD. This study aimed to evaluate the effects of MAO-A and -B gene variants when combined with adverse childhood experiences (ACEs) on the susceptibility and severity of symptoms in MDD. METHODS: A case-control study was performed, including 345 individuals, 175 MDD cases and 170 controls. Genotyping was performed using real-time PCR with hydrolysis probes. The analysis of the rs1465107 and rs1799836 gene variants of MAO-A and -B, respectively, was performed either alone or in combination with ACEs on the severity of depression, as determined through specific questionnaires, including DSM-IV diagnostic criteria for MDD. RESULTS: According to individual effects, the presence of ACEs, as well as the allele G of the rs1465107 of MAO-A, is associated with a higher severity of depression, more significantly in females. Furthermore, the allele rs1799836 G of MAO-B was associated with the severity of depression, even after being adjusted by gene variants and ACEs (IRR = 1.67, p = 0.01). In males, the allele rs1799836 G of MAO-B was shown to interact with SNP with ACEs (IRR = 1.70, p < 0.001). According to combined effect analyses, the severity of depression was associated with ACEs when combined with either allele rs1465107 of MAO-A or allele rs17993836 of MAO-B, whereas SNP risk association was influenced by gender. CONCLUSIONS: The severity of depression is related to either individual or combined effects of temperamental traits and genetic susceptibility of specific genes such as MAO-A and MAO-B.

Genes, exposures, and interactions on preterm birth risk: an exploratory study in an Argentine population.

Preterm birth (PTB) is the main condition related to perinatal morbimortality worldwide. The aim of this study was to identify associations of spontaneous PTB with genetic variants, exposures, and interactions between and within them. We carried out a retrospective case-control study including parental sociodemographic and obstetric data, and fetal genetic variants. We sequenced the coding and flanking regions of five candidate genes from the placental blood cord of 69 preterm newborns and 61 at term newborns. We identify the characteristics with the greatest predictive power of PTB using penalized regressions, in which we include exposures (E), genetic variants (G), and two-way interactions. Few prenatal visits (< 5) was the main predictor of PTB from 26 G, 35 E, 299 G × G, 564 E × E, and 875 G × E evaluated terms. Within the fetal genetic characteristics, we observed associations of rs4845397 (KCNN3, allele T) variant; G × G interaction between rs12621551 (COL4A3, allele T) and rs73993878 (COL4A3, allele A), which showed sensitivity to anemia; and G × G interaction between rs11680670 (COL4A3, allele T) and rs2074351 (PON1, allele A), which showed sensitivity to vaginal discharge. The results of this exploratory study suggest that social disparities and metabolic pathways linked to uterine relaxation, inflammation/infections, and collagen metabolism would be involved in PTB etiology. Future studies with a larger sample size are necessary to confirm these findings and to analyze a greater number of exposures.

Educational performance and conduct problem trajectories from childhood to adolescence: Observational and genetic associations in a Brazilian birth cohort.

Background: Educational difficulties are an important potential influence on both the onset and course of children's conduct problems. This study evaluated the association between school failure and children's conduct problems in Brazil, a context with high rates of both conditions, using both observational and genetic approaches. Methods: Prospective, population-based, birth cohort study in Pelotas city, Brazil. Parents reported on conduct problems four times between ages 4-15 years, and group-based trajectory analysis was used to classify 3469 children into trajectories of childhood-limited, early-onset persistent, adolescence-onset, or low conduct problems. School failure was measured as having repeated a school grade up to age 11, and a polygenic risk score (PRS) predicting educational attainment was calculated. Multinomial adjusted regression models were used to estimate the association between school failure (observational measure and the PRS) and conduct problem trajectories. To consider possible variation in effects of school failure by social context, interactions were tested with family income and school environment (using both observational and PRS methods). Results: Children repeating a school grade had increased odds of being on to childhood-limited (OR: 1.57; 95% CI 1.21; 2.03), adolescence-onset (OR: 1.96; 95% CI 1.39; 2.75), or early-onset persistent trajectory (OR: 2.99; 95% CI 1.85; 4.83), compared to the low conduct problem trajectory. School failure also predicted increased risk for early-onset persistent problems versus the childhood-limited problems (OR: 1.91; 95% CI 1.17; 3.09). Using a genetic PRS approach, similar findings were observed. Associations varied according to the school environment: school failure had larger effects on children in better school environments. Conclusion: School performance, whether measured in terms of repeating school grades or genetic susceptibility, was consistently associated with trajectories of child conduct problems into mid-adolescence. We also found a larger association for children in better school environments.

Homozygous deletion of glutathione S-transferase theta 1 and mu 1 increase the risk of non-syndromic oral clefts in a Mexican population.

OBJECTIVE: To investigate whether null variants of Glutathione S-transferase Mu 1 (GSTM1) and GST Theta 1 (GSTT1) in infants and mothers, as well as maternal exposures to environmental factors, contribute to the risk of non-syndromic cleft lip with or without palate (NSCL/P) in a Mexican population. DESIGN: We performed a matched pair case-control study, including 98 cases and 98 controls and their mothers. Sociodemographic information and environmental exposures were collected by a questionnaire. Null variants of GSTM1 and GSTT1 were assessed by multiplex Polymerase Chain Reaction (PCR). Odds ratios (OR) and their 95 % confidence intervals (CI) were calculated to estimate risks. The interaction of genetic variables with smoking and adjusted ORs were evaluated by binary logistic regression. RESULTS: Homozygous null GSTM1 was associated with the risk of NSCL/P when present in mothers (OR = 2.45, 95 % CI 1.23-4.86) or infants (OR = 2.98, 95 % CI 1.45-6.14). A higher risk was also found when children carried the homozygous null GSTT1 (OR = 4.89, 95 % CI 2.42-9.87). In mothers, this variant showed a crude risk of 9.17 (95 % CI 3.95-21.29), which increased to OR = 13.81 (95 % CI 1.63-117.09) upon interaction with frequent passive smoking (5-7 days/week). Sociodemographic and other environmental exposures were not significantly associated with the risk of NSCL/P. CONCLUSIONS: Maternal and infant GSTT1 and GSTM1 homozygous null genotypes were associated with a higher risk of NSCL/P, and the results suggest an interaction of the maternal GSTT1-null/null genotype with frequent passive smoking.

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.

Genetic susceptibility to pre diabetes mellitus and related association with obesity and physical fitness components in Mexican-Mestizos.

Pre diabetes mellitus (pre-DM) is considered an early-reversible condition that can progress to Type 2 diabetes mellitus (T2DM) which is the main cause of death for adult Mexican population. Gene variants influencing fasting glucose levels may constitute helpful tool for prevention purposes in pre-DM condition. Physically active Mexican-Mestizo adults (n=565) were genotyped for 6 single nucleotide polymorphisms (SNPs) (ADIPOQ rs2241766, ACSL1 rs9997745, LIPC rs1800588, PPARA rs1800206, PPARG rs1801282 and PPARGC1A rs8192678) related to lipid and carbohydrate metabolism. Fasting glucose was measured and values classified as pre-DM (≥100mg/dL) or normal fasting glucose. Logistic models were used to test associations between pre-DM condition and SNPs, and interaction with Body Mass Index (BMI) and physical fitness components. The A allele of ASCL1 rs9997745 conferred increased risk (OR=3.39, p=0.001) of pre-DM which is modulated by BMI. The A allele of the PPARGC1A rs8192678 showed significant SNP*BMI (OR=1.10, p=0.008) interaction effect for pre-DM risk, meaning that obese subjects showed higher pre-DM risk but normal weight subjects showed lower risk. The effect increased with age and was attenuated by higher cardiorespiratory values. We found that both ACSL1 rs9997745 and PPARGC1A rs8192678 are associated with pre-DM, and that BMI significantly modified their association.

Relationship between XPD, RAD51, and APEX1 DNA repair genotypes and prostate cancer risk in the male population of Rio de Janeiro, Brazil

Abstract Susceptibility to cancer ensues in individuals carrying malfunctioning DNA repair mechanisms. The impact of Single Nucleotide Polymorphisms (SNPs) in key DNA repair mechanisms on risk for prostate cancer was investigated in this case-control study. Samples consisted of 110 patients with confirmed prostate cancer and 200 unaffected men, from Rio de Janeiro, Brazil. XPD/Lys751Gln (rs13181), APEX1/Asp148Glu (rs1130409), and RAD51/G135C (rs1801320) SNPs were analyzed by PCR-RFLP. Allelic and genotypic frequencies were calculated and compared by Chi-Square test. The association between SNPs and clinical/epidemiological data was considered significant by Odds Ratio analysis, with IC95% and a p-value≤0.05. Only the XPD/Lys751Gln SNP significantly increased susceptibility to disease in southeastern Brazilian men, with p≤0.001 [OR=2.36 (1.46-3.84)], with no association with APEX1 or RAD51 SNPs. Combined XPD+RAD51 SNPs were highly associated with the disease, p≤0.005 [OR=3.40 (1.32-9.20)]. A Chi-Square significant association between XPD/Lys751Gln and Gleason score was also observed (OR=9.31; IC95%=1.19-428.0; p=0.022). Epidemiological inquiries revealed that exposure to pesticides significantly impacted the risk for prostate cancer in this population. DNA repair dysfunctions seem to prevail among workers exposed to chemical byproducts to cancer in this specific tissue. Non-invasive genotyping SNPs may help assessment of prostate cancer risk in environmentally exposed populations.

An Efficient Test for Gene-Environment Interaction in Generalized Linear Mixed Models with Family Data.

Gene-environment (GE) interaction has important implications in the etiology of complex diseases that are caused by a combination of genetic factors and environment variables. Several authors have developed GE analysis in the context of independent subjects or longitudinal data using a gene-set. In this paper, we propose to analyze GE interaction for discrete and continuous phenotypes in family studies by incorporating the relatedness among the relatives for each family into a generalized linear mixed model (GLMM) and by using a gene-based variance component test. In addition, we deal with collinearity problems arising from linkage disequilibrium among single nucleotide polymorphisms (SNPs) by considering their coefficients as random effects under the null model estimation. We show that the best linear unbiased predictor (BLUP) of such random effects in the GLMM is equivalent to the ridge regression estimator. This equivalence provides a simple method to estimate the ridge penalty parameter in comparison to other computationally-demanding estimation approaches based on cross-validation schemes. We evaluated the proposed test using simulation studies and applied it to real data from the Baependi Heart Study consisting of 76 families. Using our approach, we identified an interaction between BMI and the Peroxisome Proliferator Activated Receptor Gamma (PPARG) gene associated with diabetes.

Influence on serum asymmetric dimethylarginine (ADMA) concentrations of human paraoxonase 1 polymorphism (Q192R) and exposure to polycyclic aromatic hydrocarbons (PAHs) in Mexican women, a gene-environment interaction.

It has been demonstrated that Cardiovascular Diseases (CVD) are a consequence of the combination of genetic and environmental factors and/or the interaction between them. Therefore, the aim of this study was to evaluate the impact of polycyclic aromatic hydrocarbon (PAHs) exposure and PON1 Q192R polymorphism (genetic susceptibility) on serum asymmetric dimethylarginine (ADMA) levels in Mexican women (n = 206). Urinary 1-hydroxypyrene concentrations (1-OHP; exposure biomarker for PAHs) were quantified using a high-performance liquid chromatography technique, PON1 Q192R polymorphism was genotyped using TaqMan probes and serum ADMA concentrations were evaluated using a commercially available ELISA kit. Urinary 1-OHP levels detected in this study ranged from 0.07 to 9.37 µmol/mol of creatinine (0.13-18.0 µg/g of creatinine). Regarding allele frequency (PON1 Q192R polymorphism), the 192Q-allele frequency was 0.43 and for the 192R-allele it was 0.57. In relation to serum ADMA levels, the levels ranged from 0.06 to 1.46 µmol/L. Moreover, multiple linear regression analysis was performed and associations between urinary 1-OHP levels (ß = 0.05, p = 0.002), PON1 Q192R polymorphism (ß = 0.04, p = 0.003) and serum ADMA concentrations were found. Besides, an interaction (gene-environment interaction) of both independent variables (1-OHP and PON1 polymorphism) on serum ADMA levels was found (ß = 0.04, p = 0.02) in the constructed multiple linear model. Therefore, according to the significance of this research, it is necessary to execute health programs to reduce cardiovascular risk in the assessed population.

Vulnerability or Sensitivity to the Environment? Methodological Issues, Trends, and Recommendations in Gene-Environment Interactions Research in Human Behavior.

Research on the potential role of gene-environment interactions (GxE) in explaining vulnerability to psychopathology in humans has witnessed a shift from a diathesis-stress perspective to differential susceptibility approaches. This paper critically reviews methodological issues and trends in this body of research. Databases were screened for studies of GxE in the prediction of personality traits, behavior, and mental health disorders in humans published between January 2002 and January 2015. In total, 315 papers were included. Results showed that 34 candidate genes have been included in GxE studies. Independent of the type of environment studied (early or recent life events, positive or negative environments), about 67-83% of studies have reported significant GxE interactions, which is consistent with a social susceptibility model. The percentage of positive results does not seem to differ depending on the gene studied, although publication bias might be involved. However, the number of positive findings differs depending on the population studied (i.e., young adults vs. older adults). Methodological considerations limit the ability to draw strong conclusions, particularly as almost 90% (n = 283/315) of published papers are based on samples from North America and Europe, and about 70% of published studies (219/315) are based on samples that were also used in other reports. At the same time, there are clear indications of methodological improvements over time, as is shown by a significant increase in longitudinal and experimental studies as well as in improved minimum genotyping. Recommendations for future research, such as minimum quality assessment of genes and environmental factors, specifying theoretical models guiding the study, and taking into account of cultural, ethnic, and lifetime perspectives, are formulated.

Culture as a mediator of gene-environment interaction: Cultural consonance, childhood adversity, a 2A serotonin receptor polymorphism, and depression in urban Brazil.

Research on gene-environment interaction was facilitated by breakthroughs in molecular biology in the late 20th century, especially in the study of mental health. There is a reliable interaction between candidate genes for depression and childhood adversity in relation to mental health outcomes. The aim of this paper is to explore the role of culture in this process in an urban community in Brazil. The specific cultural factor examined is cultural consonance, or the degree to which individuals are able to successfully incorporate salient cultural models into their own beliefs and behaviors. It was hypothesized that cultural consonance in family life would mediate the interaction of genotype and childhood adversity. In a study of 402 adult Brazilians from diverse socioeconomic backgrounds, conducted from 2011 to 2014, the interaction of reported childhood adversity and a polymorphism in the 2A serotonin receptor was associated with higher depressive symptoms. Further analysis showed that the gene-environment interaction was mediated by cultural consonance in family life, and that these effects were more pronounced in lower social class neighborhoods. The findings reinforce the role of the serotonergic system in the regulation of stress response and learning and memory, and how these processes in turn interact with environmental events and circumstances. Furthermore, these results suggest that gene-environment interaction models should incorporate a wider range of environmental experience and more complex pathways to better understand how genes and the environment combine to influence mental health outcomes.

Interaction of lipoprotein lipase polymorphisms with body mass index and birth weight to modulate lipid profiles in children and adolescents: the CASPIAN-III Study / Interação de polimorfismos da lipoproteína lipase com índice de massa corporal e peso ao nascer para modular o perfil lipídico em crianças e adolescentes: o estudo CASPIAN-III

CONTEXT AND OBJECTIVE: Interactions between body mass index (BMI), birth weight and risk parameters may contribute to diseases rather than the individual effects of each factor. However this hypothesis needs to be confirmed. This study aimed to determine to what extent variants of lipoprotein lipase (LPL) might interact with birth weight or body weight in determining the lipid profile concentrations in children and adolescents. DESIGN AND SETTING: Substudy of the third survey of a national surveillance system (CASPIAN-III Study) in Iran. METHODS: Whole blood samples (kept frozen at -70 °C) were randomly selected from 750 students aged 10-18 years. Real-time polymerase chain reaction (PCR) and high-resolution melt analysis were performed to assess S447X (rs328), HindIII (rs320) and D9N (rs1801177) polymorphisms. RESULTS: The AG/GG genotype in D9N polymorphism was associated with higher LDL-C (low-density lipoprotein cholesterol) and lower HDL-C (high-density lipoprotein cholesterol) concentration. Significant interactions were found for D9N polymorphism and birth weight in association with plasma HDL-C concentration, and also for D9N polymorphism and BMI in association with plasma triglyceride (TG) and HDL-C levels. HindIII polymorphism had significant association with birth weight for HDL-C concentration, and with BMI for TG and HDL-C levels. Significant interactions were found for S447X polymorphism and BMI in association with plasma TG and HDL-C concentrations. CONCLUSION: We found significant interactive effects from LPL polymorphisms and birth weight on HDL-C concentration, and also effects from LPL polymorphisms and BMI on TG and HDL-C concentrations.

RESUMO CONTEXTO E OBJETIVO: Interações entre índice de massa corporal (IMC), peso ao nascer e parâmetros de risco podem contribuir para doenças, em vez de efeitos individuais de cada fator. No entanto, essa hipótese precisa de confirmação. Este estudo visou determinar o quanto variantes de lipoproteína lipase (LPL) podem interagir com peso de nascimento ou peso corporal na determinação das concentrações do perfil lipídico em crianças e adolescentes. DESENHO E LOCAL: Sub-estudo da terceira pesquisa de sistema nacional de vigilância (Estudo CASPIAN-III) no Irã. MÉTODOS: Foram selecionadas aleatoriamente amostras de sangue total (mantidas congeladas a -70 °C) de 750 estudantes com idades entre 10-18 anos. Reação de polimerase em cadeia (PCR) em tempo real e análise de fusão de alta resolução foram realizados para avaliar polimorfismo de S447X (rs328), HindIII (rs320) e D9N (rs1801177). RESULTADOS: Genótipo AG/GG em polimorfismo D9N foi associado com concentração maior de LDL-C (colesterol do tipo lipoproteína de baixa densidade) e menor de HDL-C (colesterol do tipo lipoproteína de alta densidade). Interações significativas foram encontradas para polimorfismo D9N e peso ao nascer em associação com concentração plasmática de HDL-C, bem como para polimorfismo D9N e IMC em associação com níveis plasmáticos de triglicérides (TG) e HDL-C. Polimorfismo HindIII teve associação significativa com peso de nascimento para concentração de HDL-C, e com IMC para níveis de TG e HDL-C. Interações significativas foram encontradas para polimorfismo S447X e IMC em associação com concentrações plasmáticas de TG e HDL-C. CONCLUSÃO: Encontramos efeitos interativos significativos de polimorfismo LPL e peso de nascimento sobre concentração de HDL-C, bem como efeitos de polimorfismos LPL e IMC sobre concentrações de TG e HDL-C.

The correlation between the central carbon metabolic flux distribution and the number of shared enzyme regulators in Saccharomyces cerevisiae

The central carbon metabolic system is the upstream energy source for microbial fermentation. In addition, it is a master switch for increasing the production of metabolites and an important part of the microbial metabolic network. Investigation into the relationship between genes, environmental factors, and metabolic networks is a main focus of systems biology, which significantly impacts research in biochemistry, metabolic engineering, and synthetic biology. To this end, the central carbon metabolic flux under a variety of growth conditions or using strains with various genetic modifications was previously measured in Saccharomyces cerevisiae using 13C tracer technology. However, the measured values were not integrated and investigated further. In this study, we collected and analyzed the metabolic flux rates of the central carbon metabolic system in S. cerevisiae measured in recent studies. We carried out preliminary analyses of flux values of each pathway, performed regression analyses on relationship between different fluxes, and extracted principal component factors of the flux variables. Based on the results, the general characteristics of pathway flux distribution were clustered and explored, and the effects of environmental and genetic factors on the flux distribution were analyzed. Furthermore, this study explored the relationship between similarity in the enzyme's transcriptional regulation and the correlations in the enzyme's reaction flux. Our results provide a foundation for further studies on the control of the central carbon metabolic flux and facilitate the search for targets in metabolic engineering research.

Corticosteroid receptor genes and childhood neglect influence susceptibility to crack/cocaine addiction and response to detoxification treatment.

The aim of this study was to analyze hypotheses-driven gene-environment and gene-gene interactions in smoked (crack) cocaine addiction by evaluating childhood neglect and polymorphisms in mineralocorticoid and glucocorticoid receptor genes (NR3C2 and NR3C1, respectively). One hundred thirty-nine crack/cocaine-addicted women who completed 3 weeks of follow-up during early abstinence composed our sample. Childhood adversities were assessed using the Childhood Trauma Questionnaire (CTQ), and withdrawal symptoms were assessed using the Cocaine Selective Severity Assessment (CSSA) scale. Conditional logistic regression with counterfactuals and generalized estimating equation modeling were used to test gene-environment and gene-gene interactions. We found an interaction between the rs5522-Val allele and childhood physical neglect, which altered the risk of crack/cocaine addiction (Odds ratio = 4.0, P = 0.001). Moreover, a NR3C2-NR3C1 interaction (P = 0.002) was found modulating the severity of crack/cocaine withdrawal symptoms. In the post hoc analysis, concomitant carriers of the NR3C2 rs5522-Val and NR3C1 rs6198-G alleles showed lower overall severity scores when compared to other genotype groups (P-values ≤ 0.035). This gene-environment interaction is consistent with epidemiological and human experimental findings demonstrating a strong relationship between early life stress and the hypothalamic-pituitary-adrenal (HPA) axis dysregulation in cocaine addiction. Additionally, this study extended in crack/cocaine addiction the findings previously reported for tobacco smoking involving an interaction between NR3C2 and NR3C1 genes.

Latent variable models for gene-environment interactions in longitudinal studies with multiple correlated exposures.

Many existing cohort studies designed to investigate health effects of environmental exposures also collect data on genetic markers. The Early Life Exposures in Mexico to Environmental Toxicants project, for instance, has been genotyping single nucleotide polymorphisms on candidate genes involved in mental and nutrient metabolism and also in potentially shared metabolic pathways with the environmental exposures. Given the longitudinal nature of these cohort studies, rich exposure and outcome data are available to address novel questions regarding gene-environment interaction (G × E). Latent variable (LV) models have been effectively used for dimension reduction, helping with multiple testing and multicollinearity issues in the presence of correlated multivariate exposures and outcomes. In this paper, we first propose a modeling strategy, based on LV models, to examine the association between repeated outcome measures (e.g., child weight) and a set of correlated exposure biomarkers (e.g., prenatal lead exposure). We then construct novel tests for G × E effects within the LV framework to examine effect modification of outcome-exposure association by genetic factors (e.g., the hemochromatosis gene). We consider two scenarios: one allowing dependence of the LV models on genes and the other assuming independence between the LV models and genes. We combine the two sets of estimates by shrinkage estimation to trade off bias and efficiency in a data-adaptive way. Using simulations, we evaluate the properties of the shrinkage estimates, and in particular, we demonstrate the need for this data-adaptive shrinkage given repeated outcome measures, exposure measures possibly repeated and time-varying gene-environment association.

Genetic modification of the effect of maternal household air pollution exposure on birth weight in Guatemalan newborns.

Low birth weight is associated with exposure to air pollution during pregnancy. The purpose of this study was to evaluate whether null polymorphisms of Glutathione S-transferases (GSTs), specifically GSTM1 and GSTT1 genes in infants or mothers, modify the association between high exposures to household air pollution (HAP) from cooking fires and birth weight. Pregnant women in rural Guatemala were randomized to receive a chimney stove or continue to use open fires for cooking. Newborns were measured within 48 h of birth. 132 mother-infant pairs provided infant genotypes (n=130) and/or maternal genotypes (n=116). Maternal null GSTM1 was associated with a 144 g (95% CI, -291, 1) and combined maternal/infant null GSTT1 was associated with a 155 g (95% CI, -303, -8) decrease in birth weight. Although there was a trend toward higher birth weights with increasing number of expressed GST genes, the effect modification by chimney stove use was not demonstrated.

The complex interplay of genetics, epigenetics, and environment in the predisposition to alcohol dependence / La compleja interacción genética, epigenética y ambiental en la predisposición a la dependencia al alcohol

Alcohol dependence is a major global problem, associated with lower quality of physical and mental health, higher mortality and an enormous familial and social cost. Prevention strategies and treatment of this condition are therefore crucial. Success of psychosocial programs and pharmacological treatments has been frequently reported, but a better understanding of the etiology of this chronic disease is needed. For this purpose, the identification of associated factors in different populations is of great significance. It has been clearly demonstrated by twin and adoption studies and supported by animal models that both genetic and environmental components play a substancial role in alcohol dependence. Heritabil ity estimates range from 40 to 60%, depending on the specific analyzed sample. Several coexisting genetic variants in each affected individual, rather than a single gene transmitted in a Mendelian manner, may be the rule in alcohol dependence. Similarly, many environmental factors can increase susceptibility, and because of their diversity, they do not have to be the same in every affected person. Environmental contribution may be linked to epigenetics, which refers to chemical processes that can modify gene activity without changing the sequence of DNA. In humans, the most stable epigenetic process is the union of a methyl group (one carbon atom surrounded by three hydrogen atoms) to cytosines in DNA. Other epigenetic mechanisms are modifications to nuclear proteins called histones, which alter the way DNA is packed. Moreover, non-protein coding RNAs such as microRNAs have been associated with the development of alcohol dependence. MicroRNAs could work as epigenetic intermediaries that allow ethanol to affect complex and divergent developmental mechanisms, which is added to the effect of DNA methylation, histone acetylation, and other epigenetic modifications. Most reasearch points to an association between alcohol dependence and genes related with alcohol metabolism, with neurotransmission of dopamine, GABA, serotonin, glutamate, endogenous opioids, and cannabinoids, signal transduction within the mesolimbic dopamine reward system, and stress response system, among others. During pregnancy, there are several non-genetic factors that may have an important impact on vulnerability to alcohol dependence. Given that the Central Nervous System is developing throughout the entire pregnancy and that alcohol consumed by the mother can reach the fetus through the placental barrier, the brain of a baby is always vulnerable to harm caused by alcohol exposure. Children born to alcoholic mothers may inherit genetic susceptibility variants but at the same time they may be exposed to early effects of ethanol. Heavy alcohol exposure during pregnancy has been associated with mental retardation, epilepsy, attention deficit/ hyperactivity disorder, learning disabilities, and later on with substance abuse, anxiety, personality, affective and psychotic disorders, as well as with engagement in antisocial behaviors and school or work problems. Furthermore, it has been shown that animals exposed to prenatal stress exhibit persisting modifications related to dopamine and glutamate transmission in limbic structures associated with dependence to alcohol and other substances. These alterations may later contribute to increase motivation to drink, to use large amounts of drugs of abuse or to relapse after periods of drug withdrawal. It was shown that after exposure to prenatal stress, male mice consumed more ethanol during alcohol reinforcement in adulthood. In addition, it has been well documented that affective disorders are associated with alcohol dependence. A recent meta-analysis including 54 studies that together involved more than 40749 individuals, confirmed that the 5-HTTLPR polymorphism at the promoter of the serotonin transporter gene moderates the association between stress and depression, where the short allele is related with an increased risk for depression under stress (p = 0.00002). A strong association was detected when the stressful factor was childhood maltreatment (p = 0.00007). Childhood maltreatment, including neglect as well as physical and sexual abuse, is associated with developmental difficulties, low social competence and self-esteem, and it is an important risk factor for binge drinking in adolescence and alcohol dependence in adulthood. Childhood maltreatment may interact with factors such as variants of the monoamine oxidase-A and catechol-o-methyltransferase gene. Adolescence is a critical period for initiation of alcohol intake, experimentation, and establishment of regular drinking patterns. Substance use at this age is considered a risk factor for the development of later alcohol and other drug-related problems, as well as for externalizing disorders such as antisocial personality disorder. Alcohol use initiation is affected by environmental factors such as ethanol availability, parental attitudes, and peer pressure. It has been reported that heavy drinking during adolescence can have a negative impact on brain development. Moreover, dopaminergic and GABAergic systems undergo important changes during adolescence, and they can be affected by alcohol intake. Dopamine is implicated in the rewarding effects of ethanol, and GABA in its sedating effects and development of tolerance. The way an adult copes with environmental challenges is notably influenced by early life experiences and by the familial environment he or she had as an infant, which affects neurodevelopmental behavior. While environmental factors tend to have a crucial role in drinking habits in adolescence, adultood may be characterized by a weaker effect of environment and a higher effect of genetic components. It is probable that a complex set of gene-environment interactions determine the risk to alcohol dependence. Environmental factors that may affect this vulnerability appear at different stages from pregnancy to adulthood. These interactions are mediated by DNA methylation, histone modifications, protein complexes and non-protein-coding RNAs such as microRNAs.

La dependencia al alcohol es un problema mundial grave, que se asocia con mucho sufrimiento, problemas de salud mental y física, una elevada tasa de mortalidad y un costo social y familiar muy alto. Es por esto que las estrategias de prevención y el tratamiento de la enfermedad resultan cruciales. Se ha reportado que programas psicosociales y tratamientos farmacológicos son hasta cierto punto exitosos actualmente. Sin embargo, se requiere conocer más profundamente la etiología de la enfermedad. Por esta razón, es muy importante identificar los factores que se asocien con el incremento a la susceptibilidad en distintas poblaciones. Se ha demostrado claramente a través de estudios en gemelos y de adopción, así como por investigaciones en animales, que tanto factores genéticos como ambientales son relevantes en la dependencia al alcohol. Se ha estimado que la heredabilidad de esta enfermedad se encuentra entre 40 y 60%, dependiendo de la muestra estudiada, lo cual indica que el ambiente y la genética tienen un peso similar en la susceptibilidad. Muchas variantes genéticas que aumentan la susceptibilidad, en lugar de una sola, podrían coexistir en las personas más vulnerables a la dependencia. De manera similar, muchos factores ambientales parecen estar relacionados, los cuales, debido a su diversidad, intensidad y etapas de la vida en la que se presentan, no son exactamente iguales en diferentes personas con dependencia al etanol. La contribución ambiental podría relacionarse con cambios en la expresión de genes, lo cual involucra a la epigenética. Ésta se encarga del estudio de los procesos químicos, afectados por el ambiente, que pueden modificar la actividad de los genes sin cambiar la secuencia del ADN. En humanos, el proceso epigenético más estable es la unión de un grupo metilo (un átomo de carbón unido a tres átomos de hidrógeno) a las citosinas en el ADN. Otros mecanismos epigenéticos son modificaciones a proteínas nucleares llamadas histonas, proceso que modifica la manera en que se encuentra empaquetado el ADN. Por otra parte, ARNs que no codifican para proteína, como los microARNs, se han asociado al desarrollo de la dependencia al alcohol. Ciertos microARNs podrían funcionar como intermediarios epigenéticos, lo cual propiciaría que el etanol afectara procesos complejos y divergentes del neurodesarrollo, sumándose al efecto de la mutilación en el ADN y de la acetilación de histonas, entre otros procesos epigenéticos. La mayoría de las investigaciones señalan que los genes importantes en la vulnerabilidad a la dependencia al alcohol incluyen algunos que codifican para proteínas del metabolismo del alcohol; de neurotransmisión de dopamina, GABA, serotonina, glutamato, opiodes endógenos y canabinoides; de transducción de señal en el sistema de recompensa mosolímbico; y de respuesta al estrés, entre otros. Durante el embarazo, diversos factores no genéticos tienen un impacto importante en la vulnerabilidad a la dependencia al alcohol. Por ejemplo, debido a que el Sistema Nervioso se desarrolla a lo largo de toda la gestación y que el alcohol consumido por la madre puede llegar al feto a través de la barrera placentaria, el cerebro de un feto siempre es vulnerable al daño provocado por la exposición al etanol. Se ha demostrado que los hijos de mujeres alcohólicas no sólo pueden heredar variantes genéticas de riesgo sino que también pueden estar expuestos tempranamente a los efectos del alcohol consumido por sus madres. El consumo excesivo en el embarazo se ha asociado con retraso mental, epilepsia, déficit de atención/ hiperactividad, problemas de aprendizaje, y más adelante con abuso de sutancias, ansiedad y trastornos afectivos, de personalidad y psicóticos, así como con conductas antisociales y problemas en la escuela o el trabajo. Además, se ha demostrado que animales expuestos a estrés prenatal mostraban modificaciones persistentes relacionadas con la transmisión dopaminérgica y GABAérgica en estructuras límbicas que se relacionan con dependencia al alcohol y a otras drogas. Más adelante, estas alteraciones podrían contribuir a la motivación para beber, a utilizar mayores cantidades de alcohol u otras susancias de abuso o a la recaída después de periodos de abstinencia. Se encontró que ratones macho expuestos a estrés prenatal consumían más alcohol en la edad adulta. La depresión y el estrés se han asociado fuertemente con la dependencia al alcohol. Con un metaanálisis reciente en el que se incluyeron datos de 54 estudios en los que en conjunto se habían reclutado 40 749 personas, se confirmó que el polimorfismo 5-HTTLPR del promotor del gen que codifica para el transportador de serotonina modera la asociación entre el estrés y la depresión y el alelo corto (<

Em busca das origens desenvolvimentais dos transtornos mentais / Searching for the developmental origins of mental disorders

INTRODUÇÃO: A psicopatologia desenvolvimental é uma disciplina que integra perspectivas epidemiológicas, sociais, genéticas, desenvolvimentais e de psicopatologia para entender as origens e o curso dos transtornos mentais. Neste artigo, são discutidos abordagens e conceitos utilizados para compreender as origens desenvolvimentais dos transtornos mentais. RESULTADOS: A psicopatologia desenvolvimental entende que os transtornos mentais são possíveis desfechos do processo de desenvolvimento e são dependentes de influências sociais, genéticas e ambientais. Esses diversos fatores estão inter-relacionados de diferentes formas e em diferentes níveis, exercendo um efeito dimensional. São discutidos: a) abordagens para determinar causalidade entre eventos ambientais e transtornos mentais; b) a importância de entendimento dos mecanismos biológicos através dos quais fatores ambientais e genéticos atuam; c) fatores genéticos predizendo a exposição a estressores ambientais; e d) fatores genéticos moderando o efeito de estressores ambientais. CONCLUSÕES: As origens dos transtornos mentais podem ser iluminadas por dados de estudos que utilizam enfoques e conceitos complementares e que integrem influências sociais, genéticas, ambientais e desenvolvimentais.

INTRODUCTION: Developmental psychopathology is a discipline that integrates epidemiological, social, genetic, developmental, and psychopathological perspectives to understand the origins and courses of mental disorders. In the present paper, theoretical concepts and approaches applied with the purpose of understanding the developmental origins of mental disorders are discussed. RESULTS: According to developmental psychopathology, mental disorders are possible outcomes of the developmental process that depend upon social, genetic, and environmental influences. These factors are linked in different ways and levels, exerting a dimensional effect. The following factors are addressed: a) approaches to determine a causal effect between environmental factors and mental disorders; b) the importance of understanding biological mechanisms by which environmental and genetic factors exert their effect; c) genetic factors predicting the exposure to environmental stressors; d) genetic factors moderating the effect of environmental stressors. CONCLUSIONS: The origins of mental disorders can be clarified by data from studies that use complementary approaches and concepts, integrating social, genetic, environmental and developmental influences.