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1.
Am J Psychiatry ; 177(9): 811-817, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32867523

RESUMO

Causal pathways to disruptive behavior disorders, even within the same diagnostic category, are varied. Both equifinality and multifinality pose considerable challenges to uncovering underlying mechanisms and understanding varied developmental trajectories associated with disruptive behavior disorders. Uncovering genetic causes requires improved granularity in how we operationalize presentation and developmental trajectories associated with disruptive behavior disorders. If we want to integrate the study of genetic, environmental, and neurocognitive factors within a longitudinal framework, we need to improve measurement. Furthermore, brain changes associated with disruptive behavior disorders should not simply be understood as outcomes of genetic and environmental influences, but also as factors that reciprocally influence future social environments over time in ways that are important in contributing to risk and resilience. Advancing the field with regard to these challenges will result in more truly integrated investigation of disruptive behavior disorders, which holds the promise of improving our ability to develop more effective preventive and intervention approaches.


Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo , Encéfalo , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/etiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/prevenção & controle , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Interação Gene-Ambiente , Humanos , Comportamento Problema/psicologia , Psicologia do Desenvolvimento/métodos , Psicologia do Desenvolvimento/tendências , Psicopatologia , Fatores de Risco , Meio Social
2.
Am J Psychiatry ; 177(8): 671-685, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32741287

RESUMO

Major depressive disorder is a remarkably common and often severe psychiatric disorder associated with high levels of morbidity and mortality. Patients with major depression are prone to several comorbid psychiatric conditions, including posttraumatic stress disorder, anxiety disorders, obsessive-compulsive disorder, and substance use disorders, and medical conditions, including cardiovascular disease, diabetes, stroke, cancer, which, coupled with the risk of suicide, result in a shortened life expectancy. The goal of this review is to provide an overview of our current understanding of major depression, from pathophysiology to treatment. In spite of decades of research, relatively little is known about its pathogenesis, other than that risk is largely defined by a combination of ill-defined genetic and environmental factors. Although we know that female sex, a history of childhood maltreatment, and family history as well as more recent stressors are risk factors, precisely how these environmental influences interact with genetic vulnerability remains obscure. In recent years, considerable advances have been made in beginning to understand the genetic substrates that underlie disease vulnerability, and the interaction of genes, early-life adversity, and the epigenome in influencing gene expression is now being intensively studied. The role of inflammation and other immune system dysfunction in the pathogenesis of major depression is also being intensively investigated. Brain imaging studies have provided a firmer understanding of the circuitry involved in major depression, providing potential new therapeutic targets. Despite a broad armamentarium for major depression, including antidepressants, evidence-based psychotherapies, nonpharmacological somatic treatments, and a host of augmentation strategies, a sizable percentage of patients remain nonresponsive or poorly responsive to available treatments. Investigational agents with novel mechanisms of action are under active study. Personalized medicine in psychiatry provides the hope of escape from the current standard trial-and-error approach to treatment, moving to a more refined method that augurs a new era for patients and clinicians alike.


Assuntos
Transtorno Depressivo Maior , Gerenciamento Clínico , Comorbidade , Transtorno Depressivo Maior/etiologia , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/terapia , Interação Gene-Ambiente , Humanos , Neuroimagem/métodos , Medicina de Precisão/tendências , Fatores de Risco
3.
Nat Commun ; 11(1): 4019, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782255

RESUMO

Phenotypic plasticity, the ability of a genotype of producing different phenotypes when exposed to different environments, may impact ecological interactions. We study here how within-individual plasticity in Moricandia arvensis flowers modifies its pollination niche. During spring, this plant produces large, cross-shaped, UV-reflecting lilac flowers attracting mostly long-tongued large bees. However, unlike most co-occurring species, M. arvensis keeps flowering during the hot, dry summer due to its plasticity in key vegetative traits. Changes in temperature and photoperiod in summer trigger changes in gene expression and the production of small, rounded, UV-absorbing white flowers that attract a different assemblage of generalist pollinators. This shift in pollination niche potentially allows successful reproduction in harsh conditions, facilitating M. arvensis to face anthropogenic perturbations and climate change.


Assuntos
Adaptação Fisiológica , Ecossistema , Flores/fisiologia , Polinização , Animais , Abelhas , Brassicaceae/genética , Brassicaceae/fisiologia , Flores/genética , Regulação da Expressão Gênica de Plantas , Interação Gene-Ambiente , Estações do Ano
4.
PLoS One ; 15(7): e0236261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687510

RESUMO

Dietary and physical activity behaviors formed early in life can increase risk for childhood obesity and have continued negative consequences for lifelong health. Previous research has highlighted the importance of both genetic and environmental (e.g., cultural environment or parental lifestyle) contributions to obesity risk, although these studies typically involve genetically-related individuals residing in the same household, where genetic similarity and rearing environment are inextricably linked. Here we utilize a sibling-adoption design to independently estimate genetic and environmental contributions to obesity risk in childhood and describe how these influences might vary as children age. As part of a prospective adoption study, the current investigation used data from biological siblings reared either apart or together, and nonbiological siblings reared together to estimate the contributions of genetics and environment to body mass indices (BMI) in a large cohort of children (N = 711). We used a variance partitioning model to allocate variation in BMI to that which is due to shared genetics, common environment, or unique environment in this cohort during middle childhood and adolescence. We found 63% of the total variance in BMI could be attributed to heritable factors in middle childhood sibling pairs (age 5-11.99; 95% CI [0.41,0.85]). Additionally, we observed that common environment explained 31% of variation in BMI in this group (95% CI [0.11,0.5]), with unique environment and error explaining the remaining variance. We failed to detect an influence of genetics or common environment in older sibling pairs (12-18) or pairs spanning childhood and adolescence (large sibling age difference), but home type (adoptive versus birth) was an important predictor of BMI in adolescence. The presence of strong common environment effects during childhood suggests that early interventions at the family level in middle childhood could be effective in mitigating obesity risk in later childhood and adolescence.


Assuntos
Adoção , Índice de Massa Corporal , Interação Gene-Ambiente , Obesidade Pediátrica/epidemiologia , Irmãos , Adolescente , Criança , Desenvolvimento Infantil/fisiologia , Educação Infantil , Pré-Escolar , Feminino , Humanos , Masculino , Obesidade Pediátrica/genética , Obesidade Pediátrica/fisiopatologia , Obesidade Pediátrica/prevenção & controle , Estudos Prospectivos
5.
PLoS One ; 15(7): e0236571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730284

RESUMO

The occurrence of genotype by environment interaction (G x E), which is defined as the differential response of genotypes to environmental variation, is frequently reported in maize cultures, making it challenging to recommend cultivars. Methods allowing to study the potential nonlinear pattern of genotype responses to environmental variation allied to prior beliefs on unknown parameters are interesting to evaluate the phenotypic adaptability and stability of genotypes. In this context, the present study aimed to assess the adaptability and stability of maize hybrids, by using the Bayesian segmented regression model, and evaluate the efficacy of using informative and minimally informative prior distributions for the selection of cultivars. Randomized complete-block design experiments were carried out to study the yield (kg/ha) of 25 maize hybrids, in 22 different environments, in Northeastern Brazil. The Bayesian segmented regression model fitted using informative prior distributions presented lower credibility intervals and Deviance Criterium of Information values, compared to those obtained by fitting using minimally informative distributions. Therefore, the model using informative prior distributions was considered for the adaptability and stability evaluation of maize genotypes. Once most northeastern farmers in Brazil have limited capital, the genotype P4285HX should be considered for planting, due to its high yield performance and adaptability to unfavorable environments.


Assuntos
Modelos Genéticos , Zea mays/genética , Adaptação Fisiológica/genética , Teorema de Bayes , Interação Gene-Ambiente , Genótipo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Zea mays/crescimento & desenvolvimento , Zea mays/metabolismo
6.
Gene ; 757: 144933, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640302

RESUMO

OBJECTIVES: To study associations candidate genes for age at menarche with a risk of endometrial hyperplasia (EH). METHODS: 52 candidate loci for age at menarche were analyzed for possible association with EH in a sample of 520 patients and 981 controls. Association of the polymorphisms was analyzed using the method of logistic regression. The gene-gene and gene-environment interactions were analyzed using MB-MDR. 21 polymorphisms, which were associated with EH, and 397 polymorphisms linked to them (r2 ≥ 0.8) were analyzed in silico for their functional significance. RESULTS: 21 out of the 52 studied polymorphisms had association with EH. Locus rs11031010 FSHB was individually associated with the disease according to the dominant (OR = 0.62, pperm = 0.001) and additive (OR = 0.67, pperm = 0.002) models. Haplotype GAA of loci rs555621-rs11031010-rs1782507 FSHB were associated with the EH (OR = 0.66, pperm = 0.007). Seventeen loci were associated with EH within 12 most significant models of intergenic interactions (pperm ≤ 0.001). Locus rs4374421 of the LHCGR gene appeared in the largest number of models (four models). Nine loci involved in 14 most significant models of interactions between SNP, induced abortions, and chronic endometritis were associated with EH. The polymorphisms of genes FTO (rs12324955) and FSHB (rs11031010) appeared in the largest number of the models (9 and 6, respectively). Among the 21 loci associated with EH, 16 manifested association also with either age at menarche (7 SNPs) or height and/or BMI (13 SNPs). The above 21 SNPs and 397 SNPs linked to them have non-synonymous, regulatory and eQTL significance for 25 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling (FDR ≤ 0.05). CONCLUSIONS: Candidate genes for age at menarche are associated with endometrial hyperplasia.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Hiperplasia Endometrial/genética , Subunidade beta do Hormônio Folículoestimulante/genética , Polimorfismo de Nucleotídeo Único , Receptores do LH/genética , Adulto , Feminino , Interação Gene-Ambiente , Humanos , Menarca/genética , Pessoa de Meia-Idade
7.
Medicine (Baltimore) ; 99(29): e21045, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702845

RESUMO

BACKGROUND: Previous meta-analyses have explored the association between the C677T polymorphism of methyltetrahydrofolate reductase (MTHFR) and chronic kidney disease (CKD) but there were no studies with a decisive conclusion. Furthermore, the high heterogeneity among different populations is not yet interpreted. OBJECTIVES: This study used trial sequential analysis (TSA) to evaluate whether the nowadays conclusion supported by current cumulative samples. We also applied case-weighted meta-regression to explore the potential gene-environment interactions. METHODS: For the first stage of this study we conducted a case-control study involving 847 dialysis patients from 7 hemodialysis centers in Taipei during 2015 to 2018 and 755 normal controls from a health center in the Tri-Service General Hospital. The second stage combined the results from the first stage with previous studies. The previous studies were collected from PubMed, EMBASE, and Web of Science databases before January 2018. RESULTS: From the case-control study, the T allele of MTHFR C677T appeared to have a protective effect on end-stage renal disease compared with the C allele [odds ratio (OR): 0.80, 95% CI (confidence interval) = 0.69-0.93]. However, the meta-analysis contradicted the results in Asian (OR = 1.12, 95% CI = 0.96-1.30). The same analysis was also applied in Caucasian and presented similar results from Asian (OR = 1.18, 95% CI = 0.98-1.42). The TSA showed our case-control study to be the decisive sample leading to a null association among Asian population. The high heterogeneity (I = 75%) could explain the contradictory results between the case-control study and the meta-analysis. However, further case-weighted meta-regression did not find any significant interaction between measured factors and MTHFR C677T on CKD. CONCLUSIONS: High heterogeneities were found in both Caucasian and Asian, which caused the null relationship in meta-analysis while there were significant effects in individual studies. Future studies should further explore the high heterogeneity that might be hidden in unmeasured gene-environment interactions, to explain the diverse findings among different populations.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Masculino , Taiwan
8.
BMC Bioinformatics ; 21(1): 251, 2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552674

RESUMO

BACKGROUND: Models including an interaction term and performing a joint test of SNP and/or interaction effect are often used to discover Gene-Environment (GxE) interactions. When the environmental exposure is a binary variable, analyses from exposure-stratified models which consist of estimating genetic effect in unexposed and exposed individuals separately can be of interest. In large-scale consortia focusing on GxE interactions in which only the joint test has been performed, it may be challenging to get summary statistics from both exposure-stratified and marginal (i.e not accounting for interaction) models. RESULTS: In this work, we developed a simple framework to estimate summary statistics in each stratum of a binary exposure and in the marginal model using summary statistics from the "joint" model. We performed simulation studies to assess our estimators' accuracy and examined potential sources of bias, such as correlation between genotype and exposure and differing phenotypic variances within exposure strata. Results from these simulations highlight the high theoretical accuracy of our estimators and yield insights into the impact of potential sources of bias. We then applied our methods to real data and demonstrate our estimators' retained accuracy after filtering SNPs by sample size to mitigate potential bias. CONCLUSIONS: These analyses demonstrated the accuracy of our method in estimating both stratified and marginal summary statistics from a joint model of gene-environment interaction. In addition to facilitating the interpretation of GxE screenings, this work could be used to guide further functional analyses. We provide a user-friendly Python script to apply this strategy to real datasets. The Python script and documentation are available at https://gitlab.pasteur.fr/statistical-genetics/j2s.


Assuntos
Interação Gene-Ambiente , Articulações/fisiologia , Humanos , Modelos Genéticos
10.
PLoS One ; 15(6): e0233847, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559184

RESUMO

In the area of genetic epidemiology, studies of the genotype-phenotype associations have made significant contributions to human complicated trait genetics. These studies depend on specialized statistical methods for uncover the association between traits and genetic variants, both common and rare variants. Often, in analyzing such studies, potentially confounding factors, such as social and environmental conditions, are required to be involved. Multiple linear regression is the most widely used type of regression analysis when the outcome of interest is quantitative traits. Many statistical tests for identifying genotype-phenotype associations using linear regression rely on the assumption that the traits (or the residuals) of the regression follow a normal distribution. In genomic research, the rank-based inverse normal transformation (INT) is one of the most popular approaches to reach normally distributed traits (or normally distributed residuals). Many researchers believe that applying the INT to the non-normality of the traits (or the non-normality of the residuals) is required for valid inference, because the phenotypic (or residual) outliers and non-normality have the significant influence on both the type I error rate control and statistical power, especially under the situation in rare-variant association testing procedures. Here we propose a test for exploring the association of the rare variant with the quantitative trait by using a fully adjusted full-stage INT. Using simulations we show that the fully adjusted full-stage INT is more appropriate than the existing INT methods, such as the fully adjusted two-stage INT and the INT-based omnibus test, in testing genotype-phenotype associations with rare variants, especially when genotypes are uncorrelated with covariates. The fully adjusted full-stage INT retains the advantages of the fully adjusted two-stage INT and ameliorates the problems of the fully adjusted two-stage INT for analysis of rare variants under non-normality of the trait. We also present theoretical results on these desirable properties. In addition, the two available methods with non-normal traits, the quantile/median regression method and the Yeo-Johnson power transformation, are also included in simulations for comparison with these desirable properties.


Assuntos
Interação Gene-Ambiente , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Humanos , Distribuição Normal , Polimorfismo Genético
11.
Presse Med ; 49(2): 103909, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32563946

RESUMO

Interstitial lung disease (ILD) in children (chILD) is a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and the diseases share common features of inflammatory and fibrotic changes of the lung parenchyma that impair gas exchanges. The etiologies of chILD are numerous. In this review, we chose to classify them as ILD related to exposure/environment insults, ILD related to systemic and immunological diseases, ILD related to primary lung parenchyma dysfunctions and ILD specific to infancy. A growing part of the etiologic spectrum of chILD is being attributed to molecular defects. Currently, the main genetic mutations associated with chILD are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3 and NKX2-1. Other genetic contributors include mutations in MARS, CSF2RA and CSF2RB in pulmonary alveolar proteinosis, and mutations in TMEM173 and COPA in specific auto-inflammatory forms of chILD. However, only few genotype-phenotype correlations could be identified so far. Herein, information is provided about the clinical presentation and the diagnosis approach of chILD. Despite improvements in patient management, the therapeutic strategies are still relying mostly on corticosteroids although specific therapies are emerging. Larger longitudinal cohorts of patients are being gathered through ongoing international collaborations to improve disease knowledge and targeted therapies. Thus, it is expected that children with ILD will be able to reach the adulthood transition in a better condition.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Fatores Etários , Criança , Doença Crônica , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Exposição Ambiental/efeitos adversos , Interação Gene-Ambiente , Genótipo , Humanos , Doenças do Sistema Imunitário/complicações , Lactente , Recém-Nascido , Doenças Pulmonares Intersticiais/classificação , Doenças Pulmonares Intersticiais/tratamento farmacológico , Fenótipo , Proteinose Alveolar Pulmonar/genética , Transtornos Respiratórios/complicações , Sistema Respiratório/patologia , Esteroides/uso terapêutico
12.
Phys Rev Lett ; 124(21): 218101, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32530655

RESUMO

The evolution of high-dimensional phenotypes is investigated using a statistical physics model consisting of interacting spins, in which phenotypes, genotypes, and environments are represented by spin configurations, interaction matrices, and external fields, respectively. We found that phenotypic changes upon diverse environmental change and genetic variation are highly correlated across all spins, consistent with recent experimental observations of biological systems. The dimension reduction in phenotypic changes is shown to be a result of the evolution of the robustness to thermal noise, achieved at the replica symmetric phase.


Assuntos
Evolução Biológica , Evolução Molecular , Modelos Genéticos , Mutação , Interação Gene-Ambiente , Aptidão Genética , Variação Genética , Processos Estocásticos
13.
PLoS One ; 15(6): e0234008, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530950

RESUMO

Urbanization fragments landscapes and can impede the movement of organisms through their environment, which can decrease population connectivity. Reduction in connectivity influences gene flow and allele frequencies, and can lead to a reduction in genetic diversity and the fixation of certain alleles, with potential negative effects for populations. Previous studies have detected effects of urbanization on genetic diversity and structure in terrestrial animals living in landscapes that vary in their degree of urbanization, even over very short distances. We investigated the effects of low-intensity urbanization on genetic diversity and genetic structure in Song Sparrows (Melospiza melodia). We captured 208 Song Sparrows at seven sites along a gradient of urbanization in and around Blacksburg, VA, USA, then genotyped them using a panel of fifteen polymorphic microsatellite loci. We found that genetic diversity was comparable among the seven study sites, and there was no evidence of genetic structuring among sites. These findings suggest that over a gradient of urbanization characterized by low density urban development, Song Sparrows likely exist in a single panmictic population.


Assuntos
Interação Gene-Ambiente , Variação Genética , Pardais/genética , Animais , Fluxo Gênico , Frequência do Gene , Repetições de Microssatélites , Urbanização
14.
Sci Total Environ ; 734: 139341, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32473450

RESUMO

Originating from a long history of competition between microbes, antibiotic resistance is a serious global health concern. To avoid the risk of antibiotic resistance, tremendous efforts have been directed towards restricting antibiotic consumption worldwide, but to date with limited success. Resistance is governed by multiple pressures from natural and anthropogenic origins which further create problems with control. This study identifies a chain of links from antibiotic resistant genes (ARGs) to microbial communities to environmental pressures in the surface sediments of forty-two lake clusters across the 1000-km Yangtze Basin of China, and attempts to expound on a control pathway for this resistance risk. Results show that eleven of the 670 bacterial families can be classified as antibiotic-resistant or nonresistant communities which antagonize each other. In natural systems, antagonistic competition controls the increase and decrease in ARGs. Superiority of antibiotic-resistant strains initiates a loss in microbial diversity associated with the prevalence of resistance risk. This study shows that, antibiotics shape the evolution of ARGs in resistant communities through a nonlinear role of orientor; other selected pressures serve as a facilitator to enhance the antibiotic resistance through an investigated chain of links. Furthermore, according to tolerances of the classified communities, abiogenetic development through temperature, salinity and Mg were identified and selected for study from seventy lake parameters. Linear feedbacks to selected pressures make the nonresistant communities outcompete the resistant communities, theoretically modulating the risk of antibiotic resistance.


Assuntos
Interação Gene-Ambiente , Sedimentos Geológicos , Antibacterianos , China , Resistência Microbiana a Medicamentos , Genes Bacterianos
15.
Nutr Metab Cardiovasc Dis ; 30(6): 948-959, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32402589

RESUMO

BACKGROUND AND AIMS: Fat mass and obesity-associated protein (FTO) variants are among genetic variants frequently associated with obesity. We analyzed the association between FTO rs1421085 polymorphism and obesity, dietary intake, cardiorespiratory fitness (CRF), physical activity, and socioeconomic status (SES) from the age of 9-25 years. METHODS AND RESULTS: The sample included both birth cohorts (originally n = 1176) of the Estonian Children Personality Behaviour and Health Study. The association between FTO rs1421085 and obesity, dietary intake, CRF, physical activity, and SES from the age of 15-25 years was assessed using linear mixed-effects regression models. Associations at ages 9 (younger cohort only), 15, 18, and 25 years were assessed by one-way ANOVA. Male C-allele carriers had significantly (p < 0.05) higher body mass index (BMI), sum of 5 skinfolds, body fat percentage, and hip circumference from the age of 15-25 years. Findings were similar at the age of 9 years. In female subjects, waist-to-hip ratio was significantly greater in CC homozygotes. Interestingly, female CC homozygotes had a greater decrease in the rate of change in daily energy intake and lipid intake per year and higher physical activity score at every fixed time point. Moreover, in females, an effect of FTO × SES interaction on measures of obesity was observed. CONCLUSION: The FTO rs1421085 polymorphism was associated with obesity and abdominal obesity from childhood to young adulthood in males, and with abdominal obesity from adolescence to young adulthood in females. This association is rather related to differences in adipocyte energy metabolism than lifestyle.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dieta/efeitos adversos , Metabolismo Energético/genética , Exercício Físico , Obesidade Abdominal/genética , Obesidade Pediátrica/genética , Polimorfismo de Nucleotídeo Único , Comportamento Sedentário , Determinantes Sociais da Saúde , Fatores Socioeconômicos , Adolescente , Adulto , Fatores Etários , Criança , Estônia/epidemiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Masculino , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/epidemiologia , Obesidade Abdominal/metabolismo , Obesidade Pediátrica/diagnóstico , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/metabolismo , Medição de Risco , Fatores de Risco , Fatores Sexuais , Adulto Jovem
16.
Nutr Metab Cardiovasc Dis ; 30(6): 939-947, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32404292

RESUMO

BACKGROUND AND AIMS: Elevated homocysteine concentration is associated with a higher risk of cardiovascular disease. The aim of our study was to determine the environmental and genetic factors associated with serum homocysteine concentration in healthy young adults. Moreover, we aimed to determine the cutoff value of homocysteine concentration for predicting unfavorable MTHFR genotype and to investigate whether this association is modified by dietary patterns and serum folate status. METHODS AND RESULTS: A total of 744 healthy individuals, aged 18-35 years, were included in the study. Diet quality was assessed by establishing diet quality scores and adherence to the pro-Healthy Diet Index (pHDI) and non-Healthy Diet Index (nHDI). Genotyping was performed using the TaqMan method. Multivariate analysis showed that pHDI, creatinine, folate concentrations, and the T/T genotype of the C677T polymorphism in MTHFR, as well as the interaction between the T/T genotype of MTHFR (C677T polymorphism) and folate level, were most strongly related to homocysteine concentrations. The specificity of a homocysteine >13.1 µmol/l in predicting T/T homozygous status was 76% (area under the curve 0.68). CONCLUSION: Healthy dietary patterns, folate, and creatinine levels, as well as the C677T polymorphism, proved to be the strongest predictors of homocysteine concentrations. T/T genotype of MTHFR modifies the relationship between folate and homocysteine.


Assuntos
Dieta Saudável , Comportamento Alimentar , Interação Gene-Ambiente , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Adolescente , Adulto , Fatores Etários , Biomarcadores/sangue , Creatinina/sangue , Feminino , Ácido Fólico/sangue , Voluntários Saudáveis , Humanos , Masculino , Adulto Jovem
17.
Toxicology ; 441: 152505, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32450112

RESUMO

The majority of single nucleotide variants (SNVs) identified in Genome Wide Association Studies (GWAS) fall within non-protein coding DNA and have the potential to alter gene expression. Non-protein coding DNA can control gene expression by acting as transcription factor (TF) binding sites or by regulating the organization of DNA into chromatin. SNVs in non-coding DNA sequences can disrupt TF binding and chromatin structure and this can result in pathology. Further, environmental health studies have shown that exposure to xenobiotics can disrupt the ability of TFs to regulate entire gene networks and result in pathology. However, there is a large amount of interindividual variability in exposure-linked health outcomes. One explanation for this heterogeneity is that genetic variation and exposure combine to disrupt gene regulation, and this eventually manifests in disease. Many resources exist that annotate common variants from GWAS and combine them with conservation, functional genomics, and TF binding data. These annotation tools provide clues regarding the biological implications of an SNV, as well as lead to the generation of hypotheses regarding potentially disrupted target genes, epigenetic markers, pathways, and cell types. Collectively this information can be used to predict how SNVs can alter an individual's response to exposure and disease risk. A basic understanding of the regulatory information contained within non-protein coding DNA is needed to predict the biological consequences of SNVs, and to determine how these SNVs impact exposure-related disease. We hope that this review will aid in the characterization of disease-associated genetic variation in the non-protein coding genome.


Assuntos
Interação Gene-Ambiente , Variação Genética , Genômica/métodos , Regiões não Traduzidas , Animais , Expressão Gênica , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Regiões não Traduzidas/efeitos dos fármacos
18.
PLoS Genet ; 16(5): e1008749, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453742

RESUMO

Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.


Assuntos
Metilação de DNA , Grupos Étnicos/genética , Interação Gene-Ambiente , Transcriptoma , Ilhas de CpG , Meio Ambiente , Epigênese Genética/fisiologia , Grupos Étnicos/estatística & dados numéricos , Perfilação da Expressão Gênica/estatística & dados numéricos , Genética Populacional , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genômica/métodos , Humanos , Indonésia/epidemiologia , Ilhas/epidemiologia , Ilhas do Pacífico/epidemiologia , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA-Seq
19.
Mol Genet Genomics ; 295(4): 1013-1026, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32363570

RESUMO

Obesity, a risk factor for multiple diseases (e.g. diabetes, hypertension, cancers) originates through complex interactions between genes and prevailing environment (food habit and lifestyle) that varies across populations. Indians exhibit a unique obesity phenotype with high abdominal adiposity for a given body weight compared to matched white populations suggesting presence of population-specific genetic and environmental factors influencing obesity. However, Indian population-specific genetic contributors for obesity have not been explored yet. Therefore, to identify potential genetic contributors, we performed a two-staged genome-wide association study (GWAS) for body mass index (BMI), a common measure to evaluate obesity in 5973 Indian adults and the lead findings were further replicated in 1286 Indian adolescents. Our study revealed novel association of variants-rs6913677 in BAI3 gene (p = 1.08 × 10-8) and rs2078267 in SLC22A11 gene (p = 4.62 × 10-8) at GWAS significance, and of rs8100011 in ZNF45 gene (p = 1.04 × 10-7) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped genetic data of identified signals with their DNA methylation patterns in 236 Indian individuals and performed methylation quantitative trait loci (meth-QTL) analysis. Further, functional roles of discovered variants and underlying genes were speculated using publicly available gene regulatory databases (ENCODE, JASPAR, GeneHancer, GTEx). The identified variants in BAI3 and SLC22A11 genes were found to dictate methylation patterns at unique CpGs harboring critical cis-regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were located in repressive chromatin, active enhancer, and active chromatin regions, respectively, in human subcutaneous adipose tissue in ENCODE database. Additionally, these genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, GTEx portal identify rs8100011 as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue (p = 1.6 × 10-7), and ZNF45 gene expression in skeletal muscle of Indian subjects showed an inverse correlation with BMI indicating its possible role in obesity. In conclusion, our study discovered 3 novel population-specific functional genetic variants (rs6913677, rs2078267, rs8100011) in 2 novel (SLC22A11 and ZNF45) and 1 earlier reported gene (BAI3) for BMI in Indians. Our study decodes key genomic loci underlying obesity phenotype in Indians that may serve as prospective drug targets in future.


Assuntos
Estudo de Associação Genômica Ampla , Fatores de Transcrição Kruppel-Like/genética , Obesidade/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Índice de Massa Corporal , Metilação de DNA , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Índios Norte-Americanos/genética , Masculino , Obesidade/patologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Adulto Jovem
20.
Nat Commun ; 11(1): 2316, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385268

RESUMO

Our early-life environment has a profound influence on developing organs that impacts metabolic function and determines disease susceptibility across the life-course. Using a rat model for exposure to an endocrine disrupting chemical (EDC), we show that early-life chemical exposure causes metabolic dysfunction in adulthood and reprograms histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature. This epigenomic reprogramming persists long after the initial exposure, but many reprogrammed genes remain transcriptionally silent with their impact on metabolism not revealed until a later life exposure to a Western-style diet. Diet-dependent metabolic disruption was largely driven by reprogramming of the Early Growth Response 1 (EGR1) transcriptome and production of metabolites in pathways linked to cholesterol, lipid and one-carbon metabolism. These findings demonstrate the importance of epigenome:environment interactions, which early in life accelerate epigenomic aging, and later in adulthood unlock metabolically restricted epigenetic reprogramming to drive metabolic dysfunction.


Assuntos
Epigenoma/genética , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Disruptores Endócrinos/toxicidade , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Masculino , Ratos
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