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Introduction Insomnia is highly prevalent among individuals with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the biological mechanisms shared between both conditions is still elusive. We aimed to investigate whether insomnia's genomic component is able to predict ADHD in childhood and adolescence. Methods A Brazilian sample of 259 ADHD probands and their biological parents were included in the study. Their genomic DNA genotypes were used to construct the polygenic risk score for insomnia (Insomnia PRS), using the largest GWAS summary statistics as a discovery sample. The association was tested using logistic regression, under a case-pseudocontrol design. Results Insomnia PRS was nominally associated with ADHD (OR = 1.228, p = 0.022), showing that the alleles that increase the risk for insomnia also increase the risk for ADHD. Discussion Our results suggest that genetic factors associated with insomnia may play a role in the ADHD genetic etiology, with both phenotypes likely to have a shared genetic mechanism.
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Childhood maltreatment correlates with attention-deficit/hyperactivity disorder (ADHD) in previous research. The interaction between ADHD genetic predisposition and maltreatment's impact on ADHD symptom risk remains unclear. We aimed to elucidate this relationship by examining the interplay between a polygenic score for ADHD (ADHD-PGS) and childhood maltreatment in predicting ADHD symptoms during young adulthood. Using data from the 2004 Pelotas (Brazil) birth cohort comprising 4231 participants, we analyzed gene-environment interaction (GxE) and correlation (rGE). We further explored rGE mechanisms through mediation models. ADHD symptoms were assessed at age 18 via self-report (Adult Self Report Scale - ASRS) and mother-reports (Strength and Difficulties Questionnaire - SDQ). The ADHD-PGS was derived from published ADHD GWAS meta-analysis. Physical and psychological child maltreatment was gauged using the Parent-Child Conflict Tactics Scale (CTSPC) at ages 6 and 11, with a mean score utilized as a variable. The ADHD-PGS exhibited associations with ADHD symptoms on both ASRS (ß = 0.53; 95% CI: 0.03; 1.03, p = 0.036), and SDQ (ß = 0.20; 95% CI: 0.08; 0.32, p = 0.001) scales. The total mean maltreatment score was associated with ADHD symptoms using both scales [(ßASRS = 0.51; 95% CI: 0.26;0.77) and (ßSDQ = 0.24; 95% CI: 0.18;0.29)]. The ADHD-PGS was associated with total mean maltreatment scores (ß = 0.09; 95% CI: 0.01; 0.17; p = 0.030). Approximately 47% of the total effect of ADHD-PGS on maltreatment was mediated by ADHD symptoms at age 6. No evidence supported gene-environment interaction in predicting ADHD symptoms. Our findings underscore the significant roles of genetics and childhood maltreatment as predictors for ADHD symptoms in adulthood, while also indicating a potential evocative mechanism through gene-environment correlation.
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OBJECTIVES: Vitamin D deficiency has been associated with psychiatric disorders and behavioral phenotypes such as Attention-Deficit/Hyperactivity Disorder (ADHD). Considering that vitamin D levels are polygenic, we aim to evaluate the overall effects of its genetic architecture on symptoms of inattention, hyperactivity, and impulsivity and on the serum levels of vitamin D in two independent samples of adults, as well as the specific effects of five relevant polymorphisms in vitamin D-related genes. METHODS: We evaluated 870 subjects from an ADHD sample (407 cases and 463 controls) and 319 subjects from an academic community (nutrigenetic sample). Vitamin D serum levels were obtained through Elisa test and genetic data by TaqMan™ allelic discrimination and Infinium PsychArray-24 BeadChip genotyping. Polygenic Scores (PGS) were calculated on PRSice2 based on the latest GWAS for Vitamin D and statistical analyses were conducted at Plink and SPSS software. RESULTS: Vitamin D PGSs were associated with inattention in the ADHD sample and with hyperactivity when inattention symptoms were included as covariates. In the nutrigenetic sample, CYP2R1 rs10741657 and DHCR7 rs12785878 were nominally associated with impulsivity and hyperactivity, respectively, and both with vitamin D levels. In the clinical sample, RXRG rs2134095 was associated with impulsivity. DISCUSSION: Our findings suggest a shared genetic architecture between vitamin D levels and ADHD symptoms, as evidenced by the associations observed with PGS and specific genes related to vitamin D levels. Interestingly, differential effects for vitamin D PGS were found in inattention and hyperactivity, which should be considered in further studies involving ADHD.
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SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus-Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs' regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p < 0.032). CART analysis showed that the combined effects of genotype GG in rs2144833 and CC in rs10129500 were associated with ADHD (OR = 1.78; CI95% = 1.24-2.55). The GTEx assigned the SNPs as eQTLs for genes in different tissues, including SERPINA6, and the look-up analysis revealed two SNPs associated with ADHD. These results suggest a shared genetic component between cortisol levels and ADHD. HPA dysregulation/altered stress response in ADHD might be mediated by upregulation of corticosteroid binding globulin (CBG, encoded by SERPINA6) expression.
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Transtorno do Deficit de Atenção com Hiperatividade , Transcortina , alfa 1-Antitripsina , Transtorno do Deficit de Atenção com Hiperatividade/genética , Brasil , Marcadores Genéticos , Genótipo , Humanos , Hidrocortisona/metabolismo , Polimorfismo de Nucleotídeo Único , Transcortina/genética , alfa 1-Antitripsina/genéticaRESUMO
Attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders (AD) frequently co-occur, increasing morbidity and challenging treatment. Caffeine is a central nervous system stimulant and acts in the brain through adenosine receptors, influencing attention, alertness, and anxiety. In the present study, we performed a gene-set analysis to verify if genes related to caffeine response are associated with anxiety disorders in 240 children and 406 adults with ADHD. We demonstrated an association between the gene-set with AD in children (P = 0.0054) and with the number of anxiety disorders in adults (P = 0.0197). In order to test if this effect is a result of anxiety in general or is related to AD comorbid with ADHD, we evaluated the association between caffeine gene-set with AD in an adult control sample. The gene-set was neither associated with the AD presence (P = 0.3008) nor with the number of AD (P = 0.5594) in this control sample. We also test this gene set with ADHD (n = 55,374) and AD (n = 18,186) GWAS summary statistics, and we did not observe significant results with ADHD (P = 0.5587) or AD (P = 0.3930). These findings suggest the caffeine-related genes play a role in the etiology of an anxiety disorder phenotype present in children and adults with ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Adulto , Ansiedade/epidemiologia , Ansiedade/genética , Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Cafeína/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Comorbidade , HumanosRESUMO
OBJECTIVES: To evaluate the shared genetic components, common pathways and causal relationship between ADHD and sleep-related phenotypes. METHODS: We used the largest genome-wide association summary statistics available for attention-deficit/hyperactivity disorder (ADHD) and various sleep-related phenotypes (insomnia, napping, daytime dozing, snoring, ease getting up, daytime sleepiness, sleep duration and chronotype). We estimated the genomic correlation using cross-trait linkage disequilibrium score regression (LDSR) and investigated the potential common mechanisms using gene-based cross-trait metanalyses and functional enrichment analyses. The causal effect was estimated using two-sample Mendelian randomisation (TSMR), using the inverse variance weighted method as the main estimator. RESULTS: A positive genomic correlation between insomnia, daytime napping, daytime dozing, snoring, daytime sleepiness, short and long sleep duration, and ADHD was observed. Insomnia, daytime sleepiness, and snoring shared genes with ADHD, that are involved in neurobiological functions and regulatory signalling pathways. The TSMR supported a causal effect of insomnia, daytime napping, and short sleep duration on ADHD, and of ADHD on long sleep duration and chronotype. CONCLUSION: Comorbidity between sleep phenotypes and ADHD may be mediated by common genetic factors that play an important role in neuronal signalling pathways. A causal effect of sleep disturbances and short sleep duration on ADHD reinforced their role as predictors of ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtornos do Sono-Vigília , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Comorbidade , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Fatores de Risco , Sono/genética , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/genéticaRESUMO
The association between obesity and attention-deficit hyperactivity disorder (ADHD) has been extensively reported in the literature. However, the potential mechanisms underlying this association are not completely understood. This study aimed to evaluate the association between body composition and ADHD and explore the possible genetic mechanisms involved. We used data from the 1982 Pelotas (Brazil) Birth Cohort at age 30-year follow-up (N = 3630). We first used logistic regression analysis to test whether body mass index (BMI), fat mass (FM), and fat-free mass (FFM) were associated with ADHD. We further tested the association between BMI polygenic risk score (BMI-PRS) and ADHD and the role of the genes upregulated in the reward system using a gene-set association approach. BMI (odds ratio [OR] = 1.05; 95% confidence interval [CI], 1.00-1.09; p = 0.038) and FM (OR = 1.04; 95% CI, 1.00-1.07; p = 0.043) were associated with ADHD. The BMI-PRS was associated with ADHD (using p-value threshold (PT) = 0.4; OR = 1.65; 95% CI, 1.02-2.65) at a nominal level. In gene-set analysis, the reward system genes were associated with BMI in subjects with a high BMI-PRS score, considering PT = 0.4 (p = 0.014). The results suggest that BMI genetic components, especially those genes related to the reward system, may be involved in this association.
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Transtorno do Deficit de Atenção com Hiperatividade , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Composição Corporal , Índice de Massa Corporal , Brasil , Humanos , Obesidade/epidemiologia , Obesidade/genética , Recompensa , Fatores de RiscoRESUMO
The gut microbiome is associated with psychiatric disorders; however, the molecular mechanisms mediating this association are poorly understood. The ability of host genetics to modulate the gut microbiome may be an important factor in understanding the association. In this study, we aimed to evaluate the role of genetic variants associated with the gut microbiome in the susceptibility of individuals to four psychiatric disorders: schizophrenia (SCZ), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and major depressive disorder (MDD). A total of 201 host genetic markers associated with microbiome outcomes and reported in available genome-wide association studies (GWAS) were included in the analyses. We searched for these variants in the summary statistics of the largest GWAS on these disorders to date, which were published by the Psychiatric Genomic Consortium, and performed gene-based and gene set association analyses. Two variants were significantly associated with ASD (rs9401458 and rs9401452) and one with MDD (rs75036654). For the gene-based association analysis, eight genes were associated with SCZ (ASIC2, KCND3, ITSN1, SIPA1L3, RBMS3, BANK1, CSMD1, and LHFPL3), one with MDD (ACTL8), two with ADHD (C14orf39 and FBXL17), and one with ASD (PINX). The gene set comprising 83 genes was associated with SCZ (p = 0.047). These findings suggest that genes related to microbiome composition may affect the susceptibility of individuals to psychiatric disorders, mainly schizophrenia. Although less robust, the associations with ASD, ADHD, and MDD cannot be discarded.
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Eixo Encéfalo-Intestino/fisiologia , Encéfalo/metabolismo , Bases de Dados Genéticas , Microbioma Gastrointestinal/fisiologia , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , Bases de Dados Genéticas/tendências , Marcadores Genéticos/genética , Humanos , Transtornos Mentais/diagnósticoRESUMO
Functional variants in genes of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems have already been implicated in blood pressure (BP) modulation, but few studies have focused on a nutrigenetics approach. Thus, the aim of this study is to verify the effects of the interaction between genetic polymorphisms (rs4340-ACE, rs699-AGT, and rs1799722-BDKRB2) and micronutrient consumption (sodium, potassium, calcium, and magnesium) on BP values of normotensive adult individuals. The study included 335 adults, men and women, 25.5 (6.6) years old. Biochemical, anthropometric, BP measurements, and food intake data were assessed for all participants. Gene-nutrient interaction on BP outcome was tested by multiple linear regression with manual backward stepwise modeling. Our results indicated that individuals with G allele for rs699 polymorphism, in the increase of sodium and magnesium consumption, both in the genotypic model (sodium, p = 0.035; magnesium, p = 0.016) and in the dominant model (sodium, p = 0.009; magnesium, p = 0.006) had higher systolic BP (SBP) levels compared to AA homozygotes (sodium, p = 0.001; magnesium, p < 0.001). Also, individuals with the T allele for the rs1799722 polymorphism, with higher calcium intake, had significantly higher levels of SBP and diastolic BP (DBP) when compared to CC homozygotes (p = 0.037). In conclusion, our findings pointed for significant interactions between genetic polymorphisms (rs699-AGT and rs1799722-BDKRB2) and the consumption of micronutrients (sodium, magnesium, and calcium) on the BP variation. These findings contribute to the understanding of the complex mechanisms involved in BP regulation, which probable include several gene-nutrition interactions.
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Angiotensinogênio/genética , Pressão Sanguínea , Dieta , Hipertensão/fisiopatologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Receptor B2 da Bradicinina/genética , Adulto , Cálcio/administração & dosagem , Estudos Transversais , Feminino , Humanos , Hipertensão/genética , Magnésio/administração & dosagem , Masculino , Potássio/administração & dosagem , Sódio/administração & dosagemRESUMO
Dentre os sistemas neurais responsáveis pela ingestão dos alimentos, destaca-se a via dopaminérgica mesolímbica que, através da liberação de dopamina nos núcleos de accumbens, desperta prazer e motivação para recompensas químicas e naturais. Esta via de recompensa age através dos receptores dopaminérgicos transmembranares, que variam de DRD1 a DRD5. Desta forma, considerando os efeitos prazerosos despertados pela ingestão alimentar, é plausível que variações genéticas em genes do sistema dopaminérgico possam ter um papel na arquitetura genética da obesidade. Este estudo tem como objetivo realizar uma revisão narrativa da literatura sobre a influência de variantes genéticas nos receptores dopaminérgicos em fenótipos relacionados com a obesidade. Em conjunto, os principais achados desta revisão indicaram que os genes codificadores dos receptores DRD2 e DRD4 possam ser os mais relevantes no contexto da obesidade e fenótipos relacionados. No entanto, a obesidade é uma doença complexa e multifatorial e novos estudos são ainda necessários para uma melhor compreensão do impacto da dopamina nos desfechos relacionado à obesidade. É importante também destacar que esses efeitos podem ser específicos para subgrupos de pacientes e que outros fatores, além das variantes genéticas, devem ser considerados. (AU)
Among the neural systems responsible for food ingestion, the mesolimbic dopaminergic pathway stands out by eliciting pleasure and motivation for chemical and natural rewards through the release of dopamine in the nucleus accumbens. This reward pathway is regulated by transmembrane dopaminergic receptors, which range from DRD1 to DRD5. Thus, considering the pleasurable effects aroused by food intake, it is plausible that genetic variations in genes of the dopaminergic system may have a role in the genetic architecture of obesity. This study aims to conduct a narrative review of the literature on the influence of genetic variants of dopaminergic receptors on obesity-related phenotypes. Taken together, the main findings of this review indicated that the genes encoding the DRD2 and DRD4 receptors may be the most relevant in the context of obesity and related phenotypes. However, obesity is a complex and multifactorial disease and new studies are still being conducted to better understand the impact of dopamine on obesity-related outcomes. It is also important to note that these effects can be specific to subgroups of patients and that other factors, in addition to genetic variants, must be considered. (AU)
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Dopamina , Receptores Dopaminérgicos , Comportamento Alimentar , Obesidade , Proteínas Serina-Treonina QuinasesRESUMO
OBJECTIVE: Genetic variants in the transcription factor 7-like 2 (TCF7L2) gene have been described as the most noteworthy ones regarding the type 2 diabetes mellitus (T2DM) liability. This work is aimed to evaluate the association between rs12255372 and rs7903146 polymorphisms and T2DM in patients with cardiovascular disease (CAD) risk. METHODS: A sample of six hundred and forty-seven patients that underwent the coronary angiography in a Cardiac Catheterization Lab was evaluated. The patients were investigated for the presence of T2DM and coronary stenosis. The TCF7L2 polymorphisms were genotyped by real-time PCR and the haplotype analysis was performed with the MLOCUS software. All genetic tests were carried out by considering the haplotype combinations in patients divided into three groups: 0 - carrying none disease risk allele, 1 - carrying one or two risk alleles and 2 - carrying three or four risk alleles. RESULTS: No significant associations between TCF7L2 risk haplotypes and the presence of T2DM or CAD were detected. CONCLUSIONS: Our results indicate that the TCF7L2 rs12255372 and rs7903146 polymorphisms do not influence T2DM in Brazilian patients with the high risk for CAD. Therefore, we assume that these variants may only be relevant for a specific subgroup of T2DM patients or some particular human population.
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Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Idoso , Brasil/epidemiologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The prevalence of anxiety disorders in patients with Attention Deficit/Hyperactivity Disorder (ADHD) is around 15-40%, three times higher than in the general population. The dopaminergic system, classically associated with ADHD, interacts directly with the adenosinergic system through adenosine A2A receptors (A2A) and dopamine D2 receptors (D2) forming A2A-D2 heterodimers. Both dopaminergic and adenosinergic systems are implicated in anxiety disorders. Therefore, the aims of this study were: a) to investigate the main effects of ADORA2A and DRD2 gene variants on anxiety disorders in an ADHD sample of children and adolescents; b) to test potential synergism between ADORA2A and DRD2 genes on the same outcome; c) to explore ADORA2A variants functionality using an in silico approach. The sample consists of 478 children and adolescents with ADHD and their parents, totalizing 1.239 individuals. An association between the ADORA2A rs2298383 TT genotype with the presence of anxiety disorders (Pâ¯=â¯.004) and an interaction between ADORA2A-DRD2 risk haplotypes with the same outcome (Pâ¯=â¯.005) was detected. The in silico analyses showed that rs2298383 has the highest score for regulatory function among all variants in the ADORA2A gene described up to date. Altogether, the present findings suggested that the ADORA2A gene and the interaction of ADORA2A and DRD2 genes may play a role in anxiety disorders in children and adolescents with ADHD.
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Transtornos de Ansiedade/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença/genética , Receptor A2A de Adenosina/genética , Receptores de Dopamina D2/genética , Adolescente , Transtornos de Ansiedade/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Criança , Feminino , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptor A2A de Adenosina/fisiologia , Receptores de Dopamina D2/fisiologiaRESUMO
BACKGROUND/OBJECTIVES: Attention-deficit hyperactivity disorder (ADHD), one of the most common neurodevelopmental disorders in childhood and adolescence, is associated with obesity in observational studies. However, it is unclear whether ADHD contributes to, results from or is merely correlated with obesity. This study evaluates the presence and direction of a causal effect between ADHD and obesity. SUBJECTS/METHODS: We performed a bidirectional two-sample Mendelian randomization using summary data from consortia of genome-wide association studies to investigate if ADHD (N = 55,374) has a causal effect on body mass index (BMI) in childhood (N = 35,668) and adulthood (N = 322,154-500,000), and vice-versa. The main analysis was performed using the inverse variance weighted (IVW) method. As sensitivity analyses, we used other Mendelian randomization methods that are more robust to horizontal pleiotropy (i.e., MR-Egger, weighted mode, and penalized weighted median estimators), as well as stratified the analysis by the putative mechanisms of genetic instruments (i.e., pathways involved or not in neurological processes). RESULTS: The IVW method indicated a positive causal effect of BMI on ADHD: ß = 0.324 (95% CI 0.198 to 0.449, p < 0.001; expressed as change in ln(odds ratio) of ADHD per each additional SD unit of BMI). IVW estimates were directionally consistent with other methods. On the other hand, we did not find consistent evidence for a causal effect of ADHD genetic liability on BMI. CONCLUSIONS: The results suggested that higher BMI increases the risk of developing ADHD, but not the other way around.
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Transtorno do Deficit de Atenção com Hiperatividade , Índice de Massa Corporal , Obesidade , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Pré-Escolar , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Obesidade/complicações , Obesidade/epidemiologia , População BrancaRESUMO
Circadian and sleep disorders, short sleep duration, and evening chronotype are often present in attention-deficit/hyperactivity disorder (ADHD). CLOCK, considered the master gene in the circadian rhythm, has been explored by few studies. Understanding the relationship between ADHD and CLOCK may provide additional information to understand the correlation between ADHD and sleep problems. In this study, we aimed to explore the association between ADHD and CLOCK, using several genetic markers to comprehensively cover the gene extension. A total of 259 ADHD children and their parents from a Brazilian clinical sample were genotyped for eight single nucleotide polymorphisms (SNPs) in the CLOCK locus. We tested the individual markers and the haplotype effects using binary logistic regression. Binary logistic and linear regressions considering ADHD symptoms among ADHD cases were conducted as secondary analysis. As main result, the analysis showed a risk effect of the G-A-T-G-G-C-G-A (rs534654, rs1801260, rs6855837, rs34897046, rs11931061, rs3817444, rs4864548, rs726967) haplotype on ADHD. A suggestive association between ADHD and rs534654 was observed. The results suggest that the genetic susceptibility to circadian rhythm attributed to the CLOCK gene may play an important role on ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteínas CLOCK/genética , Polimorfismo de Nucleotídeo Único , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Ritmo Circadiano , Feminino , Humanos , Masculino , SonoRESUMO
The circadian clock system drives daily rhythms in physiology, metabolism, and behavior in mammals. Molecular mechanisms of this system consist of multiple clock genes, with Circadian Locomotor Output Cycles Kaput (CLOCK) as a core member that plays an important role in a wide range of behaviors. Alterations in the CLOCK gene are associated with common psychiatric disorders as well as with circadian disturbances comorbidities. This review addresses animal, molecular, and genetic studies evaluating the role of the CLOCK gene on many psychiatric conditions, namely autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, anxiety disorder, and substance use disorder. Many animal experiments focusing on the effects of the Clock gene in behavior related to psychiatric conditions have shown consistent biological plausibility and promising findings. In humans, genetic and gene expression studies regarding disorder susceptibility, sleep disturbances related comorbidities, and response to pharmacological treatment, in general, are in agreement with animal studies. However, the number of controversial results is high. Literature suggests that the CLOCK gene exerts important influence on these conditions, and influences the susceptibility to phenotypes of psychiatric disorders.
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Proteínas CLOCK/genética , Transtornos Mentais/genética , Animais , Proteínas CLOCK/fisiologia , Relógios Circadianos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Transtornos Mentais/fisiopatologia , Modelos Animais , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: The 5-HTT gene contains polymorphisms in its promoter region, the insertion/deletion (5-HTTLPR) that creates long (L) or short (S) alleles (biallelic approach) and SNP (rs25531) in L allele (triallelic approach). OBJECTIVES: The aim of this study is to investigate the association of the 5-HTTLPR and rs25531 polymorphisms, using bi- and triallelic approach, with dietary intake and anthropometric parameters in children followed until 8 years old. METHODS: The sample were 303 children who were recruited at birth and examined at 1, 3 to 4 and 7 to 8 years old. The polymorphisms were analyzed by polymerase-chain-reaction-based methods. RESULTS: In the biallelic approach, children with the S/S genotype presented a higher body mass index Z-score in the three developmental stages and higher sum of skinfolds at 3 to 4 and 7 to 8 years old than carriers of the L allele. In the triallelic approach, S/S, Lg/S plus Lg/Lg genotypes were associated with higher energy intake daily at 1 year old and with waist circumference at 3 to 4 years old. CONCLUSIONS: In the biallelic approach, the 5-HTTLPR polymorphism is associated with food intake, body mass index Z-score and sum of skinfolds in children, reinforcing the role of the serotonin transporter in childhood obesity. Our data indicate that the biallelic approach is more sensible than the triallelic approach for detected associations with food intake and nutritional status in childhood. Identifying susceptibility genes in early life could provide the foundations for interventions in lifestyle to prevent children to become obese adults.
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Ingestão de Alimentos/genética , Estado Nutricional/genética , Polimorfismo de Nucleotídeo Único , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Alelos , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Much evidence suggests an association between vitamin D deficiency and chronic diseases such as obesity and dyslipidemia. Although genetic factors play an important role in the etiology of these diseases, only a few studies have investigated the relationship between vitamin D-related genes and anthropometric and lipid profiles. The aim of this study was to investigate the association of three vitamin D-related genes with anthropometric and lipid parameters in 542 adult individuals. We analyzed the rs2228570 polymorphism in the vitamin D receptor gene (VDR), rs2134095 in the retinoid X receptor gamma gene (RXRG) and rs7041 in the vitamin D-binding protein gene (GC). Polymorphisms were genotyped by TaqMan allelic discrimination. Gene-gene interactions were evaluated by the general linear model. The functionality of the polymorphisms was investigated using the following predictors and databases: SIFT (Sorting Intolerant from Tolerant), PolyPhen-2 (Polymorphism Phenotyping v2) and Human Splicing Finder 3. We identified a significant effect of the interaction between RXRG (rs2134095) and GC (rs7041) on low-density lipoprotein cholesterol (LDL-c) levels (P=.005). Furthermore, our in silico analysis suggested a functional role for both variants in the regulation of the gene products. Our results suggest that the vitamin D-related genes RXRG and GC affect LDL-c levels. These findings are in agreement with other studies that consistently associate vitamin D and lipid profile. Together, our results corroborate the idea that analyzing gene-gene interaction would be helpful to clarify the genetic component of lipid profile.
Assuntos
LDL-Colesterol/sangue , Predisposição Genética para Doença , Hipercolesterolemia/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Receptor X Retinoide gama/genética , Proteína de Ligação a Vitamina D/genética , Adolescente , Adulto , Alelos , Brasil , Biologia Computacional , Bases de Dados Genéticas , Sistemas Inteligentes , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Masculino , Receptores de Calcitriol/metabolismo , Receptor X Retinoide gama/metabolismo , Proteína de Ligação a Vitamina D/metabolismo , Adulto JovemRESUMO
Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. Recent studies suggest a role for γ-aminobutyric acid (GABA) on ADHD hyperactive/impulsive symptoms due to behavioral disinhibition resulting from inappropriate modulation of both glutamatergic and GABAergic signaling. The glutamic acid decarboxylase (GAD1) gene encodes a key enzyme of GABA biosynthesis. The aim of the present study was to investigate the possible influence of GAD1 SNPs rs3749034 and rs11542313 on ADHD susceptibility. The clinical sample consisted of 547 families with ADHD probands recruited at the ADHD Outpatient Clinics from Hospital de Clínicas de Porto Alegre. Hyperactive/impulsive symptoms were evaluated based on parent reports from the Swanson, Nolan, and Pelham Scale-version IV (SNAP-IV). The C allele of rs11542313 was significantly overtransmitted from parents to ADHD probands (P = 0.02). Hyperactive/impulsive score was higher in rs3749034G allele (P = 0.005, Cohen's D = 0.19) and rs11542313C allele (P = 0.03; Cohen's D = 0.16) carriers. GAD1 haplotypes were also associated with higher hyperactive/impulsive scores in ADHD youths (global P-value = 0.01). In the specific haplotype test, the GC haplotype was the one with the highest hyperactive/impulsive scores (P = 0.03). Our results suggest that the GAD1 gene is associated with ADHD susceptibility, contributing particularly to the hyperactive/impulsive symptom domain. © 2016 Wiley Periodicals, Inc.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Glutamato Descarboxilase/genética , Adolescente , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Criança , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Glutamato Descarboxilase/metabolismo , Haplótipos , Humanos , Hipercinese/genética , Hipercinese/psicologia , Comportamento Impulsivo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Conduct problems in childhood and adolescence are significant precursors of crime and violence in young adulthood. The purpose of the current study is to test the interaction between prenatal maternal smoking and COMT Val(158)Met in conduct problems and crime in the 1993 Pelotas Birth Cohort Study. Conduct problems were assessed through the parent version of the Strengths and Difficulties Questionnaire at ages 11 and 15 years. A translated version of a confidential self-report questionnaire was used to collect criminal data at 18 years of age. Negative binomial regression analyses showed an association between prenatal maternal smoking and SDQ conduct problem scores (IRR = 1.24; 95% CI: 1.14-1.34; p < 0.001) at 11 years of age. However, no evidence was found for an association between COMT genotypes and conduct scores or for an interaction between maternal smoking and this gene in predicting conduct problems. Very similar results were obtained using the 15 years conduct scores and crime measure at age 18. Prenatal maternal smoking was associated with crime (IRR = 1.28; 95% CI: 1.09-1.48; p = 0.002) but neither COMT genotypes nor the possible interaction between gene and maternal smoking were significantly associated with crime. Replications of GxE findings across different social contexts are critical for testing the robustness of findings.
Assuntos
Catecol O-Metiltransferase/genética , Crime , Efeitos Tardios da Exposição Pré-Natal/enzimologia , Efeitos Tardios da Exposição Pré-Natal/genética , Comportamento Problema , Fumar/efeitos adversos , Adolescente , Brasil , Estudos de Coortes , Demografia , Feminino , Humanos , Masculino , GravidezRESUMO
Several investigations documented that Attention-Deficit/Hyperactivity Disorder (ADHD) is better conceptualized as a dimensional disorder. At the same time, the disorder seems to have different neurobiological underpinnings and phenotypic presentation in children compared to adults. Neurodevelopmental genes could explain, at least partly these differences. The aim of the present study was to examine possible associations between polymorphisms in SNAP25, MAP1B and NOS1 genes and ADHD symptoms in Brazilian samples of children/adolescents and adults with ADHD. The youth sample consisted of 301 patients whereas the adult sample comprises 485 individuals with ADHD. Diagnoses of ADHD and comorbidities were based on the Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria. The Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV) was applied by psychiatrists blinded to genotype. The total SNAP-IV scores were compared between genotypes. Impulsivity SNAP-IV scores were also compared according to NOS1 genotypes. Adult patients homozygous for the C allele at SNAP25 rs8636 showed significantly higher total SNAP-IV scores (F = 11.215; adjusted P-value = 0.004). Impulsivity SNAP-IV scores were also significantly different according to NOS1 rs478597 polymorphisms in adults with ADHD (F = 6.282; adjusted P-value = 0.026). These associations were not observed in children and adolescents with ADHD. These results suggest that SNAP25 and NOS1 genotypes influence ADHD symptoms only in adults with ADHD. Our study corroborates previous evidences for differences in the genetic contribution to adult ADHD compared with childhood ADHD.