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1.
Environ Int ; 157: 106864, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34537521

RESUMO

BACKGROUND: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-ß (Aß) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of Aß42, Aß40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO2,) and particulate matter (PM2.5, PM2.5 abs, PM10). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF Aß status and APOE-ε4 carriership was also assessed. RESULTS: A consistent pattern of results indicated that greater exposure to NO2 and PM2.5 absorbance was associated with higher levels of brain Aß deposition, while greater exposure to PM10 and PM2.5was associated with higher levels of CSF NfL. Most associations were driven by individuals that were Aß-positive. Although APOE-ε4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-ε4 carriers. CONCLUSION: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD.


Assuntos
Poluição do Ar , Doença de Alzheimer , Adulto , Poluição do Ar/efeitos adversos , Peptídeos beta-Amiloides , Biomarcadores , Humanos , Proteínas tau
2.
Autism Res ; 14(10): 2085-2099, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34309210

RESUMO

Autism spectrum disorders (ASD) are associated with widespread brain alterations. Previous research in our group linked autistic traits with altered gyrification, but without pronounced differences in cortical thickness. Herein, we aim to replicate and extend these findings using a larger and older sample. Additionally, we examined whether (a) brain correlates of autistic traits were associated with polygenic risk scores (PRS) for ASD, and (b) autistic traits are related with brain morphological changes over time in a subset of children with longitudinal data available. The sample included 2400 children from the Generation R cohort. Autistic traits were measured using the Social Responsiveness Scale (SRS) at age 6 years. Gyrification, cortical thickness, surface area, and global morphological measures were obtained from high-resolution structural MRI scans at ages 9-to-12 years. We performed multiple linear regression analyses on a vertex-wise level. Corresponding regions of interest were tested for association with PRS. Results showed that autistic traits were related to (a) lower gyrification in the lateral occipital and the superior and inferior parietal lobes, (b) lower cortical thickness in the superior frontal region, and (c) lower surface area in inferior temporal and rostral middle frontal regions. PRS for ASD and longitudinal analyses showed significant associations that did not survive correction for multiple testing. Our findings support stability in the relationship between higher autistic symptoms and lower gyrification and smaller surface areas in school-aged children. These relationships remained when excluding ASD cases, providing neurobiological evidence for the extension of autistic traits into the general population. LAY SUMMARY: We found that school-aged children with higher levels of autistic traits had smaller total brain volume, cerebellum, cortical thickness, and surface area. Further, we also found differences in the folding patterns of the brain (gyrification). Overall, genetic susceptibility for autism spectrum disorders was not related to these brain regions suggesting that other factors could be involved in their origin. These results remained significant when excluding children with a diagnosis of ASD, providing support for the extension of the relationship between autistic traits and brain findings into the general population.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/genética , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/genética , Encéfalo/diagnóstico por imagem , Criança , Humanos , Imageamento por Ressonância Magnética , Neuroimagem
3.
Eur J Epidemiol ; 36(10): 993-1004, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34046850

RESUMO

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Narcóticos/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Espectro Autista/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Atenção , Transtorno do Espectro Autista/epidemiologia , Desenvolvimento Infantil , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia
4.
Mol Psychiatry ; 26(6): 1832-1845, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33414500

RESUMO

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.


Assuntos
Metilação de DNA , Epigenoma , Ansiedade/genética , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica , Feminino , Humanos , Gravidez
5.
Mol Psychiatry ; 26(6): 2148-2162, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33420481

RESUMO

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.


Assuntos
Metilação de DNA , Epigenoma , Adolescente , Adulto , Idoso , Agressão , Criança , Pré-Escolar , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Longevidade , Pessoa de Meia-Idade , Adulto Jovem
6.
Transl Psychiatry ; 10(1): 398, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184255

RESUMO

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Metilação de DNA , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Pré-Escolar , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Gravidez , Estudos Prospectivos , Instituições Acadêmicas
7.
Psychol Med ; : 1-9, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924895

RESUMO

BACKGROUND: Attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are child-onset neurodevelopmental disorders frequently accompanied by cognitive difficulties. In the current study, we aim to examine the genetic overlap between ADHD and ASD and cognitive measures of working memory (WM) and attention performance among schoolchildren using a polygenic risk approach. METHODS: A total of 1667 children from a population-based cohort aged 7-11 years with data available on genetics and cognition were included in the analyses. Polygenic risk scores (PRS) were calculated for ADHD and ASD using results from the largest GWAS to date (N = 55 374 and N = 46 351, respectively). The cognitive outcomes included verbal and numerical WM and the standard error of hit reaction time (HRTSE) as a measure of attention performance. These outcomes were repeatedly assessed over 1-year period using computerized version of the Attention Network Test and n-back task. Associations were estimated using linear mixed-effects models. RESULTS: Higher polygenic risk for ADHD was associated with lower WM performance at baseline time but not over time. These findings remained significant after adjusting by multiple testing and excluding individuals with an ADHD diagnosis but were limited to boys. PRS for ASD was only nominally associated with an increased improvement on verbal WM over time, although this association did not survive multiple testing correction. No associations were observed for HRTSE. CONCLUSIONS: Common genetic variants related to ADHD may contribute to worse WM performance among schoolchildren from the general population but not to the subsequent cognitive-developmental trajectory assessed over 1-year period.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32674437

RESUMO

Involving and engaging stakeholders is crucial for studying and managing the complex interactions between marine ecosystems and human health and wellbeing. The Oceans and Human Health Chair was founded in the town of Roses (Catalonia, Spain, NW Mediterranean) in 2018, the fruit of a regional partnership between various stakeholders, and for the purpose of leading the way to better health and wellbeing through ocean research and conservation. The Chair is located in an area of the Mediterranean with a notable fishing, tourist, and seafaring tradition and is close to a marine reserve, providing the opportunity to observe diverse environmental conditions and coastal and maritime activities. The Chair is a case study demonstrating that local, collaborative, transdisciplinary, trans-sector, and bottom-up approaches offer tremendous opportunities for engaging coastal communities to help support long-lasting solutions that benefit everyone, and especially those living by the sea or making their living from the goods and services provided by the sea. Furthermore, the Chair has successfully integrated most of its experts in oceans and human health from the most prestigious institutions in Catalonia. The Chair focuses on three main topics identified by local stakeholders: Fish and Health; Leisure, Health, and Wellbeing; and Medicines from the Sea. Led by stakeholder engagement, the Chair can serve as a novel approach within the oceans and human health field of study to tackle a variety of environmental and public health challenges related to both communicable and non-communicable diseases, within the context of sociocultural issues. Drawing on the example provided by the Chair, four principles are established to encourage improved participatory processes in the oceans and human health field: bottom-up, "think local", transdisciplinary and trans-sectorial, and "balance the many voices".


Assuntos
Ecossistema , Oceanos e Mares , Participação dos Interessados , Animais , Saúde Ambiental , Humanos , Biologia Marinha , Espanha
9.
Biol Psychiatry ; 87(2): 132-138, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629460

RESUMO

BACKGROUND: Impaired neuromotor development is often one of the earliest observations in children with autism spectrum disorder (ASD). We investigated whether a genetic predisposition to developmental disorders was associated with nonoptimal neuromotor development during infancy and examined the genetic correlation between nonoptimal neuromotor development and autistic traits in the general population. METHODS: In a population-based cohort in The Netherlands (2002-2006), we calculated polygenic risk scores (PRSs) for ASD and attention-deficit/hyperactivity disorder (ADHD) using genome-wide association study summary statistics. In 1921 children with genetic data, parents rated autistic traits at 6 years of age. Among them, 1174 children (61.1%) underwent neuromotor examinations (tone, responses, senses, and other observations) during infancy (9-20 weeks of age). We used linear regressions to examine associations of PRSs with neuromotor scores and autistic traits. We performed a bivariate genome-based restricted maximum likelihood analysis to explore whether genetic susceptibility underlies the association between neuromotor development and autistic traits. RESULTS: Higher PRSs for ASD were associated with less optimal overall infant neuromotor development, in particular low muscle tone. Higher PRSs for ADHD were associated with less optimal senses. PRSs for ASD and those for ADHD both were associated with autistic traits. The single nucleotide polymorphism-based heritability of overall motor development was 20% (SE = .21) and of autistic traits was 68% (SE = .26). The genetic correlation between overall motor development and autistic traits was .35 (SE = .21, p < .001). CONCLUSIONS: We found that genetic liabilities for ASD and ADHD covary with neuromotor development during infancy. Shared genetic liability might partly explain the association between nonoptimal neuromotor development during infancy and autistic traits in childhood.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Criança , Estudo de Associação Genômica Ampla , Humanos , Lactente , Países Baixos/epidemiologia , Fatores de Risco
10.
Environ Res ; 178: 108734, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31539824

RESUMO

OBJECTIVE: Air pollution (AP) may affect neurodevelopment, but studies about the effects of AP on the growing human brain are still scarce. We aimed to investigate the effects of prenatal exposure to AP on lateral ventricles (LV) and corpus callosum (CC) volumes in children and to determine whether the induced brain changes are associated with behavioral problems. METHODS: Among the children recruited through a set of representative schools of the city of Barcelona, (Spain) in the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) study, 186 typically developing participants aged 8-12 years underwent brain MRI on the same 1.5 T MR unit over a 1.5-year period (October 2012-April 2014). Brain volumes were derived from structural MRI scans using automated tissue segmentation. Behavioral problems were assessed using the Strengths and Difficulties Questionnaire (SDQ) and the criteria of the Attention Deficit Hyperactivity Disorder DSM-IV list. Prenatal fine particle (PM2.5) levels were retrospectively estimated at the mothers' residential addresses during pregnancy with land use regression (LUR) models. To determine whether brain structures might be affected by prenatal PM2.5 exposure, linear regression models were run and adjusted for age, sex, intracranial volume (ICV), maternal education, home socioeconomic vulnerability index, birthweight and mothers' smoking status during pregnancy. To test for associations between brain changes and behavioral outcomes, negative binomial regressions were performed and adjusted for age, sex, ICV. RESULTS: Prenatal PM2.5 levels ranged from 11.8 to 39.5 µg/m3 during the third trimester of pregnancy. An interquartile range increase in PM2.5 level (7 µg/m3) was significantly linked to a decrease in the body CC volume (mm3) (ß = -53.7, 95%CI [-92.0, -15.5] corresponding to a 5% decrease of the mean body CC volume) independently of ICV, age, sex, maternal education, socioeconomic vulnerability index at home, birthweight and mothers' smoking status during the third trimester of pregnancy. A 50 mm3 decrease in the body CC was associated with a significant higher hyperactivity subscore (Rate Ratio (RR) = 1.09, 95%CI [1.01, 1.17) independently of age, sex and ICV. The statistical significance of these results did not survive to False Discovery Rate correction for multiple comparisons. CONCLUSIONS: Prenatal exposure to PM2.5 may be associated with CC volume decrease in children. The consequences might be an increase in behavioral problems.


Assuntos
Poluentes Atmosféricos , Poluição do Ar/estatística & dados numéricos , Corpo Caloso/fisiologia , Exposição Materna/estatística & dados numéricos , Transtornos Mentais/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Comportamento Problema , Criança , Feminino , Humanos , Masculino , Material Particulado , Gravidez , Estudos Retrospectivos , Espanha
11.
Neuroinformatics ; 17(4): 583-592, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30903541

RESUMO

Multivariate methods have the potential to better capture complex relationships that may exist between different biological levels. Multiple Factor Analysis (MFA) is one of the most popular methods to obtain factor scores and measures of discrepancy between data sets. However, singular value decomposition in MFA is based on PCA, which is adequate only if the data is normally distributed, linear or stationary. In addition, including strongly correlated variables can overemphasize the contribution of the estimated components. In this work, we introduced a novel method referred as Independent Multifactorial Analysis (ICA-MFA) to derive relevant features from multiscale data. This method is an extended implementation of MFA, where the component value decomposition is based on Independent Component Analysis. In addition, ICA-MFA incorporates a predictive step based on an Independent Component Regression. We evaluated and compared the performance of ICA-MFA with both, the MFA method and traditional univariate analyses, in a simulation study. We showed how ICA-MFA explained up to 10-fold more variance than MFA and univariate methods. We applied the proposed algorithm in a study of 4057 individuals belonging to the population-based Rotterdam Study with available genetic and neuroimaging data, as well as information about executive cognitive functioning. Specifically, we used ICA-MFA to detect relevant genetic features related to structural brain regions, which in turn were involved, in the mechanisms of executive cognitive function. The proposed strategy makes it possible to determine the degree to which the whole set of genetic and/or neuroimaging markers contribute to the variability of the symptomatology jointly, rather than individually. While univariate results and MFA combinations only explained a limited proportion of variance (less than 2%), our method increased the explained variance (10%) and allowed the identification of significant components that maximize the variance explained in the model. The potential application of the ICA-MFA algorithm constitutes an important aspect of integrating multivariate multiscale data, specifically in the field of Neurogenetics.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Neuroimagem/métodos , Neuroimagem/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único/genética , Algoritmos , Análise Fatorial , Humanos
12.
J Am Acad Child Adolesc Psychiatry ; 58(6): 600-607, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30768412

RESUMO

OBJECTIVE: This study examined the relation between polygenic scores (PGSs) for 5 major psychiatric disorders and 2 cognitive traits with brain magnetic resonance imaging morphologic measurements in a large population-based sample of children. In addition, this study tested for differences in brain morphology-mediated associations between PGSs for psychiatric disorders and PGSs for related behavioral phenotypes. METHOD: Participants included 1,139 children from the Generation R Study assessed at 10 years of age with genotype and neuroimaging data available. PGSs were calculated for schizophrenia, bipolar disorder, major depression disorder, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, intelligence, and educational attainment using results from the most recent genome-wide association studies. Image processing was performed using FreeSurfer to extract cortical and subcortical brain volumes. RESULTS: Greater genetic susceptibility for ADHD was associated with smaller caudate volume (strongest prior = 0.01: ß = -0.07, p = .006). In boys, mediation analysis estimates showed that 11% of the association between the PGS for ADHD and the PGS attention problems was mediated by differences in caudate volume (n = 535), whereas mediation was not significant in girls or the entire sample. PGSs for educational attainment and intelligence showed positive associations with total brain volume (strongest prior = 0.5: ß = 0.14, p = 7.12 × 10-8; and ß = 0.12, p = 6.87 × 10-7, respectively). CONCLUSION: The present findings indicate that the neurobiological manifestation of polygenic susceptibility for ADHD, educational attainment, and intelligence involve early morphologic differences in caudate and total brain volumes in childhood. Furthermore, the genetic risk for ADHD might influence attention problems through the caudate nucleus in boys.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Encéfalo/patologia , Cognição , Herança Multifatorial , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Inteligência , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Transtornos Mentais/genética , Transtornos Mentais/patologia , Transtornos Mentais/psicologia
13.
Environ Health Perspect ; 126(8): 087001, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30073950

RESUMO

BACKGROUND: Traffic-related air pollution is emerging as a risk factor for Alzheimer's disease (AD) and impaired brain development. Individual differences in vulnerability to air pollution may involve the ε4 allele of Apolipoprotein E (APOE) gene, the primary genetic risk factor for AD. OBJECTIVE: We analyzed whether the association between traffic air pollution and neurodevelopmental outcomes is modified by APOEε4 status in children. METHODS: Data on parent-reported behavior problems (total difficulties scores, Strengths and Difficulties Questionnaire), teacher-reported attention-deficit hyperactivity disorder (ADHD) symptom scores, cognitive performance trajectories (computerized tests of inattentiveness and working memory repeated 2-4 times during January 2012-March 2013), and APOE genotypes were obtained for 1,667 children age 7-11 y attending 39 schools in or near Barcelona. Basal ganglia volume (putamen, caudate, and globus pallidum) was measured in 163 of the children by MRI (October 2012-April 2014.) Average annual outdoor polycyclic aromatic hydrocarbons (PAHs), elemental carbon (EC), and nitrogen dioxide (NO2) concentrations were estimated based on measurements at each school (two 1-wk campaigns conducted 6 months apart in 2012). RESULTS: APOEε4 allele carriers had significantly higher behavior problem scores than noncarriers, and adverse associations with PAHs and NO2 were stronger or limited to ε4 carriers for behavior problem scores (P-interaction 0.03 and 0.04), caudate volume (P-interaction 0.04 and 0.03), and inattentiveness trajectories (P-interaction 0.15 and 0.08, respectively). Patterns of associations with the same outcomes were similar for EC. CONCLUSION: PAHs, EC, and NO2 were associated with higher behavior problem scores, smaller reductions in inattentiveness over time, and smaller caudate volume in APOEε4 allele carriers in our study population, and corresponding associations were weak or absent among ε4 noncarriers. These findings support a potential role of APOE in biological mechanisms that may contribute to associations between air pollution and neurobehavioral outcomes in children. https://doi.org/10.1289/EHP2246.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Apolipoproteína E4/genética , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Comportamento Problema , Poluição Relacionada com o Tráfego/efeitos adversos , Apolipoproteína E4/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Criança , Cognição/efeitos dos fármacos , Feminino , Genótipo , Humanos , Masculino , Espanha/epidemiologia
14.
Int J Methods Psychiatr Res ; 27(3): e1738, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30105890

RESUMO

OBJECTIVES: We proposed the application of a multivariate cross-sectional framework based on a combination of a variable selection method and a multiple factor analysis (MFA) in order to identify complex meaningful biological signals related to attention-deficit/hyperactivity disorder (ADHD) symptoms and hyperactivity/inattention domains. METHODS: The study included 135 children from the general population with genomic and neuroimaging data. ADHD symptoms were assessed using a questionnaire based on ADHD-DSM-IV criteria. In all analyses, the raw sum scores of the hyperactivity and inattention domains and total ADHD were used. The analytical framework comprised two steps. First, zero-inflated negative binomial linear model via penalized maximum likelihood (LASSO-ZINB) was performed. Second, the most predictive features obtained with LASSO-ZINB were used as input for the MFA. RESULTS: We observed significant relationships between ADHD symptoms and hyperactivity and inattention domains with white matter, gray matter regions, and cerebellum, as well as with loci within chromosome 1. CONCLUSIONS: Multivariate methods can be used to advance the neurobiological characterization of complex diseases, improving the statistical power with respect to univariate methods, allowing the identification of meaningful biological signals in Imaging Genetic studies.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Cerebelo/diagnóstico por imagem , Cromossomos Humanos Par 1/genética , Substância Cinzenta/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Criança , Estudos Transversais , Análise Fatorial , Feminino , Humanos , Masculino , Modelos Estatísticos , Neuroimagem
15.
Neurosci Biobehav Rev ; 93: 57-70, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29944960

RESUMO

Imaging Genetics (IG) integrates neuroimaging and genomic data from the same individual, deepening our knowledge of the biological mechanisms behind neurodevelopmental domains and neurological disorders. Although the literature on IG has exponentially grown over the past years, the majority of studies have mainly analyzed associations between candidate brain regions and individual genetic variants. However, this strategy is not designed to deal with the complexity of neurobiological mechanisms underlying behavioral and neurodevelopmental domains. Moreover, larger sample sizes and increased multidimensionality of this type of data represents a challenge for standardizing modeling procedures in IG research. This review provides a systematic update of the methods and strategies currently used in IG studies, and serves as an analytical framework for researchers working in this field. To complement the functionalities of the Neuroconductor framework, we also describe existing R packages that implement these methodologies. In addition, we present an overview of how these methodological approaches are applied in integrating neuroimaging and genetic data.


Assuntos
Técnicas Genéticas , Genômica/métodos , Neuroimagem , Projetos de Pesquisa , Humanos , Neuroimagem/métodos
16.
PLoS One ; 11(9): e0163048, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27656889

RESUMO

BACKGROUND: Attention function filters and selects behaviorally relevant information. This capacity is impaired in some psychiatric disorders and has been proposed as an endophenotype for Attention-Deficit/Hyperactivity Disorder; however, its genetic basis remains largely unknown. This study aimed to identify single nucleotide polymorphism (SNPs) associated with attention function. MATERIALS AND METHODS: The discovery sample included 1655 children (7-12 years) and the replication sample included 546 children (5-8 years). Five attention outcomes were assessed using the computerized Attentional Network Test (ANT): alerting, orienting, executive attention, Hit Reaction time (HRT) and the standard error of HRT (HRTSE). A Genome-wide Association Study was conducted for each outcome. Gene set enrichment analyses were performed to detect biological pathways associated with attention outcomes. Additional neuroimaging analyses were conducted to test neural effects of detected SNPs of interest. RESULTS: Thirteen loci showed suggestive evidence of association with attention function (P<10-5) in the discovery sample. One of them, the rs4321351 located in the PID1 gene, was nominally significant in the replication sample although it did not survive multiple testing correction. Neuroimaging analysis revealed a significant association between this SNP and brain structure and function involving the frontal-basal ganglia circuits. The mTOR signaling and Alzheimer disease-amyloid secretase pathways were significantly enriched for alerting, orienting and HRT respectively (FDR<5%). CONCLUSION: These results suggest for the first time the involvement of the PID1 gene, mTOR signaling and Alzheimer disease-amyloid secretase pathways, in attention function during childhood. These genes and pathways have been proposed to play a role in neuronal plasticity, memory and neurodegenerative disease.

18.
Am J Med Genet B Neuropsychiatr Genet ; 168(6): 459-470, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26174813

RESUMO

Attention deficit is one of the core symptoms of the attention-deficit/hyperactivity disorder (ADHD). However, the specific genetic variants that may be associated with attention function in adult ADHD remain largely unknown. The present study aimed to identifying SNPs associated with attention function in adult ADHD and tested whether these associations were enriched for specific biological pathways. Commissions, hit-reaction time (HRT), the standard error of HRT (HRTSE), and intraindividual coefficient variability (ICV) of the Conners Continuous Performance Test (CPT-II) were assessed in 479 unmedicated adult ADHD individuals. A Genome-Wide Association Study (GWAS) was conducted for each outcome and, subsequently, gene set enrichment analyses were performed. Although no SNPs reached genome-wide significance (P < 5E-08), 27 loci showed suggestive evidence of association with the CPT outcomes (P < E-05). The most relevant associated SNP was located in the SORCS2 gene (P = 3.65E-07), previously associated with bipolar disorder (BP), Alzheimer disease (AD), and brain structure in elderly individuals. We detected other genes suggested to be involved in synaptic plasticity, cognitive function, neurological and neuropsychiatric disorders, and smoking behavior such as NUAK1, FGF20, NETO1, BTBD9, DLG2, TOP3B, and CHRNB4. Also, several of the pathways nominally associated with the CPT outcomes are relevant for ADHD such as the ubiquitin proteasome, neurodegenerative disorders, axon guidance, and AD amyloid secretase pathways. To our knowledge, this is the first GWAS and pathway analysis of attention function in patients with persistent ADHD. Overall, our findings reinforce the conceptualization of attention function as a potential endophenotype for studying the molecular basis of adult ADHD. © 2015 Wiley Periodicals, Inc.

19.
PLoS One ; 10(6): e0129616, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26086820

RESUMO

BACKGROUND: Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles. AIMS: We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects. RESULTS: Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders. CONCLUSION: The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.


Assuntos
Transtornos de Ansiedade/etiologia , Peso ao Nascer , Córtex Cerebral/patologia , Transtorno Depressivo/etiologia , Inteligência , Adulto , Transtornos de Ansiedade/patologia , Transtorno Depressivo/patologia , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Psicopatologia , Gêmeos Monozigóticos , Adulto Jovem
20.
PLoS One ; 9(8): e103639, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25171170

RESUMO

Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.


Assuntos
Peso ao Nascer , Epigênese Genética , Fator de Crescimento Insulin-Like II/genética , Memória de Curto Prazo/fisiologia , Gêmeos Monozigóticos/genética , Metilação de DNA , Feminino , Humanos , Mosaicismo , Gravidez , Processos Estocásticos
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