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1.
Am J Hum Genet ; 105(2): 334-350, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374203

RESUMO

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

3.
Nat Genet ; 50(8): 1112-1121, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30038396

RESUMO

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

4.
Twin Res Hum Genet ; 21(5): 394-397, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30001766

RESUMO

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

5.
Nat Genet ; 50(7): 912-919, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29942086

RESUMO

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

6.
Nat Commun ; 9(1): 2098, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844566

RESUMO

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

7.
Schizophr Res ; 195: 306-317, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28982554

RESUMO

BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.


Assuntos
Transtornos Cognitivos/etiologia , Predisposição Genética para Doença/genética , Imagem por Ressonância Magnética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Transtornos Cognitivos/diagnóstico por imagem , Endofenótipos , Feminino , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Estatísticas não Paramétricas , Adulto Jovem
8.
Cell Rep ; 21(9): 2597-2613, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29186694

RESUMO

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Nootrópicos/farmacologia , Cefotaxima/análogos & derivados , Cefotaxima/farmacologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
9.
Schizophr Bull ; 41(6): 1237-47, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26409223

RESUMO

First-episode schizophrenia (FES) spectrum disorders are associated with pronounced cognitive dysfunction across all domains. However, less is known about the course of cognitive functioning, following the first presentation of psychosis, and the relationship of cognition to clinical course during initial treatment. The present longitudinal study examined the magnitude of neurocognitive impairment, using the MATRICS Consensus Cognitive Battery, in patients experiencing their first episode of psychosis at baseline and after 12 weeks of randomized antipsychotic treatment with either aripiprazole or risperidone. At baseline, FES patients evidenced marked impairments in cognitive functioning. Notably, performance on the mazes task of planning and reasoning significantly predicted the likelihood of meeting stringent criteria for positive symptom remission during the first 12 weeks of the trial. Performance on indices of general cognitive function, working memory, and verbal learning improved over time, but these improvements were mediated by improvements in both positive and negative symptoms. We did not detect any differential effects of antipsychotic medication assignment (aripiprazole vs risperidone) on cognitive functioning. Our results suggest that a brief paper-and-pencil measure reflecting planning/reasoning abilities may index responsivity to antipsychotic medication. However, improvements in cognitive functioning over time were related to clinical symptom improvement, reflecting "pseudospecificity."


Assuntos
Antipsicóticos/farmacologia , Transtornos Cognitivos , Avaliação de Resultados (Cuidados de Saúde)/métodos , Transtornos Psicóticos , Esquizofrenia , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Aripiprazol/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Feminino , Humanos , Masculino , Transtornos Psicóticos/complicações , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/fisiopatologia , Indução de Remissão , Risperidona/administração & dosagem , Risperidona/farmacologia , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Adulto Jovem
10.
J Cogn Neurosci ; 27(9): 1766-74, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25961639

RESUMO

Here we provide novel convergent evidence across three independent cohorts of healthy adults (n = 531), demonstrating that a common polymorphism in the gene encoding the α2 subunit of neuronal voltage-gated type II sodium channels (SCN2A) predicts human general cognitive ability or "g." Using meta-analysis, we demonstrate that the minor T allele of a common polymorphism (rs10174400) in SCN2A is associated with significantly higher "g" independent of gender and age. We further demonstrate using resting-state fMRI data from our discovery cohort (n = 236) that this genetic advantage may be mediated by increased capacity for information processing between the dorsolateral PFC and dorsal ACC, which support higher cognitive functions. Collectively, these findings fill a gap in our understanding of the genetics of general cognitive ability and highlight a specific neural mechanism through which a common polymorphism shapes interindividual variation in "g."


Assuntos
Encéfalo/fisiologia , Cognição/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Polimorfismo Genético , Adulto , Mapeamento Encefálico , Estudos de Coortes , Feminino , Técnicas de Genotipagem , Humanos , Individualidade , Imagem por Ressonância Magnética , Masculino , Vias Neurais/fisiologia , Testes Neuropsicológicos , Descanso , Adulto Jovem
11.
Am J Med Genet B Neuropsychiatr Genet ; 168B(5): 363-73, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25951819

RESUMO

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.


Assuntos
Transtornos Cognitivos/genética , Cognição/fisiologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
12.
Arch Clin Neuropsychol ; 29(4): 315-21, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24777554

RESUMO

Mutations in the mitochondrial genome can impair normal metabolic function in the central nervous system (CNS) where cellular energy demand is high. Primary mitochondrial DNA (mtDNA) mutations have been linked to several mitochondrial disorders that have comorbid psychiatric, neurologic, and cognitive sequelae. Here, we present a series of cases with primary mtDNA mutations who were genotyped and evaluated across a common neuropsychological battery. Nineteen patients with mtDNA mutations were genotyped and clinically and cognitively evaluated. Pronounced deficits in nonverbal/visuoperceptual reasoning, verbal recall, semantic word generativity, and processing speed were evident and consistent with a "mitochondrial dementia" that has been posited. However, variation in cognitive performance was noteworthy, suggesting that the phenotypic landscape of cognition linked to primary mtDNA mutations is heterogeneous. Our patients with mtDNA mutations evidenced cognitive deficits quite similar to those commonly seen in Alzheimer's disease and could have clinical relevance to the evaluation of dementia.


Assuntos
Transtornos Cognitivos/genética , DNA Mitocondrial/genética , Mutação/genética , Adolescente , Adulto , Transtornos Cognitivos/diagnóstico , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Rememoração Mental/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Aprendizagem Verbal , Adulto Jovem
13.
JAMA Psychiatry ; 71(6): 647-56, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24718902

RESUMO

IMPORTANCE: One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation. OBJECTIVE: To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals. DESIGN, SETTING, AND PARTICIPANTS: Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals. MAIN OUTCOMES AND MEASURES: We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts. RESULTS: The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10(-10)). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10(-9)). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects. CONCLUSIONS AND RELEVANCE: The findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.


Assuntos
Encéfalo/fisiologia , Cognição/fisiologia , Predisposição Genética para Doença/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/genética , Psicologia do Esquizofrênico , Adolescente , Adulto , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Neuroimagem Funcional , Expressão Gênica/genética , Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/fisiologia , RNA Mensageiro/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Irmãos , Adulto Jovem
14.
Dev Sci ; 17(4): 584-95, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24410775

RESUMO

We tested the hypothesis that dopamine D1 and D2 receptor gene (DRD1 and DRD2, respectively) polymorphisms and the development of working memory skills can interact to influence symptom change over 10 years in children with attention-deficit/hyperactivity disorder (ADHD). Specifically, we examined whether improvements in working memory maintenance and manipulation from childhood to early adulthood predicted the reduction of ADHD symptoms as a function of allelic variation in DRD1 and DRD2. Participants were 76 7-11-year-old children with ADHD who were genotyped and prospectively followed for almost 10 years. ADHD symptoms were rated using the Attention Problems scale on the Child Behavior Checklist, and verbal working memory maintenance and manipulation, measured by Digit Span forward and backward, respectively, were assessed at baseline and follow-up. After correction for multiple testing, improvements in working memory manipulation, not maintenance, predicted reduction of symptomatology over development and was moderated by major allele homozygosity in two DRD1 polymorphisms (rs4532 and rs265978) previously linked with variation in D1 receptor expression. Depending on genetic background, developmental factors including age-dependent variation in DRD1 penetrance may facilitate the link between improvements in higher-order working memory and the remission of symptoms in individuals with childhood-diagnosed ADHD. Furthermore, the current findings suggest that DRD1 might contribute minimally to the emergence of symptoms and cognitive difficulties associated with ADHD in childhood, but may act as a modifier gene of these clinical features and outcome during later development for those with ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Memória de Curto Prazo , Polimorfismo Genético , Receptores de Dopamina D1/genética , Receptores Dopaminérgicos/genética , Adolescente , Adulto , Fatores Etários , Atenção , Criança , Comportamento Infantil , Desenvolvimento Infantil , Cognição , Transtornos Cognitivos , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Resultado do Tratamento , Adulto Jovem
15.
Am J Psychiatry ; 170(10): 1205-11, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23897408

RESUMO

OBJECTIVE: This longitudinal study examined if changes in neuropsychological functioning were associated with the trajectory of symptoms related to attention deficit hyperactivity disorder (ADHD) and impairment between preschool and school age. METHOD: The sample consisted of 3- and 4-year-old children (N=138) who were identified as being at risk for ADHD based on parent and teacher reports. Neuropsychological functioning was measured annually using the NEPSY at four time points (mean ages, 4.19, 5.36, 6.35, and 7.35 years). ADHD symptoms and impairment were assessed with semiannual parent and teacher reports using the ADHD Rating Scale-IV and the Children's Problems Checklist at 10 time points (mean ages at baseline and final assessment, 4.19 and 8.81 years, respectively). Hierarchical linear modeling was used to assess the trajectories of change in neuropsychological functioning and ADHD severity as well as the association of change in neuropsychological functioning with change in ADHD severity over time. RESULTS: Baseline neuropsychological functioning was not significantly associated with the slope of change in ADHD severity. However, the magnitude of change in neuropsychological functioning was linearly associated with the trajectory of ADHD symptom severity and impairment, such that individuals with greater neuropsychological growth over time had a greater diminution of ADHD severity and impairment. Family socioeconomic status at baseline was significantly associated with initial ADHD severity and impairment, but not with change over time. CONCLUSIONS: Interventions that enhance neuropsychological functioning at an early age may be beneficial in attenuating long-term ADHD severity and impairment.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Testes Neuropsicológicos/estatística & dados numéricos , Lista de Checagem , Criança , Pré-Escolar , Feminino , Humanos , Estudos Longitudinais , Masculino , Determinação da Personalidade/estatística & dados numéricos , Valor Preditivo dos Testes
16.
Neuropsychopharmacology ; 38(3): 525-32, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23132269

RESUMO

The BDNF Val(66)Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val(66)Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val(66)Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Metionina/genética , Fibras Nervosas Mielinizadas/patologia , Polimorfismo Genético/genética , Valina/genética , Adulto , Anisotropia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Homozigoto , Humanos , Masculino , Fibras Nervosas Mielinizadas/metabolismo , Adulto Jovem
17.
Neuropsychology ; 24(4): 424-34, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20604617

RESUMO

OBJECTIVE: This study examined perceptual and motor inhibition in a longitudinal sample of adolescents/young adults who were diagnosed with ADHD in childhood, and as a function of the relative persistence of ADHD. METHOD: Ninety-eight participants diagnosed with ADHD in childhood were reevaluated approximately 10 years later. Eighty-five never-ADHD controls similar in age, IQ, sociodemographic background, and gender distribution served as a comparison group. Participants were administered a psychiatric interview and the Stimulus and Response Conflict Tasks (Nassauer & Halperin, 2003). RESULTS: Participants with childhood ADHD demonstrated slower and less accurate responses to both control and conflict conditions relative to the comparison group, as well as more variable responses in both conditions of the motor inhibition task; there was no specific effect of childhood ADHD on perceptual or motor inhibition. ADHD persisters and partial remitters did not differ in overall accuracy, speed or variability in responding, but relative to partial remitters, persisters demonstrated greater slowing in response to perceptual conflict. CONCLUSIONS: These findings are consistent with theories positing state regulation, but not inhibitory control deficits in the etiology of ADHD, and suggest that improved perceptual inhibition may be associated with better outcome for ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Inibição (Psicologia) , Percepção/fisiologia , Desempenho Psicomotor/fisiologia , Adolescente , Análise de Variância , Comportamento de Escolha/fisiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Tempo de Reação/fisiologia , Estatística como Assunto , Adulto Jovem
18.
J Atten Disord ; 13(2): 127-36, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18757845

RESUMO

OBJECTIVE: To examine cognitive and psychosocial factors associated with high school dropout in urban adolescents with and without childhood ADHD. METHOD: In a longitudinal study, 49 adolescents/young adults with childhood ADHD and 44 controls who either dropped out or graduated from high school are included. Risk factors examined as potential correlates of dropout were intelligence, reading skills, socioeconomic status, marijuana use, and paternal contact. RESULTS: Lower IQ, reading ability, socioeconomic status, frequent marijuana use, and limited paternal contact significantly differentiated dropouts from graduates, irrespective of childhood ADHD. Follow-up analyses determined that IQ, marijuana use, and paternal contact independently contribute to the likelihood of dropout. CONCLUSION: Selected cognitive and psychosocial factors appear independently associated with the likelihood of high school dropout irrespective of ADHD. Notably, childhood ADHD did not increase this risk, suggesting that previous reports of increased dropout because of ADHD may become negated in urban areas when matched with similar community controls.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Evasão Escolar/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Comorbidade , Estudos Transversais , Relações Pai-Filho , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Abuso de Maconha/diagnóstico , Abuso de Maconha/epidemiologia , Abuso de Maconha/psicologia , Leitura , Fatores de Risco , Socialização , Fatores Socioeconômicos , Evasão Escolar/psicologia , Escalas de Wechsler , Adulto Jovem
19.
J Clin Child Adolesc Psychol ; 37(4): 785-93, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18991129

RESUMO

Children with attention deficit/hyperactivity disorder (ADHD) are at heightened risk for maltreatment and later substance use disorders (SUDs). We investigated the relationship of childhood maltreatment and other risk factors to SUDs among adolescents diagnosed with ADHD in childhood. Eighty adolescents diagnosed with ADHD when they were 7 to 11 years old were screened for histories of childhood maltreatment, and SUD diagnoses were formulated in accordance with the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders. Lifetime history of problematic substance use was obtained for each parent at baseline. Childhood maltreatment predicted SUD outcome over and above that accounted for by childhood conduct disorder and problematic parental substance use, two potent predictors of adolescent SUDs.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Maus-Tratos Infantis/estatística & dados numéricos , Transtorno da Conduta/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adolescente , Fatores Etários , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Maus-Tratos Infantis/diagnóstico , Maus-Tratos Infantis/psicologia , Filho de Pais Incapacitados/psicologia , Filho de Pais Incapacitados/estatística & dados numéricos , Comorbidade , Transtorno da Conduta/diagnóstico , Transtorno da Conduta/psicologia , Estudos Transversais , Feminino , Humanos , Controle Interno-Externo , Estudos Longitudinais , Masculino , Transtornos do Humor/diagnóstico , Transtornos do Humor/epidemiologia , Transtornos do Humor/psicologia , Fatores de Risco , Fatores Sexuais , Estatística como Assunto , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem
20.
J Child Psychol Psychiatry ; 49(9): 958-66, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18573145

RESUMO

BACKGROUND: This study examined neuropsychological functioning in a longitudinal sample of adolescents/young adults with attention deficit/hyperactivity disorder (ADHD) and controls as a function of the persistence of ADHD. We hypothesized that measures of executive processes would parallel adolescent clinical status, with ADHD-persisters, but not remitters, differing significantly from controls. In contrast, persisters and remitters were hypothesized to perform similarly, and different from controls, on tasks requiring less effortful processing. METHODS: Ninety-eight participants diagnosed with ADHD in childhood were reevaluated approximately 10 years later. Eighty-five never-ADHD controls similar in age, IQ, and sex distribution served as a comparison group. Participants were administered a psychiatric interview and neuropsychological test battery. RESULTS: Those with childhood ADHD demonstrated broad neuropsychological deficits relative to controls. When the group with childhood ADHD was subdivided based on adolescent ADHD status, compared to controls, both persisters and remitters showed deficient perceptual sensitivity and response variability, and increased ankle movements recorded by a solid-state actigraph. Only persisters differed from controls on several measures of more effortful executive processes. CONCLUSIONS: Findings provide preliminary support to the hypothesis that ADHD is associated with early-appearing and enduring subcortical dysfunction, while recovery over the course of development is associated with improvements in executive control functions.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Adolescente , Criança , Progressão da Doença , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Indução de Remissão , Índice de Gravidade de Doença , Adulto Jovem
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