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1.
J Neurooncol ; 142(1): 39-48, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30607709

RESUMO

PURPOSE: Advances in the treatment of pediatric medulloblastoma have led to improved survival rates, though treatment-related toxicity leaves children with significant long-term deficits. There is significant variability in the cognitive outcome of medulloblastoma survivors, and it has been suggested that this variability may be attributable to genetic factors. The aim of this study was to explore the contributions of single nucleotide polymorphisms (SNPs) in two genes, peroxisome proliferator activated receptor (PPAR) and glutathione-S-transferase (GST), to changes in general intellectual functioning in medulloblastoma survivors. METHODS: Patients (n = 44, meanage = 6.71 years, 61.3% males) were selected on the basis of available tissue samples and neurocognitive measures. Patients received surgical tumor resection, craniospinal radiation, radiation boost to the tumor site, and multiagent chemotherapy. Genotyping analyses were completed using the Illumina Human Omni2.5 BeadChip, and 41 single nucleotide polymorphisms (SNPs) were assessed across both genes. We used a machine learning algorithm to identify polymorphisms that were significantly associated with declines in general intellectual functioning following treatment for medulloblastoma. RESULTS: We identified age at diagnosis, radiation therapy, chemotherapy, and eight SNPs associated with PPARs as predictors of general intellectual functioning. Of the eight SNPs identified, PPARα (rs6008197), PPARγ (rs13306747), and PPARδ (rs3734254) were most significantly associated with long-term changes in general intellectual functioning in medulloblastoma survivors. CONCLUSIONS: PPAR polymorphisms may predict intellectual outcome changes in children treated for medulloblastoma. Importantly, emerging evidence suggests that PPAR agonists may provide an opportunity to minimize the effects of treatment-related cognitive sequelae in these children.


Assuntos
Sobreviventes de Câncer , Neoplasias Cerebelares/genética , Glutationa Transferase/genética , Inteligência/genética , Meduloblastoma/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/psicologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Meduloblastoma/patologia , Meduloblastoma/psicologia
2.
Proc Natl Acad Sci U S A ; 115(26): 6674-6678, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29891660

RESUMO

Population intelligence quotients increased throughout the 20th century-a phenomenon known as the Flynn effect-although recent years have seen a slowdown or reversal of this trend in several countries. To distinguish between the large set of proposed explanations, we categorize hypothesized causal factors by whether they accommodate the existence of within-family Flynn effects. Using administrative register data and cognitive ability scores from military conscription data covering three decades of Norwegian birth cohorts (1962-1991), we show that the observed Flynn effect, its turning point, and subsequent decline can all be fully recovered from within-family variation. The analysis controls for all factors shared by siblings and finds no evidence for prominent causal hypotheses of the decline implicating genes and environmental factors that vary between, but not within, families.


Assuntos
Inteligência , Modelos Genéticos , Meio Social , Adulto , Ordem de Nascimento , Estudos de Coortes , Escolaridade , Emigrantes e Imigrantes/psicologia , Características da Família , Fertilidade , Humanos , Inteligência/genética , Masculino , Pessoa de Meia-Idade , Militares/psicologia , Noruega , Estado Nutricional , Irmãos/psicologia
3.
PLoS One ; 13(5): e0196597, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29738571

RESUMO

A well-known hypothesis in the behavioral genetic literature predicts that the heritability of cognitive abilities is higher in the presence of higher socioeconomic contexts. However, studies suggest that the effect of socioeconomic status (SES) on the heritability of cognitive ability may not be universal, as it has mostly been demonstrated in the United States, but not in other Western nations. In the present study we tested whether the importance of genetic and environmental effects on cognitive abilities varies as a function of parental education in a German twin sample. Cognitive ability scores (general, verbal, and nonverbal) were obtained on 531 German twin pairs (192 monozygotic, 339 dizygotic, ranging from 7 to 14 years of age; Mage = 10.25, SD = 1.83). Data on parental education were available from mothers and fathers. Results for general cognitive ability and nonverbal ability indicated no significant gene x parental education interaction effect. For verbal ability, a significant nonshared environment (E) x parental education interaction was found in the direction of greater nonshared environmental influences on verbal abilities among children raised by more educated parents.


Assuntos
Cognição , Escolaridade , Interação Gene-Ambiente , Inteligência/genética , Pais/educação , Gêmeos Dizigóticos/psicologia , Gêmeos Monozigóticos/psicologia , Adolescente , Adulto , Idoso , Criança , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Comportamento Verbal
4.
Eur J Paediatr Neurol ; 22(4): 662-666, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29661537

RESUMO

AIM: In pyridoxine dependent epilepsy (PDE), patients usually present with neonatal seizures. A small subgroup is characterized by late-onset beyond 2 months of age. We aim to analyze the observation of relatively good cognitive outcome in this subgroup of late-onset PDE patients. METHODS: We retrospectively analyzed data from four metabolically and genetically confirmed late-onset patients with PDE due to antiquitin (ALDH7A1) deficiency. Data were analyzed regarding ALDH7A1 mutations, alpha-Aminoadipic semialdehyde (α-AASA) and pipecolic acid (PA) levels, medication during pregnancy, delivery, treatment delay, amount of seizures, pyridoxine dose, adjuvant therapy and findings on brain MRI. RESULTS: Results showed that three patients had relatively good outcome (IQ 80-97), while one patient did not undergo formal testing and was considered mildly delayed. We were unable to find a clear association between the above-mentioned variables and cognitive outcome, although a less severe genotype may be present in three patients, and maternal medication could be accountable for better outcome in two patients. INTERPRETATION: We suggest that favorable outcome in late onset PDE might be explained by a combination of factors. A yet unknown protective factor, different genetic variations, functional variation and secondarily variation in treatment regimens and absence of neonatal seizure induced brain damage.


Assuntos
Idade de Início , Epilepsia/complicações , Deficiência Intelectual/genética , Aldeído Desidrogenase/genética , Epilepsia/genética , Feminino , Genótipo , Humanos , Lactente , Deficiência Intelectual/epidemiologia , Inteligência/genética , Imagem por Ressonância Magnética , Masculino , Mutação , Piridoxina/uso terapêutico , Estudos Retrospectivos
5.
Behav Genet ; 48(2): 147-154, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29264815

RESUMO

A previous meta-analysis (Van der Linden et al., Psychol Bull 143:36-52, 2017) showed that the General Factor of Personality (GFP) overlaps with ability as well as trait emotional intelligence (EI). The correlation between trait EI and the GFP was so high (ρ = 0.88) in that meta-analysis that these two may be considered virtually identical constructs. The present study builds on these findings by examining whether the strong phenotypic correlation between the GFP and trait EI has a genetic component. In a sample of monozygotic and dizygotic twins, the heritability estimates for the GFP and trait EI were 53 and 45%, respectively. Moreover, there was a strong genetic correlation of r = .90 between the GFP and trait EI. Additional analyses suggested that a substantial proportion of the genetic correlations reflects non-additive genetic effects (e.g., dominance and epistasis). These findings are discussed in light of evolutionary accounts of the GFP.


Assuntos
Inteligência Emocional/genética , Personalidade/genética , Adolescente , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inteligência/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Inquéritos e Questionários , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto Jovem
6.
Psychol Med ; 48(2): 187-207, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28595670

RESUMO

In the face of shifting demographics and an increase in human longevity, it is important to examine carefully what is known about cognitive ageing, and to identify and promote possibly malleable lifestyle and health-related factors that might mitigate age-associated cognitive decline. The Lothian Birth Cohorts of 1921 (LBC1921, n = 550) and 1936 (LBC1936, n = 1091) are longitudinal studies of cognitive and brain ageing based in Scotland. Childhood IQ data are available for these participants, who were recruited in later life and then followed up regularly. This overview summarises some of the main LBC findings to date, illustrating the possible genetic and environmental contributions to cognitive function (level and change) and brain imaging biomarkers in later life. Key associations include genetic variation, health and fitness, psychosocial and lifestyle factors, and aspects of the brain's structure. It addresses some key methodological issues such as confounding by early-life intelligence and social factors and emphasises areas requiring further investigation. Overall, the findings that have emerged from the LBC studies highlight that there are multiple correlates of cognitive ability level in later life, many of which have small effects, that there are as yet few reliable predictors of cognitive change, and that not all of the correlates have independent additive associations. The concept of marginal gains, whereby there might be a cumulative effect of small incremental improvements across a wide range of lifestyle and health-related factors, may offer a useful way to think about and promote a multivariate recipe for healthy cognitive and brain ageing.


Assuntos
Alostase/fisiologia , Encéfalo/diagnóstico por imagem , Envelhecimento Cognitivo/fisiologia , Nível de Saúde , Desenvolvimento Humano/fisiologia , Inteligência/fisiologia , Estilo de Vida , Aptidão Física/fisiologia , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4 , Feminino , Humanos , Individualidade , Inteligência/genética , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Escócia
7.
Biochemistry (Mosc) ; 83(12): 1504-1516, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30878025

RESUMO

There are two points of view on the evolution of aging. The classical theory of aging suggests that natural selection does not efficiently eliminate mutations or alleles that are harmful to organisms at later age. Another hypothesis is that the genetic program of aging has evolved as an adaptation that contributes to the optimization of the evolutionary process. Academician V. P. Skulachev advocates the latter hypothesis, which he has illustrated with the "Fable of hares". In this paper, we have used computer simulation to search for conditions when, according to the "Fable", aging develops as an adaptation required for the evolution of useful traits. The simulation has shown that the evolutionary mechanism presented in the "Fable of hares" is only partially functional. We have found that under certain conditions, programmed deterioration of some organismal functions makes it possible to increase the efficiency of natural selection of other functions. However, we have not identified mechanisms that would ensure the distribution and support of genes of aging within the population.


Assuntos
Envelhecimento/fisiologia , Simulação por Computador , Evolução Molecular , Seleção Genética , Adaptação Fisiológica , Envelhecimento/genética , Genótipo , Inteligência/genética , Mutagênese , Fenótipo
8.
J Neurogenet ; 31(4): 344-351, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29105523

RESUMO

Schizophrenia (SCZ), is considered as one of the most debilitating mental disorders around the world. Symptom-based clinical interview and numerous tests have been used to evaluate the diagnosis and also cognitive disturbances in patients with SCZ. All these tests measure phenotype-based functions. Thus, it seems accurate diagnosis of such complex disorders must rely on more valid and reliable factors. In this study, we evaluated the association of transcription factor 4 (TCF4) gene mRNA level in peripheral blood with SCZ, and also its psychopathology, cognitive and intellectual impairments. In this study, using real-time PCR, we compared TCF4 mRNA level between the case (70 unmedicated schizophrenia patients) and healthy control (n = 72) groups. In addition, all subjects underwent Psychopathology (PANSS) and cognitive and intelligence (WAIS, WMS, Stroop, WCST) assessments, and scores were compared between the two groups. Also, to determine the effect of TCF4 expression on psychopathology, cognitive and intellectual functions, the correlation between expression level and test scores was measured. The correlation between gene expression and age of onset and duration of the disorder was evaluated as well. Our results showed that the TCF4 mRNA level, psychopathology, cognitive and intellectual functions were significantly different in all, male, and female patients compared to healthy participants. Additionally, it was found that TCF4 level is positively correlated with scores of WAIS and WMS and is negatively correlated with Stroop and WCST errors and PANSS score. Our results showed that the mRNA level of TCF4 may be associated with SCZ, its psychopathology, IQ and cognitive impairments in an Iranian group of patients with SCZ. These results may help to better understanding the TCF4 role in the psychopathogenesis of SCZ and also may shed some light on the ongoing works conducted on peripheral biomarker-based diagnosis of complicated mental disorders.


Assuntos
Disfunção Cognitiva/genética , Inteligência/genética , Esquizofrenia/genética , Fator de Transcrição 4/genética , Adulto , Cognição/fisiologia , Disfunção Cognitiva/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/metabolismo , Fator de Transcrição 4/metabolismo , Adulto Jovem
9.
Dement Geriatr Cogn Disord ; 44(3-4): 153-159, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28848214

RESUMO

AIMS: This study examined differences in corticocortical communication between adolescent ε4 carriers (ε4+) and noncarriers (ε4-) during a fluid intelligence task (Comprehensive Test of Nonverbal Intelligence [CTONI]). METHODS: Sixteen ε4+ and 20 ε4- individuals aged 13-15 years performed the CTONI while real-time EEG signals were acquired. Inter- and intrahemispheric coherences were analyzed. RESULTS: The ε4+ subjects exhibited lower inter- and intrahemispheric coherences than the ε4- individuals. CONCLUSION: ε4 carriers have lower corticocortical communication than noncarriers during an intelligence task, implying that carrying the ε4 allele may reduce brain networking in adolescence, several decades before the onset of Alzheimer disease.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Córtex Cerebral/fisiopatologia , Triagem de Portadores Genéticos , Inteligência/genética , Rede Nervosa/fisiopatologia , Adolescente , Idoso , Doença de Alzheimer/fisiopatologia , Atenção/fisiologia , Dominância Cerebral/fisiologia , Eletroencefalografia , Feminino , Humanos , Inteligência/fisiologia , Masculino , Testes Neuropsicológicos , Tempo de Reação/fisiologia , Valores de Referência
10.
Clin Endocrinol (Oxf) ; 87(6): 651-659, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28771762

RESUMO

OBJECTIVE: Impaired cognition has been reported in patients with congenital adrenal hyperplasia (CAH), although the findings have been conflicting. It has been hypothesized that the major causes of the deficits are prenatal hormonal imbalances and/or excessive glucocorticoid treatment. DESIGN: An observational study investigating cognition in patients with CAH. PATIENTS: A total of 55 patients with CAH and 58 control subjects from the general population, aged 16-33 years. Nine CAH subjects had been treated prenatally with dexamethasone. SETTING: Singel research institute. MEASUREMENTS: Standardized neuropsychological tests (Wechsler Scales and Stroop Interference Test) and questionnaires (Barkley Deficit in Executive Functioning Scale) were used. RESULTS: Compared to controls, patients with CAH had impaired performance in tests measuring verbal working memory (P = .024), visual-spatial working memory (P = .005 and P = .003) and inhibition (P = .002). In measures of fluid intelligence/nonverbal logical reasoning, males with CAH performed poorer than control males (P = .033). Patients with salt-wasting CAH performed equally compared to patients with simple virilizing CAH. However, patients with a null genotype performed poorer than patients with a non-null genotype and significantly worse on fluid intelligence/nonverbal logical reasoning (P = .042). Prenatally-treated women performed worse on most cognitive measures than women with CAH not treated prenatally. CONCLUSIONS: Patients with CAH had normal psychometric intelligence but impaired executive functions compared with population controls. A null CAH genotype was associated with poorer general cognitive capacity.


Assuntos
Hiperplasia Suprarrenal Congênita/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Adolescente , Hiperplasia Suprarrenal Congênita/genética , Adulto , Cognição/fisiologia , Disfunção Cognitiva/genética , Feminino , Genótipo , Humanos , Inteligência/genética , Inteligência/fisiologia , Masculino , Testes Neuropsicológicos , Inquéritos e Questionários , Adulto Jovem
11.
Behav Genet ; 47(5): 469-479, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28711986

RESUMO

Impairments in reading and in language have negative consequences on life outcomes, but it is not known to what extent genetic effects influence this association. We constructed polygenic scores for difficulties with language and learning to read from genome-wide data in ~6,600 children, adolescents and young adults, and tested their association with health, socioeconomic outcomes and brain structure measures collected in adults (maximal N = 111,749). Polygenic risk of reading difficulties was associated with reduced income, educational attainment, self-rated health and verbal-numerical reasoning (p < 0.00055). Polygenic risk of language difficulties predicted income (p = 0.0005). The small effect sizes ranged 0.01-0.03 of a standard deviation, but these will increase as genetic studies for reading ability get larger. Polygenic scores for childhood cognitive ability and educational attainment were correlated with polygenic scores of reading and language (up to 0.09 and 0.05, respectively). But when they were included in the prediction models, the observed associations between polygenic reading and adult outcomes mostly remained. This suggests that the pathway from reading ability to social outcomes is not only via associated polygenic loads for general cognitive function and educational attainment. The presence of non-overlapping genetic effect is indicated by the genetic correlations of around 0.40 (childhood intelligence) and 0.70 (educational attainment) with reading ability. Mendelian randomization approaches will be important to dissociate any causal and moderating effects of reading and related traits on social outcomes.


Assuntos
Polimorfismo de Nucleotídeo Único/genética , Leitura , Classe Social , Adolescente , Adulto , Encéfalo/fisiologia , Criança , Cognição , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Inteligência/genética , Linguagem , Desequilíbrio de Ligação/genética , Masculino , Herança Multifatorial/genética , Qualidade de Vida , Adulto Jovem
12.
J Alzheimers Dis ; 59(2): 723-735, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28671113

RESUMO

BACKGROUND: Cognitive functions are highly heritable and polygenic, though the source of this genetic influence is unclear. On the neurobiological level, these functions rely on effective neuroplasticity, in which the activity-regulated cytoskeleton associated protein (ARC) plays an essential role. OBJECTIVES: To examine whether the ARC gene complex may contribute to the genetic components of intellectual function given the crucial role of ARC in brain plasticity and memory formation. METHODS: The ARC complex was tested for association with intelligence (IQ) in children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5,165). As Alzheimer's disease (AD) shares genetics with cognitive functioning, the association was followed up in an AD sample (17,008 cases, 37,154 controls). RESULTS: The ARC complex revealed association with verbal and total IQ (empirical p = 0.027 and 0.041, respectively) in the ALSPAC. The strongest single variant signal (rs2830077; empirical p = 0.018), within the APP gene, was confirmed in the AD sample (p = 2.76E-03). Functional analyses of this variant showed its preferential binding to the transcription factor CP2. DISCUSSION: This study implicates APP in childhood IQ. While follow-up studies are needed, this observation could help elucidate the etiology of disorders associated with cognitive dysfunction, such as AD.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Proteínas do Citoesqueleto/genética , Inteligência/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Doença de Alzheimer/genética , Criança , Simulação por Computador , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Memória/fisiologia , Modelos Genéticos , Comportamento Verbal
13.
Behav Genet ; 47(5): 507-515, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28744605

RESUMO

We examine a sample of Norwegian twin conscripts for evidence of an interaction between parental education and the heritability of general cognitive ability (GA). Ability scores were obtained on 1706 pairs of twins who were conscripted into the Norwegian Armed Forces between 1931and 1960. Education scores were available for mothers and fathers; the majority of the parents had less than a high school education. GA scores were heteroscadistic with respect to mid-parent education, with reduced variability at higher levels of education. Both MZ and DZ twin correlations for GA were linearly and negatively related to mid-parent education, DZ twins substantially more so. When the model was extended to an ACE model consisting of standardized positive ACE variance components, the modification appeared to disappear. Further analysis revealed that this occurred because the steep decline of DZ twin correlations with increasing mid-parent education resulted in a violation of the classical twin model for much of the parameter space. Other phenomena that might result in large declines in DZ twin correlations are considered, along with implications for other studies of socioeconomic interactions with the heritability of GA in European samples.


Assuntos
Inteligência/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto , Cognição/fisiologia , Educação , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Herança Multifatorial/genética , Noruega , Pais/educação , Gêmeos Dizigóticos/psicologia , Gêmeos Monozigóticos/psicologia
14.
Clin Neuropsychol ; 31(6-7): 1073-1086, 2017 Aug - Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28555512

RESUMO

OBJECTIVE: We sought to derive a 'neuropsychological intelligence quotient' (NIQ) to replace IQ testing in some routine assessments. METHOD: We administered neuropsychological testing and a seven-subtest short form of the Wechsler Adult Intelligence Scale to a community sample of 394 adults aged 18-96 years. We regressed Wechsler Full Scale IQs (W-FSIQ) on 23 neuropsychological scores and derived an NIQ from 9 measures that explained significant variance in W-FSIQ. We then compared subgroups of 284 healthy and 108 unhealthy participants in NIQ and W-FSIQ to assess criterion validity, correlated NIQ and W-FSIQ scores with education level and independence for activities of daily living to assess convergent validity, and compared validity coefficients for the NIQ with those of 'hold' and 'no-hold' indices. RESULTS: By design, NIQ and W-FSIQ scores correlated highly (r = .84), and both were higher in healthy participants. The difference was larger for NIQ, which accounted for more variability in activities of daily living. The NIQ and 'no-hold' index were better predicted by health status and less predicted by educational status than the 'hold' index. CONCLUSIONS: We constructed an NIQ that correlates highly with Wechsler FSIQ. Tests required to obtain NIQ are commonly used and can be administered in about 45 min. Validity properties of NIQ and W-FSIQ are similar. The NIQ bore greater resemblance to a 'no-hold' than 'hold' index. One can obtain a reasonably accurate estimate of current Full Scale IQ without formal intelligence testing from a brief neuropsychological battery.


Assuntos
Testes de Inteligência/normas , Inteligência/genética , Testes Neuropsicológicos/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Nat Genet ; 49(7): 1107-1112, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530673

RESUMO

Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10-8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10-6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10-6). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10-29). These findings provide new insight into the genetic architecture of intelligence.


Assuntos
Estudo de Associação Genômica Ampla , Inteligência/genética , Adolescente , Adulto , Idoso , Encéfalo/metabolismo , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Lactente , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Nat Genet ; 49(7): 978-985, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28504703

RESUMO

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.


Assuntos
Transtorno do Espectro Autista/genética , Variação Genética , Herança Multifatorial , Adulto , Transtorno do Espectro Autista/epidemiologia , Criança , Estudos de Coortes , Escolaridade , Grupos Étnicos/genética , Saúde da Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genética Comportamental , Humanos , Deficiência Intelectual/genética , Inteligência/genética , Masculino , Fenótipo , Fatores de Risco , Esquizofrenia/genética , Deleção de Sequência
17.
Sci Rep ; 7: 45977, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28383074

RESUMO

Myopia, or near-sightedness, is our most common eye condition and the prevalence is increasing globally. Visual impairment will occur if uncorrected, whilst high myopia causes sight-threatening complications. Myopia is associated with higher intelligence. As both are heritable, we set out to examine whether there is a genetic correlation between myopia and intelligence in over 1,500 subjects (aged 14-18 years) from a twin birth cohort. The phenotypic correlation between refractive error and intelligence was -0.116 (p < 0.01) - the inverse correlation due to the fact that myopia is a negative refractive error. Bivariate twin modeling confirmed both traits were heritable (refractive error 85%, intelligence 47%) and the genetic correlation was -0.143 (95% CI -0.013 to -0.273). Of the small phenotypic correlation the majority (78%) was explained by genetic factors. Polygenic risk scores were constructed based on common genetic variants identified in previous genome-wide association studies of refractive error and intelligence. Genetic variants for intelligence and refractive error explain some of the reciprocal variance, suggesting genetic pleiotropy; in the best-fit model the polygenic score for intelligence explained 0.99% (p = 0.008) of refractive error variance. These novel findings indicate shared genetic factors contribute significantly to the covariance between myopia and intelligence.


Assuntos
Estudos de Associação Genética , Inteligência/genética , Miopia/genética , Adolescente , Feminino , Genoma Humano , Humanos , Modelos Lineares , Masculino , Herança Multifatorial/genética , Erros de Refração , Fatores de Risco , Gêmeos/genética
18.
Brain Behav ; 7(3): e00645, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28293480

RESUMO

INTRODUCTION: The determinants of cognitive deficits among individuals with Klinefelter syndrome (KS) are not well understood. This study was conducted to assess the impact of general intelligence, personality, and social engagement on cognitive performance among patients with KS and a group of controls matched for age and years of education. METHODS: Sixty-nine patients with KS and 69 controls were assessed in terms of IQ, NEO personality inventory, the Autism Spectrum Quotient (AQ) scale, and measures of cognitive performance reflecting working memory and executive function. RESULTS: Patients with KS performed more poorly on memory and executive-function tasks. Patients with KS also exhibited greater neuroticism and less extraversion, openness, and conscientiousness than controls. Memory deficits among patients with KS were associated with lower intelligence, while diminished executive functioning was mediated by both lower intelligence and less social engagement. CONCLUSION: Our results suggest that among patients with KS, memory deficits are principally a function of lower general intelligence, while executive-function deficits are associated with both lower intelligence and poorer social skills. This suggests a potential influence of social engagement on executive cognitive functioning (and/or vice-versa) among individuals with KS, and perhaps those with other genetic disorders. Future longitudinal research would be important to further clarify this and other issues discussed in this research.


Assuntos
Disfunção Cognitiva/fisiopatologia , Função Executiva/fisiologia , Inteligência/fisiologia , Síndrome de Klinefelter/fisiopatologia , Memória de Curto Prazo/fisiologia , Personalidade/fisiologia , Habilidades Sociais , Adolescente , Adulto , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Humanos , Inteligência/genética , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Personalidade/genética , Adulto Jovem
19.
Am J Psychiatry ; 174(6): 576-585, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28253736

RESUMO

OBJECTIVE: Aside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes or loci. METHOD: Analyses preemptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains. RESULTS: Children with de novo mutations (N=112) had a greater likelihood of motor delay during early development (later age at walking), but they were less impaired on certain measures of ASD core symptoms (parent-rated social communication abnormalities and clinician-rated diagnostic certainty about ASD) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language (i.e., regular use of complex sentences). CONCLUSIONS: Children with ASD with de novo mutations may exhibit a "muted" symptom profile with respect to social communication and language deficits relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental and demographic variables are properly accounted for first.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Genótipo , Fenótipo , Adolescente , Transtorno do Espectro Autista/psicologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Análise Mutacional de DNA , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/psicologia , Feminino , Humanos , Inteligência/genética , Inteligência/fisiologia , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/psicologia , Funções Verossimilhança , Masculino , Prognóstico , Valores de Referência
20.
Am J Med Genet A ; 173(3): 762-765, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28211987

RESUMO

Koolen-de Vries Syndrome (KdVS), also referred to as 17q21.31 microdeletion syndrome, is caused by haploinsufficiency of the KANSL1 gene. This genetic disorder is associated with a clinical phenotype including facial dysmorphism, developmental delay, and friendly disposition, as well as mild-to-moderate intellectual disability. We present the case of a 10 year 8 month old female with KdVS due to a de novo intragenic KANSL1 mutation. At this time, she does not present with intellectual disability, and her verbal intelligence is relatively preserved, although she has perceptual deficits, developmental dyspraxia, and severe speech disorder. This case expands the mild end of the neurodevelopmental spectrum seen in children with de novo KANSL1 mutation and KdVS. © 2017 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Mutação , Proteínas Nucleares/genética , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Alelos , Criança , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Mutação da Fase de Leitura , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Inteligência/genética , Testes Neuropsicológicos , Comportamento Verbal
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