Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.538
Filtrar
3.
Nat Genet ; 51(6): 933-940, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086352

RESUMO

The genetic architecture of psychiatric disorders is characterized by a large number of small-effect variants1 located primarily in non-coding regions, suggesting that the underlying causal effects may influence disease risk by modulating gene expression2-4. We provide comprehensive analyses using transcriptome data from an unprecedented collection of tissues to gain pathophysiological insights into the role of the brain, neuroendocrine factors (adrenal gland) and gastrointestinal systems (colon) in psychiatric disorders. In each tissue, we perform PrediXcan analysis and identify trait-associated genes for schizophrenia (n associations = 499; n unique genes = 275), bipolar disorder (n associations = 17; n unique genes = 13), attention deficit hyperactivity disorder (n associations = 19; n unique genes = 12) and broad depression (n associations = 41; n unique genes = 31). Importantly, both PrediXcan and summary-data-based Mendelian randomization/heterogeneity in dependent instruments analyses suggest potentially causal genes in non-brain tissues, showing the utility of these tissues for mapping psychiatric disease genetic predisposition. Our analyses further highlight the importance of joint tissue approaches as 76% of the genes were detected only in difficult-to-acquire tissues.


Assuntos
Perfilação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Transtornos Mentais/genética , Transtornos Mentais/psicologia , Transcriptoma , Algoritmos , Biologia Computacional/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Humanos , Transtornos Mentais/diagnóstico , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável
4.
Nat Commun ; 10(1): 1891, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015401

RESUMO

Genome-wide association studies (GWASs) of medication use may contribute to understanding of disease etiology, could generate new leads relevant for drug discovery and can be used to quantify future risk of medication taking. Here, we conduct GWASs of self-reported medication use from 23 medication categories in approximately 320,000 individuals from the UK Biobank. A total of 505 independent genetic loci that meet stringent criteria (P < 10-8/23) for statistical significance are identified. We investigate the implications of these GWAS findings in relation to biological mechanism, potential drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes are 16 known therapeutic-effect target genes for medications from 9 categories. Two of the medication classes studied are for disorders that have not previously been subject to large GWAS (hypothyroidism and gastro-oesophageal reflux disease).


Assuntos
Uso de Medicamentos/estatística & dados numéricos , Genoma Humano , Estudo de Associação Genômica Ampla , Testes Farmacogenômicos/estatística & dados numéricos , Medicamentos sob Prescrição/uso terapêutico , Idoso , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Bases de Dados Factuais , Feminino , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/genética , Gastroenteropatias/fisiopatologia , Loci Gênicos , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/tratamento farmacológico , Doenças Musculoesqueléticas/genética , Doenças Musculoesqueléticas/fisiopatologia , Autoadministração , Autorrelato , Reino Unido
5.
Br J Radiol ; 92(1101): 20180885, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30982323

RESUMO

Psychiatric disease is one of the leading causes of disability worldwide. Despite the global burden and need for accurate diagnosis and treatment of mental illness, psychiatric diagnosis remains largely based on patient-reported symptoms, allowing for immense symptomatic heterogeneity within a single disease. In renewed efforts towards improved diagnostic specificity and subsequent evaluation of treatment response, a greater understanding of the underlying of the neuropathology and neurobiology of neuropsychiatric disease is needed. However, dissecting these mechanisms of neuropsychiatric illness in clinical populations are problematic with numerous experimental hurdles limiting hypothesis-driven studies including genetic confounds, variable life experiences, different environmental exposures, therapeutic histories, as well as the inability to investigate deeper molecular changes in vivo . Preclinical models, where many of these confounding factors can be controlled, can serve as a crucial experimental bridge for studying the neurobiological origins of mental illness. Furthermore, although behavioral studies and molecular studies are relatively common in these model systems, focused neuroimaging studies are very rare and represent an opportunity to link the molecular changes in psychiatric illness with advanced quantitative neuroimaging studies. In this review, we present an overview of well-validated genetic and environmental models of psychiatric illness, discuss gene-environment interactions, and examine the potential role of neuroimaging towards understanding genetic, environmental, and gene-environmental contributions to psychiatric illness.


Assuntos
Encéfalo/diagnóstico por imagem , Interação Gene-Ambiente , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/genética , Neuroimagem/métodos , Humanos , Imagem por Ressonância Magnética/métodos
6.
Psychol Psychother ; 92(2): 190-207, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30924323

RESUMO

Many mental health difficulties have developmental origins. Understanding the mechanisms for how psychosocial experiences are biologically embedded and influence lifelong development is a key challenge for the mental health disciplines. In recent years, epigenetic processes have emerged as a potential mechanism mediating the long-lasting vulnerability following the experience of adversity. Animal models provide evidence that early-life adversity can produce enduring epigenetic modifications in the brain, which mediate disorder-like behaviours, and there is emerging evidence to support that environmental factors influence epigenetic processes in humans. The investigation of DNA methylation, a chemical modification of the DNA with a role in gene regulatory processes, is becoming increasingly popular in psychological studies. A particular interest for the psychotherapy field lies in the potential for psychological interventions to influence epigenetic processes. Hence, the focus of this review will be on studies that have investigated intervention-associated changes in DNA methylation. Results of the first few studies will be critically reviewed, and a model of how therapy-associated changes of DNA methylation in peripheral, non-brain tissue might be useful as epigenetic biomarkers of treatment outcome will be presented. PRACTITIONER POINTS: Many mental health difficulties have substantial developmental origin. Epigenetic processes have emerged as a potential mechanism mediating the long-term effects of early adversity Epigenetic refers to cellular mechanisms that control gene expression states, independent of changes to the underlying DNA sequence. The epigenome can be highly dynamic and potentially influenced by external factors A particular interest for the psychotherapy field lies in the potential for psychological interventions to influence epigenetic processes.


Assuntos
Epigênese Genética , Transtornos Mentais/genética , Transtornos Mentais/terapia , Psicoterapia/métodos , Animais , Metilação de DNA , Modelos Animais de Doenças , Humanos
9.
Transl Psychiatry ; 9(1): 47, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705257

RESUMO

Differential DNA methylation in the brain is associated with many psychiatric diseases, but access to brain tissues is essentially limited to postmortem samples. The use of surrogate tissues has become common in identifying methylation changes associated with psychiatric disease. In this study, we determined the extent to which peripheral tissues can be used as surrogates for DNA methylation in the brain. Blood, saliva, buccal, and live brain tissue samples from 27 patients with medically intractable epilepsy undergoing brain resection were collected (age range 5-61 years). Genome-wide methylation was assessed with the Infinium HumanMethylation450 (n = 12) and HumanMethylationEPIC BeadChip arrays (n = 21). For the EPIC methylation data averaged for each CpG across subjects, the saliva-brain correlation (r = 0.90) was higher than that for blood-brain (r = 0.86) and buccal-brain (r = 0.85) comparisons. However, within individual CpGs, blood had the highest proportion of CpGs correlated to brain at nominally significant levels (20.8%), as compared to buccal tissue (17.4%) and saliva (15.1%). For each CpG and each gene, levels of brain-peripheral tissue correlation varied widely. This indicates that to determine the most useful surrogate tissue for representing brain DNA methylation, the patterns specific to the genomic region of interest must be considered. To assist in that objective, we have developed a website, IMAGE-CpG, that allows researchers to interrogate DNA methylation levels and degree of cross-tissue correlation in user-defined locations across the genome.


Assuntos
Encéfalo/metabolismo , Metilação de DNA , Transtornos Mentais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Ilhas de CpG , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Saliva/metabolismo , Adulto Jovem
11.
EBioMedicine ; 41: 517-525, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30745170

RESUMO

BACKGROUND: Suicide is a major issue for global public health. Suicidality describes a broad spectrum of thoughts and behaviours, some of which are common in the general population. Although suicide results from a complex interaction of multiple social and psychological factors, predisposition to suicidality is at least partly genetic. METHODS: Ordinal genome-wide association study of suicidality in the UK Biobank cohort comparing: 'no suicidality' controls (N = 83,557); 'thoughts that life was not worth living' (N = 21,063); 'ever contemplated self-harm' (N = 13,038); 'act of deliberate self-harm in the past' (N = 2498); and 'previous suicide attempt' (N = 2666). OUTCOMES: We identified three novel genome-wide significant loci for suicidality (on chromosomes nine, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (rg 0·81). INTERPRETATION: These findings provide new information about genetic variants relating to increased risk of suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level. FUND: UKRI Innovation-HDR-UK Fellowship (MR/S003061/1). MRC Mental Health Data Pathfinder Award (MC_PC_17217). MRC Doctoral Training Programme Studentship at the University of Glasgow (MR/K501335/1). MRC Doctoral Training Programme Studentship at the Universities of Glasgow and Edinburgh. UKRI Innovation Fellowship (MR/R024774/1).


Assuntos
Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Suicídio , Adulto , Idoso , Bancos de Espécimes Biológicos , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ideação Suicida , Tentativa de Suicídio/psicologia , Reino Unido
12.
Nervenarzt ; 90(2): 99-106, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30758637

RESUMO

A long-established hypothesis is that genetic factors contribute to the development of psychiatric diseases, including common illnesses such as schizophrenia and the affective disorders; however, reliable molecular identification of these factors represents a far more recent innovation. This has been rendered possible by technological advances in the individual characterization of the human genome and the combining of large genetic datasets at the international level. For the first time, the results of genome-wide analyses provide researchers with systematic insights into disease-relevant biological mechanisms. Here, the integrated analysis of different omics level data generates important insights into the functional interpretation of the genetic findings. The results of genetic studies also demonstrated the degree of etiological overlap between differing psychiatric disorders, with the greatest commonality having been observed to date between schizophrenia and bipolar affective disorder. Although the translation of genetic findings into routine clinical practice is being pursued at various levels, elaborate follow-up studies are typically necessary. The diagnostic investigation of rare genomic deletions/duplications (so-called copy number variants) in patients with schizophrenia is likely to represent one of the first examples of routine clinical application. The necessary prerequisites for this are currently being defined.


Assuntos
Predisposição Genética para Doença , Transtornos Mentais , Transtorno Bipolar/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Genômica , Humanos , Transtornos Mentais/genética , Esquizofrenia/genética
13.
Transl Psychiatry ; 9(1): 39, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696804

RESUMO

A consistent gene set undergoes age-associated expression changes in the human cerebral cortex, and our Age-by-Disease Model posits that these changes contribute to psychiatric diseases by "pushing" the expression of disease-associated genes in disease-promoting directions. DNA methylation (DNAm) is an attractive candidate mechanism for age-associated gene expression changes. We used the Illumina HumanMethylation450 array to characterize genome-wide DNAm in the postmortem orbital frontal cortex from 20 younger (<42 years) and 19 older (>60 years) subjects. DNAm data were integrated with existing normal brain aging expression data and sets of psychiatric disease risk genes to test the hypothesis that age-associated DNAm changes contribute to age-associated gene expression changes and, by extension, susceptibility to psychiatric diseases. We found that age-associated differentially methylated regions (aDMRs) are common, robust, bidirectional, concentrated in CpG island shelves and sea, depleted in CpG islands, and enriched among genes undergoing age-associated expression changes (OR = 2.30, p = 1.69 × 10-27). We found the aDMRs are enriched among genetic association-based risk genes for schizophrenia, Alzheimer's disease (AD), and major depressive disorder (MDD) (OR = 2.51, p = 0.00015; OR = 2.38, p = 0.036; and OR = 3.08, p = 0.018, respectively) as well as expression-based MDD-associated genes (OR = 1.48, p = 0.00012). Similar patterns of enrichment were found for aDMRs that correlate with local gene expression. These results were replicated in a large publically-available dataset, and confirmed by meta-analysis of the two datasets. Our findings suggest DNAm is a molecular mechanism for age-associated gene expression changes and support a role for DNAm in age-by-disease interactions through preferential targeting of disease-associated genes.


Assuntos
Envelhecimento/genética , Metilação de DNA , Lobo Frontal/metabolismo , Transtornos Mentais/genética , Adulto , Idoso , Doença de Alzheimer/genética , Ilhas de CpG , Transtorno Depressivo Maior/genética , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Esquizofrenia/genética
14.
Nat Commun ; 10(1): 134, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635555

RESUMO

The development of the mammalian cerebral cortex depends on careful orchestration of proliferation, maturation, and migration events, ultimately giving rise to a wide variety of neuronal and non-neuronal cell types. To better understand cellular and molecular processes that unfold during late corticogenesis, we perform single-cell RNA-seq on the mouse cerebral cortex at a progenitor driven phase (embryonic day 14.5) and at birth-after neurons from all six cortical layers are born. We identify numerous classes of neurons, progenitors, and glia, their proliferative, migratory, and activation states, and their relatedness within and across age. Using the cell-type-specific expression patterns of genes mutated in neurological and psychiatric diseases, we identify putative disease subtypes that associate with clinical phenotypes. Our study reveals the cellular template of a complex neurodevelopmental process, and provides a window into the cellular origins of brain diseases.


Assuntos
Linhagem da Célula/genética , Desenvolvimento Embrionário/genética , Perfilação da Expressão Gênica , Neocórtex/embriologia , Animais , Sequência de Bases , Linhagem Celular , Ciliopatias/genética , Feminino , Células HEK293 , Humanos , Masculino , Transtornos Mentais/genética , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/genética , Neurônios/citologia , Neurônios/metabolismo , Análise de Sequência de RNA , Análise de Célula Única , Células-Tronco/citologia , Transcrição Genética/genética
15.
Nervenarzt ; 90(2): 107-113, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30643952

RESUMO

Environmental factors are among the strongest risk factors for psychiatric disorders. Differences in exposure to such environments have been associated with lasting biological changes. In recent years epigenetic mechanisms have been brought to the forefront as central in mediating a lasting embedding of environmental risk factors. This article first summarizes the different levels of epigenetic regulation and then focuses on mechanisms transducing environmental signals into lasting epigenetic changes. This is followed by examples of how environmentally induced epigenetic changes relate to risk and resilience to psychiatric disorders and their treatment.


Assuntos
Epigênese Genética , Transtornos Mentais , Humanos , Transtornos Mentais/genética , Fatores de Risco
16.
Nat Commun ; 10(1): 431, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683880

RESUMO

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias de Cabeça e Pescoço/genética , Padrões de Herança , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etnologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Transtornos Mentais/etnologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia , Fumar/etnologia , Fumar/genética , Fumar/fisiopatologia
17.
Nat Neurosci ; 22(3): 353-361, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692689

RESUMO

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.


Assuntos
Encéfalo/embriologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Transtornos Mentais/genética , Encéfalo/metabolismo , Estudos de Coortes , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
18.
Mol Pharmacol ; 95(1): 62-69, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30397000

RESUMO

Schizophrenia (SZ), schizoaffective (SZA), and bipolar (BP) disorder are neurodevelopmental psychopathological conditions related, in part, to genetic load and, in part, to environmentally induced epigenetic dysregulation of chromatin structure and function in neocortical GABAergic, glutamatergic, and monoaminergic neurons. To test the above hypothesis, we targeted our scientific efforts on identifying whether the molecular epigenetic signature of postmortem brains of patients with SZ, SZA, and BP disorder are also present in the brains of adult mice born from dams prenatally restraint stressed (PRS) during gestation. The brains of PRS mice, which are similar to the brains of patients with SZ and BP disorder, show an ∼2-fold increased binding of DNMT1 to psychiatric candidate promoters (glutamic acid decarboxylase 67, Reelin, and brain-derived neurotrophic factor), leading to their hypermethylation, reduced expression, as well as the behavioral endophenotypes reminiscent of those observed in the above psychiatric disorders. To establish whether clozapine (CLO) produces its behavioral and molecular action through a causal involvement of DNA methylation/demethylation processes, we compared the epigenetic action of CLO with that of the DNMT1 competitive inhibitor N-phthalyl-l-tryptophan (RG108). The intracerebroventricular injection of RG108 (20 nmol/day per 5 days), similar to the systemic administration of CLO, corrects the altered behavioral and molecular endophenotypes that are typical of PRS mice. These results are consistent with an epigenetic etiology underlying the behavioral endophenotypic profile in PRS mice. Further, it suggests that PRS mice may be useful in the preclinical screening of antipsychotic drugs acting to correct altered epigenetic mechanisms.


Assuntos
Encéfalo/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Cromatina/efeitos dos fármacos , Clozapina/farmacologia , Transtornos Mentais/genética , Ftalimidas/farmacologia , Triptofano/análogos & derivados , Animais , Antipsicóticos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Moléculas de Adesão Celular Neuronais/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Proteínas da Matriz Extracelular/genética , Feminino , Glutamato Descarboxilase/genética , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Serina Endopeptidases/genética , Triptofano/farmacologia
19.
Eur J Neurol ; 26(1): 66-e7, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30063100

RESUMO

BACKGROUND AND PURPOSE: CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. METHODS: Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. RESULTS: Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. CONCLUSIONS: Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.


Assuntos
Canais de Cálcio/genética , Transtornos Mentais/genética , Doenças do Sistema Nervoso/genética , Adolescente , Adulto , Ataxia/genética , Ataxia Cerebelar/genética , Criança , Pré-Escolar , Comorbidade , Escolaridade , Feminino , Genótipo , Humanos , Masculino , Transtornos Mentais/psicologia , Transtornos de Enxaqueca/genética , Doenças do Sistema Nervoso/psicologia , Testes Neuropsicológicos , Fenótipo , Desempenho Psicomotor , Estudos Retrospectivos , Ataxias Espinocerebelares/genética , Adulto Jovem
20.
Methods Mol Biol ; 1916: 41-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30535680

RESUMO

Mental disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are generally characterized by a combination of abnormal thoughts, perceptions, emotions, behavior, and relationships with others. Multiple risk factors incorporating genetic and environmental susceptibility are associated with development of these disorders. Mitochondria have a central role in the energy metabolism, and the literature suggests energy metabolism abnormalities are widespread in the brains of subjects with MDD, BD, and SZ. Numerous studies have shown altered expressions of mitochondria-related genes in these mental disorders. In addition, environmental factors for these disorders, such as stresses, have been suggested to induce mitochondrial abnormalities. Moreover, animal studies have suggested that interactions of altered expression of mitochondria-related genes and environmental factors might be involved in mental disorders. Further investigations into interactions of mitochondrial abnormalities with environmental factors are required to elucidate of the pathogenesis of these mental disorders.


Assuntos
Encéfalo/metabolismo , Metabolismo Energético/genética , Transtornos Mentais/metabolismo , Mitocôndrias/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/patologia , Encéfalo/patologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/patologia , Humanos , Transtornos Mentais/genética , Transtornos Mentais/patologia , Mitocôndrias/patologia , Fatores de Risco , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA