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1.
Transl Psychiatry ; 9(1): 12, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30664633

RESUMO

Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno Bipolar/fisiopatologia , Substância Cinzenta/fisiopatologia , Esquizofrenia/fisiopatologia , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno Bipolar/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico por imagem , Adulto Jovem
2.
Neuroimage ; 189: 459-467, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30641241

RESUMO

Encoding and retrieval of emotionally arousing stimuli depend on the activation of multiple interconnected brain regions, with people showing differences in their individual strength of emotional perception and recollection. Understanding the association between these brain regions and the behavioral outcome might therefore have important clinical implications as dysfunctional emotional memory processes are characteristic of many psychiatric disorders. Based on behavioral and fMRI data collected from healthy young adults (N = 1'385), we investigated brain activation patterns, arousal ratings and memory performance during encoding and retrieval of negative and neutral pictures. We performed multi-voxel pattern analysis (MVPA) and voxel-wise association analyses. Subjects' individual strength of perceived arousal at encoding and subjects' memory performance at recognition could be predicted from the fMRI data of the respective tasks by using a topographically identical network of brain regions. This network was mainly left lateralized including dense clusters of voxels in the occipital and parietal lobe and including the amygdala. Voxel-wise association analyses confirmed the close link between the brain activation of both tasks and their relation to the respective behavioral outcome. These results point to the importance of the here identified brain network for emotional memory processes in health and, possibly, disease.

3.
Transl Psychiatry ; 8(1): 251, 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30467376

RESUMO

The probability to develop posttraumatic stress disorder (PTSD), characterized by vivid, intrusive emotional memories of the encountered traumatic events, depends - among other factors - on the number of previous traumatic experiences (traumatic load) and individual genetic vulnerability. So far, our knowledge regarding the biological underpinnings of PTSD is relatively sparse. Genome-wide association studies (GWAS) followed by independent replication might help to discover novel, so far unknown biological mechanisms associated with the development of traumatic memories. Here, a GWAS was conducted in N = 924 Northern Ugandan rebel war survivors and identified seven suggestively significant single nucleotide polymorphisms (SNPs; p ≤ 1 × 10-5) for lifetime PTSD risk. Of these seven SNPs, the association of rs3852144 on chromosome 5 was replicated in an independent sample of Rwandan genocide survivors (N = 370, p < .01). While PTSD risk increased with accumulating traumatic experiences, the vulnerability was reduced in carriers of the minor G-allele in an additive manner. Correspondingly, memory for aversive pictures decreased with higher number of the minor G-allele in a sample of N = 2698 healthy Swiss individuals. Finally, investigations on N = 90 PTSD patients treated with Narrative Exposure Therapy indicated an additive effect of genotype on PTSD symptom change from pre-treatment to four months after treatment, but not between pre-treatment and the 10-months follow-up. In conclusion, emotional memory formation seems to decline with increasing number of rs3852144 G-alleles, rendering individuals more resilient to PTSD development. However, the impact on therapy outcome remains preliminary and further research is needed to determine how this intronic marker may affect memory processes in detail.

4.
Mol Psychiatry ; 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279459

RESUMO

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer's disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields' genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10-16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

5.
Psychophysiology ; : e13288, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30328613

RESUMO

The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.

6.
Cell Physiol Biochem ; 48(3): 1201-1214, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30045020

RESUMO

BACKGROUND: Reductions in the volume of brain white matter are a common feature in schizophrenia and bipolar disorder while the association between white matter and polygenic schizophrenia-related risk is unclear. To look at the intermediate state between health and the full-blown disorder, we investigated this aspect in groups of patients before and after the onset of psychosis. METHODS: On a 3 Tesla scanner, total and regional white matter volumes were investigated by structural magnetic resonance imaging (MRI) in the following groups: 37 at-risk mental state patients (ARMS), including 30 with no transition to psychosis (ARMS-NT) and 7 with a transition to psychosis (ARMS-T) pooled with 25 first episode psychosis (FEP) patients. These T1-weighted images were automatically processed with the FreeSurfer software and compared with an odds-ratio-weighted polygenic schizophrenia-related risk score (PSRS) based on the publicly available top white matter single-nucleotide polymorphisms. RESULTS: We found no association, only a trend, between PSRS and white matter volume over all groups (ß = 0.24, p = 0.07, 95% confidence interval = [-0.02 - 0.49]). However, a higher PSRS was significantly associated with a higher probability of being assigned to the ARMS-T + FEP group rather than to the ARMS-NT group (ß = 0.70, p = 0.02, 95% confidence interval = [0.14 - 1.33]); there was no such association with white matter volume. Additionally, a positive association was found between PSRS and the Brief Psychiatric Rating Scale (BPRS) total score for the pooled ARMS-NT/ARMS-T+FEP sample and for the ARMS-T + FEP group also, but none for the ARMS-NT group only. CONCLUSION: These findings suggest that at-risk mental state patients with a transition and first-episode psychosis patients have a higher genetic risk for schizophrenia than at-risk mental state patients with no transition to psychosis; this risk was associated with psychopathological symptoms. Further analyses may allow polygenic schizophrenia-related risk scores to be used as biomarkers to predict psychosis.


Assuntos
Encéfalo/patologia , Transtornos Psicóticos/patologia , Esquizofrenia/patologia , Substância Branca/patologia , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/genética , Fatores de Risco , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Adulto Jovem
7.
Transl Psychiatry ; 8(1): 31, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29382824

RESUMO

The large biological distance between genetic risk loci and their mechanistic consequences in the tissue of interest limits the ability to establish functionality of susceptibility variants for genetically complex traits. Such a biological gap may be reduced through the systematic study of molecular mediators of genomic action, such as epigenetic modification. Here, we report the identification of robust genetic estimators of whole-blood CpG methylation, which can serve as intermediate molecular traits amenable to association testing with other genetically complex traits. We describe the relationship between these estimators and gene expression, demonstrate their genome-wide applicability to association testing even in the absence of individual genotypic data, and show that these estimators powerfully identify methylation-related genomic loci associated with polygenic traits and common diseases, such as schizophrenia. The use of genetic estimators for blood DNA methylation, which are made publically available, can serve as a valuable tool for the identification of epigenetic underpinnings of complex traits.

8.
eNeuro ; 5(1)2018 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29464194

RESUMO

Working memory (WM) is an important cognitive domain for everyday life functioning and is often disturbed in neuropsychiatric disorders. Functional magnetic resonance imaging (fMRI) studies in humans show that distributed brain areas typically described as fronto-parietal regions are implicated in WM tasks. Based on data from a large sample of healthy young adults (N = 1369), we applied independent component analysis (ICA) to the WM-fMRI signal and identified two distinct networks that were relevant for differences in individual WM task performance. A parietally-centered network was particularly relevant for individual differences in task measures related to WM performance ("WM dependent") and a frontally-centered network was relevant for differences in attention-dependent task performance. Importantly, frontal areas that are typically considered as key regions for WM were either involved in both WM-dependent and attention-dependent performance, or in attention-dependent performance only. The networks identified here are provided as publicly available datasets. These networks can be applied in future studies to derive a low-dimensional representation of the overall WM brain activation.

9.
Bioinformatics ; 34(1): 107-108, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28968639

RESUMO

Motivation: Next-generation sequencing is now an established method in genomics, and massive amounts of sequencing data are being generated on a regular basis. Analysis of the sequencing data is typically performed by lab-specific in-house solutions, but the agreement of results from different facilities is often small. General standards for quality control, reproducibility and documentation are missing. Results: We developed NGS-pipe, a flexible, transparent and easy-to-use framework for the design of pipelines to analyze whole-exome, whole-genome and transcriptome sequencing data. NGS-pipe facilitates the harmonization of genomic data analysis by supporting quality control, documentation, reproducibility, parallelization and easy adaptation to other NGS experiments. Availability and implementation: https://github.com/cbg-ethz/NGS-pipe. Contact: niko.beerenwinkel@bsse.ethz.ch.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos , Software , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/normas , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Neoplasias/genética , Reprodutibilidade dos Testes , Análise de Sequência de DNA/normas , Análise de Sequência de RNA/normas
10.
Sci Rep ; 7(1): 13669, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29057891

RESUMO

Studies assessing the existence and magnitude of epistatic effects on complex human traits provide inconclusive results. The study of such effects is complicated by considerable increase in computational burden, model complexity, and model uncertainty, which in concert decrease model stability. An additional source introducing significant uncertainty with regard to the detection of robust epistasis is the biological distance between the genetic variation and the trait under study. Here we studied CpG methylation, a genetically complex molecular trait that is particularly close to genomic variation, and performed an exhaustive search for two-locus epistatic effects on the CpG-methylation signal in two cohorts of healthy young subjects. We detected robust epistatic effects for a small number of CpGs (N = 404). Our results indicate that epistatic effects explain only a minor part of variation in DNA-CpG methylation. Interestingly, these CpGs were more likely to be associated with gene-expression of nearby genes, as also shown by their overrepresentation in DNase I hypersensitivity sites and underrepresentation in CpG islands. Finally, gene ontology analysis showed a significant enrichment of these CpGs in pathways related to HPV-infection and cancer.

11.
Proc Natl Acad Sci U S A ; 114(34): 9176-9181, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28790188

RESUMO

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Norepinefrina/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Moléculas de Adesão Celular Neuronais/genética , Metilação de DNA/efeitos dos fármacos , Discriminação (Psicologia)/efeitos dos fármacos , Discriminação (Psicologia)/fisiologia , Proteínas da Matriz Extracelular/genética , Agonistas de Receptores de GABA-A/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Memória de Longo Prazo/fisiologia , Muscimol/farmacologia , Proteínas do Tecido Nervoso/genética , Norepinefrina/administração & dosagem , Ratos Sprague-Dawley , Serina Endopeptidases/genética , Transcriptoma/efeitos dos fármacos
12.
Brain Behav ; 7(7): e00721, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28729929

RESUMO

INTRODUCTION: Memory functions are highly variable between healthy humans. The neural correlates of this variability remain largely unknown. METHODS: Here, we investigated how differences in free recall performance are associated with DTI-based properties of the brain's structural connectome and with grey matter volumes in 664 healthy young individuals tested in the same MR scanner. RESULTS: Global structural connectivity, but not overall or regional grey matter volumes, positively correlated with recall performance. Moreover, a set of 22 inter-regional connections, including some with no previously reported relation to human memory, such as the connection between the temporal pole and the nucleus accumbens, explained 7.8% of phenotypic variance. CONCLUSIONS: In conclusion, this large-scale study indicates that individual memory performance is associated with the level of structural brain connectivity.


Assuntos
Encéfalo/diagnóstico por imagem , Conectoma , Substância Cinzenta/diagnóstico por imagem , Rememoração Mental/fisiologia , Adulto , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Adulto Jovem
13.
J Neurosci ; 37(28): 6661-6672, 2017 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-28592692

RESUMO

The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in Caenorhabditis elegans hermaphrodites. Here, we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follows three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Compared with the previously published positive LTAM gene set (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory-related genes. On the other hand, the remaining genes were not previously identified in positive associative memory and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memory-implicated genes as well as conditioning-type-dependent gene sets.SIGNIFICANCE STATEMENT The identification of genes regulating different steps of memory is of major interest in neuroscience. Identification of common memory genes across different learning paradigms and the temporal activation of the genes are poorly studied. Here, we investigated the temporal aspects of Caenorhabditis elegans gene expression changes using aversive olfactory associative long-term memory (LTAM) and identified three major gene activation waves. Like in previous studies, aversive LTAM is also CREB dependent, and CREB activity is necessary immediately after training. Finally, we define a list of memory paradigm-independent core gene sets as well as conditioning-dependent genes.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Regulação da Expressão Gênica/fisiologia , Memória de Longo Prazo/fisiologia , Proteínas do Tecido Nervoso/genética , Proteoma/metabolismo , Animais , Aprendizagem por Associação/fisiologia , Proteínas de Caenorhabditis elegans/genética , Mapeamento Cromossômico , Perfilação da Expressão Gênica , Genoma/genética , Proteoma/genética
15.
Nat Commun ; 8: 15193, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28443631

RESUMO

Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10-8) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P<0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits.


Assuntos
Envelhecimento/genética , Metilação de DNA/genética , Epigênese Genética/genética , Sistema Imunitário/imunologia , Memória/fisiologia , Neocórtex/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG/genética , Transtorno Depressivo Maior/genética , Feminino , Variação Genética/genética , Humanos , Sistema Imunitário/citologia , Masculino , Pessoa de Meia-Idade , Suíça , Adulto Jovem
16.
J Psychiatr Res ; 91: 116-123, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28334615

RESUMO

Depressive symptoms exist on a continuum, the far end of which is found in depressive disorders. Utilizing the continuous spectrum of depressive symptoms may therefore contribute to the understanding of the biological underpinnings of depression. Gene set enrichment analysis (GSEA) is an important tool for the identification of gene groups linked to complex traits, and was applied in the present study on genome-wide association study (GWAS) data of depression scores and their brain-level structural correlates in healthy young individuals. On symptom level (i.e. depression scores), robust enrichment was identified for two gene sets: NCAM1 Interactions and Collagen Formation. Depression scores were also associated with decreased fractional anisotropy (FA) - a brain white matter property - within the forceps minor and the left superior temporal longitudinal fasciculus. Within each of these tracts, mean FA value of depression score-associated voxels was used as a phenotype in a subsequent GSEA. The NCAM1 Interactions gene set was significantly enriched in these tracts. By linking the NCAM1 Interactions gene set to depression scores and their structural brain correlates in healthy participants, the current study contributes to the understanding of the molecular underpinnings of depressive symptomatology.


Assuntos
Encéfalo/patologia , Antígeno CD56/genética , Colágeno/genética , Depressão/genética , Depressão/patologia , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Anisotropia , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Colágeno/metabolismo , Imagem de Tensor de Difusão , Feminino , Estudos de Associação Genética , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
17.
J Psychiatr Res ; 83: 260-268, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27710795

RESUMO

DNA methylation represents an important link between structural genetic variation and complex phenotypes. The study of genome-wide CpG methylation and its relation to traits relevant to psychiatry has become increasingly important. Here, we analyzed quality metrics of 394,043 CpG sites in two samples of 568 and 319 mentally healthy young adults. For 25% of all CpGs we observed medium to large common epigenetic variation. These CpGs were overrepresented in open sea and shore regions, as well as in intergenic regions. They also showed a strong enrichment of significant hits in association analyses. Furthermore, a significant proportion of common DNA methylation is at least partially genetically driven and thus may be observed similarly across tissues. These findings could be of particular relevance for studies of complex neuropsychiatric traits, which often rely on proxy tissues.


Assuntos
Ilhas de CpG/genética , Epigênese Genética/genética , Saúde Mental , Adulto , Metilação de DNA/genética , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Voluntários Saudáveis , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
19.
Dev Psychopathol ; 28(4pt2): 1401-1412, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26753719

RESUMO

Child abuse is associated with a number of emotional and behavioral problems. Nevertheless, it has been argued that these adverse consequences may not hold for societies in which many of the specific acts of abuse are culturally normed. Epigenetic modifications in the genes of the hypothalamus-pituitary-adrenal axis may provide a potential mechanism translating abuse into altered gene expression, which subsequently results in behavioral changes. Our investigation took place in Tanzania, a society in which many forms of abuse are commonly employed as disciplinary methods. We included 35 children with high exposure and compared them to 25 children with low exposure. Extreme group comparisons revealed that children with high exposure reported more mental health problems. Child abuse was associated with differential methylation in the proopiomelanocortin gene (POMC), measured both in saliva and in blood. Hierarchical clustering based on the methylation of the POMC gene found two distinct clusters. These corresponded with children's self-reported abuse, with two-thirds of the children allocated into their respective group. Our results emphasize the consequences of child abuse based on both molecular and behavioral grounds, providing further evidence that acts of abuse affect children, even when culturally acceptable. Furthermore, on a molecular level, our findings strengthen the credibility of children's self-reports.


Assuntos
Maus-Tratos Infantis/psicologia , Transtornos do Comportamento Infantil/etiologia , Epigênese Genética , Saúde Mental , Pró-Opiomelanocortina/genética , Adolescente , Criança , Transtornos do Comportamento Infantil/genética , Transtornos do Comportamento Infantil/psicologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Tanzânia
20.
JAMA Psychiatry ; 72(10): 1029-36, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26332608

RESUMO

IMPORTANCE: Human episodic memory performance is linked to the function of specific brain regions, including the hippocampus; declines as a result of increasing age; and is markedly disturbed in Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human episodic memory is key to the understanding of hippocampus-dependent cognitive physiology and pathophysiology. OBJECTIVE: To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and AD. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter collaborative study, which began in August 2008 and is ongoing, gene set enrichment analysis was done by using primary and meta-analysis data from 57 968 participants. The Swiss cohorts consisted of 3043 healthy young adults assessed for episodic memory performance. In a subgroup (n = 1119) of one of these cohorts, functional magnetic resonance imaging was used to identify gene set-dependent differences in brain activity related to episodic memory. The German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). Analyses were conducted between January 2014 and June 2015. Gene set enrichment analysis in all samples was done using genome-wide single-nucleotide polymorphism data. MAIN OUTCOMES AND MEASURES: Episodic memory performance in the Swiss cohort and German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. In the functional magnetic resonance imaging experiment, activation of the hippocampus during encoding of pictures served as the phenotype of interest. In the International Genomics of Alzheimer's Project sample, diagnosis of sporadic AD served as the phenotype of interest. RESULTS: In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (P = 2 × 10-4). This enrichment was replicated in 2 additional samples of healthy young individuals (P = .02 and .04, respectively) and a sample of healthy elderly participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium. CONCLUSIONS AND RELEVANCE: By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.


Assuntos
Doença de Alzheimer/genética , Sinalização do Cálcio/genética , Hipocampo/fisiopatologia , Memória Episódica , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
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