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1.
Mol Psychiatry ; 28(10): 4321-4330, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37587247

RESUMO

Obsessive-compulsive disorder (OCD) is a prevalent mental disorder affecting ~2-3% of the population. This disorder involves genetic and, possibly, epigenetic risk factors. The dynamic nature of epigenetics also presents a promising avenue for identifying biomarkers associated with symptom severity, clinical progression, and treatment response in OCD. We, therefore, conducted a comprehensive case-control investigation using Illumina MethylationEPIC BeadChip, encompassing 185 OCD patients and 199 controls recruited from two distinct sites in Germany. Rigorous clinical assessments were performed by trained raters employing the Structured Clinical Interview for DSM-IV (SCID-I). We performed a robust two-step epigenome-wide association study that led to the identification of 305 differentially methylated CpG positions. Next, we validated these findings by pinpointing the optimal set of CpGs that could effectively classify individuals into their respective groups. This approach identified a subset comprising 12 CpGs that overlapped with the 305 CpGs identified in our EWAS. These 12 CpGs are close to or in genes associated with the sweet-compulsive brain hypothesis which proposes that aberrant dopaminergic transmission in the striatum may impair insulin signaling sensitivity among OCD patients. We replicated three of the 12 CpGs signals from a recent independent study conducted on the Han Chinese population, underscoring also the cross-cultural relevance of our findings. In conclusion, our study further supports the involvement of epigenetic mechanisms in the pathogenesis of OCD. By elucidating the underlying molecular alterations associated with OCD, our study contributes to advancing our understanding of this complex disorder and may ultimately improve clinical outcomes for affected individuals.


Assuntos
Epigenoma , Transtorno Obsessivo-Compulsivo , Humanos , Transtorno Obsessivo-Compulsivo/genética , Gravidade do Paciente , Índice de Gravidade de Doença , Alemanha
2.
Plant Physiol ; 192(2): 821-836, 2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-36946207

RESUMO

Meiotic recombination is an essential mechanism during sexual reproduction and includes the exchange of chromosome segments between homologous chromosomes. New allelic combinations are transmitted to the new generation, introducing novel genetic variation in the offspring genomes. With the improvement of high-throughput whole-genome sequencing technologies, large numbers of recombinant individuals can now be sequenced with low sequencing depth at low costs, necessitating computational methods for reconstructing their haplotypes. The main challenge is the uncertainty in haplotype calling that arises from the low information content of a single genomic position. Straightforward sliding window-based approaches are difficult to tune and fail to place recombination breakpoints precisely. Hidden Markov model (HMM)-based approaches, on the other hand, tend to over-segment the genome. Here, we present RTIGER, an HMM-based model that exploits in a mathematically precise way the fact that true chromosome segments typically have a certain minimum length. We further separate the task of identifying the correct haplotype sequence from the accurate placement of haplotype borders, thereby maximizing the accuracy of border positions. By comparing segmentations based on simulated data with known underlying haplotypes, we highlight the reasons for RTIGER outperforming traditional segmentation approaches. We then analyze the meiotic recombination pattern of segregants of 2 Arabidopsis (Arabidopsis thaliana) accessions and a previously described hyper-recombining mutant. RTIGER is available as an R package with an efficient Julia implementation of the core algorithm.


Assuntos
Algoritmos , Polimorfismo de Nucleotídeo Único , Humanos , Genótipo , Cadeias de Markov , Haplótipos/genética , Análise de Sequência de DNA/métodos
3.
Nat Genet ; 54(4): 412-436, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379992

RESUMO

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Disfunção Cognitiva/psicologia , Estudo de Associação Genômica Ampla , Humanos , Proteínas tau/genética
4.
Brain ; 145(7): 2507-2517, 2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-35088840

RESUMO

Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-ß 42 (Aß42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aß42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aß42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aß42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Metaloproteinase 10 da Matriz , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Biomarcadores , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Humanos , Estudos Longitudinais , Metaloproteinase 10 da Matriz/líquido cefalorraquidiano , Fragmentos de Peptídeos , Proteínas tau
5.
Epigenetics ; 17(6): 642-652, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34269138

RESUMO

Obsessive-compulsive disorder (OCD) has recently been linked to increased methylation levels in the oxytocin receptor (OXTR) gene, and OXTR hypermethylation has predicted a worse treatment response to cognitive-behavioural therapy (CBT). Furthermore, OCD is associated with childhood trauma and stressful life events, which have both been shown to affect OXTR methylation. Here, we aimed to replicate findings of increased OXTR methylation as a predictor of disease and worse treatment response in an independent sample that received treatment within the public health care system. In addition, we aimed to extend previous findings by examining associations between OXTR hypermethylation, environmental stressors, OCD diagnosis, and treatment response. Methylation levels at two CpGs within OXTR exon III were compared between n = 181 OCD patients and n = 199 healthy controls using linear regression analysis. In a subsample of OCD patients (n = 98) with documented treatment data, we examined associations between methylation and treatment response to CBT. Childhood adversity and stressful life events were assessed using Childhood Trauma Questionnaire and Life Experience Survey, respectively. OCD patients exhibited significant hypermethylation at CpG site cg04523291 compared to controls, and increased methylation was associated with impaired treatment response. Moreover, hypermethylation at cg04523291 was associated with stressful life events in OCD patients, and with childhood adversity in controls. Yet, there were no significant mediation effects. In conclusion, we replicated the association between OXTR hypermethylation and OCD in the largest sample, so far. Furthermore, our findings support the role of OXTR methylation as a promising biomarker for treatment response in OCD.


Assuntos
Metilação de DNA , Transtorno Obsessivo-Compulsivo , Receptores de Ocitocina , Biomarcadores , Humanos , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/terapia , Ocitocina , Receptores de Ocitocina/genética
6.
Proc Natl Acad Sci U S A ; 118(35)2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34429357

RESUMO

The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and -intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a role for HCN channel subunits as a part of a general mechanism influencing cortical development in mammals.


Assuntos
Proliferação de Células/fisiologia , Córtex Cerebral/embriologia , Canalopatias/etiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia , Microcefalia/etiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Animais , Ciclo Celular , Morte Celular , Células Cultivadas , Córtex Cerebral/citologia , Canalopatias/embriologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/fisiologia , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Camundongos , Camundongos Transgênicos , Microcefalia/embriologia , Células-Tronco Neurais/metabolismo , Ratos
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