Biology subjects

Rutten, B. P. F.

Publications and source records attributed to Rutten, B. P. F..

6 recordsLinked to original sources

bioRxiv2023

Epigenome-wide profiling in the dorsal raphe nucleus highlights cell-type-specific changes in TNXB in Alzheimer's disease

Recent studies have demonstrated that the dorsal raphe nucleus (DRN) is among the first brain regions affected in Alzheimers disease. Hence, in this study we conducted the first comprehensive epigenetic analysis of the DRN in AD, targeting both bulk tissue and single isolated cells. The Illumina Infinium MethylationEPIC BeadChip array was used to analyze the bulk tissue, assessing differentially modified positions (DMoPs) and regions (DMoRs) associated with Braak stage. The strongest Braak stage-associated DMoR in TNXB was targeted in a second patient cohort utilizing single laser-capture microdissected serotonin-positive (5-HT+) and -negative (5-HT-) cells isolated from the DRN. Our study revealed previously identified epigenetic loci, including TNXB and PGLYRP1, and novel loci, including RBMXL2, CAST, GNAT1, MALAT1, and DNAJB13. Strikingly, we found that the methylation profile of TNXB depends both on disease phenotype and cell type analyzed, emphasizing the significance of single cell(-type) neuroepigenetic studies in AD.

neuroscience↗

bioRxiv2021

A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data. Unfortunately, measurements for individual CpGs can be surprisingly unreliable due to technical noise, and this may limit the utility of epigenetic clocks. We report that noise produces deviations up to 3 to 9 years between technical replicates for six major epigenetic clocks. The elimination of low-reliability CpGs does not ameliorate this issue. Here, we present a novel computational multi-step solution to address this noise, involving performing principal component analysis on the CpG-level data followed by biological age prediction using principal components as input. This method extracts shared systematic variation in DNAm while minimizing random noise from individual CpGs. Our novel principal-component versions of six clocks show agreement between most technical replicates within 0 to 1.5 years, equivalent or improved prediction of outcomes, and more stable trajectories in longitudinal studies and cell culture. This method entails only one additional step compared to traditional clocks, does not require prior knowledge of CpG reliabilities, and can improve the reliability of any existing or future epigenetic biomarker. The high reliability of principal component-based epigenetic clocks will make them particularly useful for applications in personalized medicine and clinical trials evaluating novel aging interventions.

bioinformatics↗

bioRxiv2020

Transcranial Magnetic stimulation (TMS) modulates functional activity of SH-SY5Y cells: An in vitro model provides support for assumed excitability changes

Repetitive Transcranial Magnetic Stimulation (rTMS) is an established neuromodulation technique, using electromagnetic pulses that, depending on the precise parameters, are assumed to lead to lasting neural excitability changes. rTMS has widespread applications in both research and therapy, where it has been FDA approved and is considered a first-line treatment for depression, according to recent North American and European guidelines. However, these assumed excitability effects are often difficult to replicate, and highly unreliable on the single subject/patient level. Given the increasing application of rTMS, especially in clinical practice, the absence of a method to unequivocally determine effects of rTMS on human neuronal excitability is problematic. We have taken a first step in addressing this bottleneck, by administering excitatory and inhibitory rTMS protocols, iTBS and cTBS, to a human in vitro neuron model; differentiated SH-SY5Y cells. We use live calcium imaging to assess changes in neural activity following stimulation, through quantifying fluorescence response to chemical depolarization. We found that iTBS and cTBS have opposite effects on fluorescence response; with iTBS increasing and cTBS decreasing response to chemical depolarization. Our results are promising, as they provide a clear demonstration of rTMS after-effects in a living human neuron model. We here present an in-vitro live calcium imaging setup that can be further applied to more complex human neuron models, for developing and evaluating subject/patient-specific brain stimulation protocols.

neuroscience↗

bioRxiv2019

Interaction between polygenic liability for schizophrenia and childhood adversity influences daily-life emotional dysregulation and psychosis proneness

BackgroundThe earliest stages of the pluripotent psychopathology on the pathway to psychotic disorders is represented by emotional dysregulation and subtle psychosis expression, which can be measured using the Ecological Momentary Assessment (EMA). However, it is not clear to what degree common genetic and environmental risk factors for psychosis contribute to variation in these early expressions of psychopathology.\n\nMethodsIn this largest ever EMA study of a general population twin cohort including 593 adolescents and young adults between the ages of 15 and 35 years, we tested whether polygenic risk score for schizophrenia (PRS-S) interacts with childhood adversity (the Childhood Trauma Questionnaire score) and daily-life stressors to influence momentary mental state domains (negative affect, positive affect, and subtle psychosis expression) and stress-sensitivity measures.\n\nResultsBoth childhood adversity and daily-life stressors were associated with increased negative affect, decreased positive affect, and increased subtle psychosis expression, while PRS-S was only associated with increased positive affect. No gene-environment correlation was detected. We have provided novel evidence for interaction effects between PRS-S and childhood adversity to influence momentary mental states [negative affect (b = 0.07, 95% CI 0.01 to 0.13, P = 0.013), positive affect (b = -0.05, 95% CI -0.10 to -0.00, P = 0.043), and subtle psychosis expression (b = 0.11, 95% CI 0.03 to 0.19, P = 0.007)] and stress-sensitivity measures.\n\nConclusionExposure to childhood adversities, particularly in individuals with high PRS-S, is pleiotropically associated with emotional dysregulation and psychosis proneness.

genomics↗

bioRxiv2019

Meta-analysis of longitudinal epigenome-wide association studies of military cohorts reveals multiple CpG sites associated with post-traumatic stress disorder

BackgroundEpigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts composed of male military members were combined to assess whether DNA methylation profiles are associated with the development of PTSD.\n\nMethodsA total of 123 cases and 143 trauma-exposed controls were included. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis. We first combined two cohorts in a discovery stage (N=126 and 78), sought targeted replication in the third cohort (N=62) and then performed a meta-analysis of all three datasets.\n\nResultsThe discovery stage identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was associated with PTSD status after adjustment for multiple comparisons. The most significant CpG (p = 1.0 x 10-08) was located on 5q31 and replicated in the third cohort. When combining all cohorts, this intergenic site remained most significant along with two CpGs located in MAD1L1 and HEXDC. Interestingly, the CpG site of MAD1L1 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP. Twelve differential methylated regions (DMRs) were also identified, one of which was located in MAD1L1 and four were situated in the human leukocyte antigen (HLA) region.\n\nConclusionThis study suggests that the development of PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent finding points to the involvement of MAD1L1 which was previously associated with PTSD.

genetics↗

bioRxiv2019

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci

Differences in susceptibility to posttraumatic stress disorder (PTSD) may be related to epigenetic differences between PTSD cases and trauma-exposed controls. Such epigenetic differences may provide insight into the biological processes underlying the disorder. Here we describe the results of the largest DNA methylation meta-analysis of PTSD to date with data from the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. Ten cohorts, military and civilian, contributed blood-derived DNA methylation data (HumanMethylation450 BeadChip) from 1,896 PTSD cases (42%) and trauma-exposed controls (58%). Utilizing a common QC and analysis strategy, we identified ten CpG sites associated with PTSD (9.61E-07<p<4.72E-11) after adjustment for multiple comparisons (FDR<.05). Several CpGs were located in genes previously implicated in PTSD and other psychiatric disorders. The top four CpG sites fell within the aryl-hydrocarbon receptor repressor (AHRR) locus and were associated with lower DNA methylation in PTSD cases relative to controls. Interestingly, this association appeared to uncorrelated with smoking status and was most pronounced in non-smokers with PTSD. Additional evaluation of metabolomics data supported our findings and revealed that AHRR methylation associated with kynurenine levels, which were lower among subjects with PTSD relative to controls. Overall, this study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

genomics↗