Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths

Spíndola, Letícia; Santoro, Marcos; Pan, Pedro Mário; Ota, Vanessa Kiyomi; Xavier, Gabriela; Carvalho, Carolina Muniz; Talarico, Fernanda; Sleiman, Patrick; March, Michael; Pellegrino, Renata; Brietzke, Elisa; Grassi‐Oliveira, Rodrigo; Mari, Jair J.; Gadelha, Ary; Miguel, Eurí­pedes Constantino; Rohde, Luís Augusto; Bressan, Rodrigo; Mazzotti, Diego R.; Sato, João Ricardo; Salum, Giovanni Abrahão; Hákonarson, Hákon; Belangero, Síntia Iole

doi:10.1186/s13148-019-0740-z

Cited by 16 publications

(12 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, the 218 CpGs contained in the co-methylated module were not restricted to a specific genomic location, but spanned different genes ( n = 198) and all 22 autosomal chromosomes. This finding supports previous research showing scattered genomic findings for differentially methylated probes associated with an increase in psychopathology symptoms (low-high CBCL total scores) in youths at a 3-year follow-up ( Spindola et al, 2019 ). Future studies are needed to identify any potential common characteristic of these CpG sites.…”

Section: Discussionsupporting

confidence: 91%

Genome-wide DNA methylation patterns associated with general psychopathology in children

Rijlaarsdam

Barker

Caserini

et al. 2021

Journal of Psychiatric Research

View full text Add to dashboard Cite

Psychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to individual psychiatric outcomes, associations with GPF remain unclear. Using data from 440 children aged 10 years participating in the Generation R Study, we examined the associations of DNAm with both general and specific (internalizing, externalizing) factors of psychopathology. Genome-wide DNAm levels, measured in peripheral blood using the Illumina 450K array, were clustered into wider co-methylation networks (‘modules’) using a weighted gene co-expression network analysis. One co-methylated module associated with GPF after multiple testing correction, while none associated with the specific factors. This module comprised of 218 CpG probes, of which 198 mapped onto different genes. The CpG most strongly driving the association with GPF was annotated to FZD1, a gene that has been implicated in schizophrenia and wider neurological processes. Associations between the probes contained in the co-methylated module and GPF were supported in an independent sample of children from the Avon Longitudinal Study of Parents and Children (ALSPAC), as evidenced by significant correlations in effect sizes. These findings might contribute to improving our understanding of dynamic molecular processes underlying complex psychiatric phenotypes.

show abstract

Section: Discussionsupporting

confidence: 91%

Genome-wide DNA methylation patterns associated with general psychopathology in children

Rijlaarsdam

Barker

Caserini

et al. 2021

Journal of Psychiatric Research

View full text Add to dashboard Cite

show abstract

“…Moreover, DMRs are tissue specific and associate with disease state and may reflect autoimmune/inflammatory disease stages ( Eckhardt et al, 2006 ). As coordinated DNA methylation changes in wider genomic regions are more likely to have downstream biological effects and implications for diseases development and progression than methylation changes in a single CpG, we analyzed DMRs across study sub-cohorts ( Hotta et al, 2018 ; Spindola et al, 2019 ). Indeed, findings from DMP analyses were largely confirmed investigating wider DMRs, and additionally allowed differentiation between skin psoriasis vs. PsA in subsequent GO analyses.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Patterns in CD8+ T Cells Discern Psoriasis From Psoriatic Arthritis and Correlate With Cutaneous Disease Activity

Charras

Garau

Hofmann

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Background: Psoriasis is a T cell-mediated chronic autoimmune/inflammatory disease. While some patients experience disease limited to the skin (skin psoriasis), others develop joint involvement (psoriatic arthritis; PsA). In the absence of disease- and/or outcome-specific biomarkers, and as arthritis can precede skin manifestations, diagnostic and therapeutic delays are common and contribute to disease burden and damage accrual.Objective: Altered epigenetic marks, including DNA methylation, contribute to effector T cell phenotypes and altered cytokine expression in autoimmune/inflammatory diseases. This project aimed at the identification of disease-/outcome-specific DNA methylation signatures in CD8+ T cells from patients with psoriasis and PsA as compared to healthy controls.Method: Peripheral blood CD8+ T cells from nine healthy controls, 10 psoriasis, and seven PsA patients were collected to analyze DNA methylation marks using Illumina Human Methylation EPIC BeadChips (>850,000 CpGs per sample). Bioinformatic analysis was performed using R (minfi, limma, ChAMP, and DMRcate packages).Results: DNA methylation profiles in CD8+ T cells differentiate healthy controls from psoriasis patients [397 Differentially Methylated Positions (DMPs); 9 Differentially Methylated Regions (DMRs) when ≥CpGs per DMR were considered; 2 DMRs for ≥10 CpGs]. Furthermore, patients with skin psoriasis can be discriminated from PsA patients [1,861 DMPs, 20 DMRs (≥5 CpGs per region), 4 DMRs (≥10 CpGs per region)]. Gene ontology (GO) analyses considering genes with ≥1 DMP in their promoter delivered methylation defects in skin psoriasis and PsA primarily affecting the BMP signaling pathway and endopeptidase regulator activity, respectively. GO analysis of genes associated with DMRs between skin psoriasis and PsA demonstrated an enrichment of GABAergic neuron and cortex neuron development pathways. Treatment with cytokine blockers associated with DNA methylation changes [2,372 DMPs; 1,907 DMPs within promoters, 7 DMRs (≥5 CpG per regions)] affecting transforming growth factor beta receptor and transmembrane receptor protein serine/threonine kinase signaling pathways. Lastly, a methylation score including TNF and IL-17 pathway associated DMPs inverse correlates with skin disease activity scores (PASI).Conclusion: Patients with skin psoriasis exhibit DNA methylation patterns in CD8+ T cells that allow differentiation from PsA patients and healthy individuals, and reflect clinical activity of skin disease. Thus, DNA methylation profiling promises potential as diagnostic and prognostic tool to be used for molecular patient stratification toward individualized treatment.

show abstract

“…To verify the correlation between DNA methylation of INSR (cg00441765) in the whole blood and brain, we used the UNAGE-CpG tool 16 . Spearman rho value of variable CpGs in the brain and blood was 0.64 (p = 0.0021, Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, the correlation between intensive insulin treatment and neurologic outcomes has yet to be firmly established 15 . To verify the correlation between DNA methylation of INSR (cg00441765) in the whole blood and brain, we used the UNAGE-CpG tool 16 . Spearman rho value of variable CpGs in the brain and blood was 0.64 (p = 0.0021, Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage

Kim

Youn

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Little is known about the epigenetic changes associated with delayed cerebral ischemia (DCI) pathogenesis after subarachnoid hemorrhage (SAH). Here, we investigated genome-wide DNA methylation profiles specifically associated with DCI, which is a major contributor to poor clinical outcomes. An epigenome-wide association study (EWAS) and quantitative real-time PCR (qRT-PCR) were conducted in 40 SAH patients (DCI, n = 13; non-DCI, n = 27). A replication study using bisulfite modification and methylation-specific PCR was further performed in 36 patients (DCI, n = 12; non-DCI, n = 24). The relative degree of methylation was described as the median and 25th-75th percentile. No significant differences in clinical characteristics between DCI and non-DCI groups were observed. Among the top 10 differentially methylated genes analyzed via EWAS, two aberrantly methylated CpG sites of cg00441765 (INSR gene) and cg11464053 (CDHR5 gene) were associated with decreased mRNA expression (2 −ΔCt). They include INSR [0.00020 (0.00012-0.00030) in DCI vs. 0.00050 (0.00030-0.00068) in non-DCI] and CDHR5 [0.114 (0.053-0.143) in DCI vs. 0.170 (0.110-0.212) in non-DCI]. Compared with non-DCI cases, patients with DCI exhibited an increased degree of methylation in the replication study: INSR, 0.855 (0.779-0.913) in DCI vs. 0.582 (0.565-0.689) in non-DCI; CDHR5, 0.786 (0.708-0.904) in DCI vs. 0.632 (0.610-0.679) in non-DCI. Hypermethylation of two novel genes, INSR and CDHR5 may serve as a biomarker for early detection of DCI following SAH. Delayed cerebral ischemia (DCI) is a major contributor to poor neurologic outcomes in patients diagnosed with subarachnoid hemorrhage (SAH) 1. However, it is also a preventable and treatable complication. Well-known risk factors for DCI include female gender, cigarette smoking, hyperglycemia, high Hunt-Hess (HH) grade and thick hemorrhage at admission 1-3. The majority of genetic studies investigating DCI have focused on gene expression or linkage analyses of candidate genes 4. Candidate genes include those associated with inflammation, endothelial dysfunction, fibrinolysis, and brain metabolism. A previous meta-analysis 5 showed that ApoE ε4 carriers had a higher risk of DCI than non-ε4 carriers. Kim et al. 6 reported that DCI was more frequently observed in patients expressing haptoglobin (Hp) 2-2 than Hp 1-1 phenotype. In particular, SAH patients with Hp 2-1, and non-DCI patients showed higher α1intensities than DCI patients. A genome-wide association study (GWAS) 7 revealed that SNP rs999662 encompassing solute carrier family 12 member 3 (SLC12A3) was significantly associated with high transcranial Doppler (TCD) velocities, such as angiographic vasospasm, which leads to DCI 7. Genetic background accounts for approximately 37.9% of stroke pathogenesis 8-10. However, the frequency of susceptible genetic variants in stroke patients varies between 5 and 10% 9 , which indicates cryptic genetic changes beyond DNA sequences 8,11. One of these cryptic variations involving novel epigenetic pathways is DNA

show abstract

Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths

Cited by 16 publications

References 70 publications

Genome-wide DNA methylation patterns associated with general psychopathology in children

Genome-wide DNA methylation patterns associated with general psychopathology in children

DNA Methylation Patterns in CD8+ T Cells Discern Psoriasis From Psoriatic Arthritis and Correlate With Cutaneous Disease Activity

Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage

Contact Info

Product

Resources

About