Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhang L
PROVIDER: S-EPMC7704686 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status.We utilized the genome-wide methylation data of psoriatic skin (PP, N?=?114) and unaffected control skin (NN, N?=?62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility.We identified 129 SNP-CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P?<?0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106, the TSS1500 promoter region of DMBX1 and the body of SIK3.This study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis.
| S-EPMC5139011 | biostudies-literature
Project description:ImportanceDNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk.ObjectiveTo scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls.Design, setting, and participantsEpigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases and 250 controls (n = 497) from the Genomic Psychiatry Cohort.Main outcomes and measuresIdentification of differentially methylated positions across the genome in SZ cases compared with controls.ResultsOf the 689 case participants in the discovery set, 477 (69%) were men and 258 (37%) were non-African American; of the 645 controls, 273 (42%) were men and 419 (65%) were non-African American. In our replication set, cases/controls were 76% male and 100% non-African American. We identified SZ-associated methylation differences at 923 CpGs in the discovery set (false discovery rate, <0.2). Of these, 625 showed changes in the same direction including 172 with P < .05 in the replication set. Some replicated differentially methylated positions are located in a top-ranked SZ region from genome-wide association study analyses.Conclusions and relevanceThis analysis identified 172 replicated new associations with SZ after careful correction for cell type heterogeneity and other potential confounders. The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for SZ.
| S-EPMC6353566 | biostudies-literature
Project description:BACKGROUND:Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). METHODS:In this study, we performed an EWAS of PTSD in a cohort of Veterans (n?=?378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n?=?72). RESULTS:The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p?=?1.19?×?10-7, padj?=?0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p?=?0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p?=?9.16?×?10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p?=?1.19?×?10-5, padj?=?0.60, in brain, p?=?0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p?=?6.97?×?10-6, padj?=?0.042). CONCLUSIONS:The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.
| S-EPMC7071645 | biostudies-literature
Project description:Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.
| S-EPMC9106882 | biostudies-literature
Project description:Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.
| S-EPMC9395387 | biostudies-literature
Project description:Knowledge of epigenetically regulated biomarkers linked to obesity development is still scarce. Improving molecular understanding of the involved factors and pathways would improve obesity phenotype characterization and reveal potentially relevant targets for obesity intervention. The Illumina Infinium HumanMethylation450 BeadChip was used in a leucocyte epigenome-wide association study (EWAS) to quantify differential DNA methylation in 60 lean compared with 60 obese young women. Replication was done in monozygotic twins discordant for obesity. At adolescence and adulthood, the two weight groups differed significantly in obesity-related traits and metabolic risk factors. Differential hypomethylation was overrepresented in obese compared to lean women. In the adjusted model, the EWAS revealed 10 differentially methylated CpG sites linked to 8 gene loci - COX6A1P2/FGD2, SBNO2, TEX41, RPS6KA2, IGHE/IGHG1/IGHD, DMAP1, SOCS3, and SETBP1- and an enhancer locus at chromosome 2 (2p25.1). The sites linked to TEX41, IGHE/IGHG1/IGHD, DMAP1, and SETBP1 were novel findings, while COX6A1P/FGD2, SBNO2, RPS6KA2, and SOCS3 had been identified previously with concordant direction of effects. RPS6KA2, DMAP1, and SETBP1 were replicated in the BMI-discordant monozygotic twin cohort using the FDR of 5%.
| S-EPMC6218540 | biostudies-literature
Project description:BackgroundThe apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.MethodsUsing the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer's disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses.ResultsWe obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10-100 ≤ P ≤ 2.44 × 10-8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10-4 ≤ P ≤ 3.01 × 10-2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24.ConclusionsAPOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.
| S-EPMC7784364 | biostudies-literature
Project description:Epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer's disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource ( www.epigenomicslab.com/ad-meta-analysis/ ).
| S-EPMC8192929 | biostudies-literature
Project description:The increase in the prevalence of allergic diseases is believed to partially depend on environmental changes. DNA methylation is a major epigenetic mechanism, which is known to respond to environmental factors. A number of studies have revealed that patterns of DNA methylation may potentially predict allergic diseases.Here, we examined how maternal atopy is associated with methylation patterns in the cord blood of neonates.We conducted an epigenome-wide association study in a cohort of 96 mother-child pairs. Pregnant women aged not more than 35 years old, not currently smoking or exposed to environmental tobacco smoke, who did not report obesity before conception were considered eligible. They were further tested for atopy. Converted DNA from cord blood was analysed using Infinium MethylationEPIC; for statistical analysis, RnBeads software was applied. Gestational age and sex were included as covariates in the final analysis.83 DM sites were associated with maternal atopy. Within the top DM sites, there were CpG sites which mapped to genes SCD, ITM2C, NT5C3A and NPEPL1. Regional analysis revealed 25 tiling regions, 4 genes, 3 CpG islands and 5 gene promoters, (including PIGCP1, ADAM3A, ZSCAN12P1) associated with maternal atopy. Gene content analysis revealed pointwise enrichments in pathways related to purine-containing compound metabolism, the G1/S transition of the mitotic cell cycle, stem cell division and cellular glucose homoeostasis.These findings suggest that maternal atopy provides a unique intrauterine environment that may constitute the first environment in which exposure is associated with methylation patterns in newborn.
| S-EPMC8143219 | biostudies-literature
Project description:In adult patients with obsessive-compulsive disorder (OCD), altered DNA methylation has been discerned in several candidate genes, while DNA methylation on an epigenome-wide level has been investigated in only one Chinese study so far. Here, an epigenome-wide association study (EWAS) was performed in a sample of 76 OCD patients of European ancestry (37 women, age ± SD: 33.51 ± 10.92 years) and 76 sex- and age-matched healthy controls for the first time using the Illumina MethylationEPIC BeadChip. After quality control, nine epigenome-wide significant quantitative trait methylation sites (QTMs) and 21 suggestive hits were discerned in the final sample of 68 patients and 68 controls. The top hit (cg24159721) and four other significant QTMs (cg11894324, cg01070250, cg11330075, cg15174812) map to the region of the microRNA 12136 gene (MIR12136). Two additional significant CpG sites (cg05740793, cg20450977) are located in the flanking region of the MT-RNR2 (humanin) like 8 gene (MT-RNRL8), while two further QTMs (cg16267121, cg15890734) map to the regions of the MT-RNR2 (humanin) like 3 (MT-RNRL3) and MT-RNR2 (humanin) like 2 (MT-RNRL2) genes. Provided replication of the present findings in larger samples, the identified QTMs might provide more biological insight into the pathogenesis of OCD and thereby could in the future serve as peripheral epigenetic markers of OCD risk with the potential to inform targeted preventive and therapeutic efforts.
| S-EPMC9160220 | biostudies-literature