scholarly journals Epigenome-Wide Association Study of Tic Disorders

2015 ◽  
Vol 18 (6) ◽  
pp. 699-709 ◽  
Author(s):  
Nuno R. Zilhão ◽  
Shanmukha S. Padmanabhuni ◽  
Luca Pagliaroli ◽  
Csaba Barta ◽  
Dirk J. A. Smit ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Association Study ◽  
Developmental Process ◽  
Chromosome 8 ◽  
Tic Disorders ◽  
Self Report ◽  
Methylation Data ◽  
Genome Wide ◽  
Tic Severity ◽  
Future Work

Tic disorders are moderately heritable common psychiatric disorders that can be highly troubling, both in childhood and in adulthood. In this study, we report results obtained in the first epigenome-wide association study (EWAS) of tic disorders. The subjects are participants in surveys at the Netherlands Twin Register (NTR) and the NTR biobank project. Tic disorders were measured with a self-report version of the Yale Global Tic Severity Scale Abbreviated version (YGTSS-ABBR), included in the 8th wave NTR data collection (2008). DNA methylation data consisted of 411,169 autosomal methylation sites assessed by the Illumina Infinium HumanMethylation450 BeadChip Kit (HM450k array). Phenotype and DNA methylation data were available in 1,678 subjects (mean age = 41.5). No probes reached genome-wide significance (p < 1.2 × 10−7). The strongest associated probe was cg15583738, located in an intergenic region on chromosome 8 (p = 1.98 × 10−6). Several of the top ranking probes (p < 1 × 10−4) were in or nearby genes previously associated with neurological disorders (e.g., GABBRI, BLM, and ADAM10), warranting their further investigation in relation to tic disorders. The top significantly enriched gene ontology (GO) terms among higher ranking methylation sites included anatomical structure morphogenesis (GO:0009653, p = 4.6 × 10−15) developmental process (GO:0032502, p = 2.96 × 10−12), and cellular developmental process (GO:0048869, p = 1.96 × 10−12). Overall, these results provide a first insight into the epigenetic mechanisms of tic disorders. This first study assesses the role of DNA methylation in tic disorders, and it lays the foundations for future work aiming to unravel the biological mechanisms underlying the architecture of this disorder.

scholarly journals Epigenome-Wide Association Study of Acute Lymphoblastic Leukemia in Children with Down Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 214-214
Author(s):  
Shaobo Li ◽  
Pagna Sok ◽  
Keren Xu ◽  
Ivo S Muskens ◽  
Natalina Elliott ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Association Study ◽  
Lymphoblastic Leukemia ◽  
Replication Study ◽  
Methylation Data ◽  
Cell Type ◽  
Genome Wide

Abstract Background: Down syndrome (DS) is associated with an up to 30-fold increased risk of B-cell acute lymphoblastic leukemia (ALL), and DS-ALL patients have worse overall survival and increased long-term treatment-related health conditions compared with non-DS ALL patients. In a recent genome-wide association study of DS-ALL, established ALL genetic risk loci were associated with DS-ALL, with several single nucleotide polymorphisms (SNPs) conferring a larger effect on ALL risk in the context of DS than in euploidy. We performed an epigenome-wide association study (EWAS) to elucidate whether epigenetic differences at birth are associated with risk of subsequent DS-ALL. Methods: The DS-ALL Discovery Study included 147 DS-ALL cases and 198 DS controls from the International Study of Down Syndrome Acute Leukemia, with newborn dried bloodspots (DBS) obtained from California (n=326) and Washington state (n=19) biobanks. The DS-ALL Replication Study included 24 DS-ALL cases and 24 DS controls with newborn DBS from the Michigan Neonatal Biobank. DNA was isolated from DBS, bisulfite converted, and assayed using Illumina Infinium MethylationEPIC Beadchip genome-wide DNA methylation arrays. Raw data were processed using "minfi" and "noob" packages in R. Reference-based deconvolution of blood cell proportions was performed using the Identifying Optimal DNA methylation Libraries (IDOL) algorithm, using DNA methylation data from cord blood reference samples, to estimate proportions of B cells, T cells (CD4+ and CD8+), monocytes, granulocytes, natural killer cells, and nucleated red blood cells. We compared each cell type proportion between DS-ALL cases and DS controls using linear regression adjusting for sex, plate, and principal components (PCs) to account for genetic ancestry. To identify single CpG probes associated with DS-ALL risk, we performed a multiethnic EWAS of DS-ALL in each study using linear regression adjusting for sex, plate, and PCs related to: 1) cell-type proportions and 2) genetic ancestry. Differentially methylated regions (DMRs) were identified using DMRcate and comb-p methods. In the Discovery Study, genome-wide SNP array data were available for 131 cases and 130 controls, and data from targeted sequencing of somatic mutations in exons 2/3 of GATA1 were available for 184/198 DS controls. Results: Deconvolution of blood cell proportions in the DS-ALL Discovery Study showed significantly higher B cell proportions in newborns with DS who later developed ALL (mean=0.0128, sd=0.0151) compared with DS controls (mean=0.00826, sd=0.0115) (P=6.4x10 -4, coefficient=0.0052). A significantly higher B cell proportion at birth was also found in DS-ALL cases in the independent Replication Study (cases mean=0.048, sd=0.024; controls mean=0.039, sd=0.028; P=0.03, coefficient=0.015). In the Discovery Study, the B cell difference remained significant (P=5.8x10 -3) with a similar effect size (coefficient=0.0045) after removal of GATA1 mutation-positive DS controls (n=30). We also investigated whether DS-ALL risk SNPs at ARID5B, IKZF1, GATA3, and CDKN2A may confound the association, but the increased B cell proportions in DS-ALL remained significant and effect estimates slightly increased in SNP genotype-adjusted models (coefficient range:0.0055-0.0059). In the EWAS of DS-ALL, 9 CpGs reached epigenome-wide significance (P&lt;7.67x10 -8), including 2 CpGs overlapping the promoter of the tumor suppressor gene TRIM13, frequently deleted in B-CLL, although none of these showed evidence of association (P&lt;0.05) in the Replication Study. We identified 125 DMRs associated with DS-ALL in the Discovery Study. For 3 DMRs, overlapping genes HOPX, SMIM24, and PPP1R10, all implicated in normal and leukemic stem cell function, there were multiple significant CpGs in the Replication Study (P&lt;0.05) all with effects in the same direction as the Discovery Study DMRs. Conclusions: Increased B cell proportions in newborns with DS may be a risk factor for development of DS-ALL in childhood. This finding, based on DNA methylation data, requires confirmation using conventional cell count measures, and should be explored as a novel biomarker for ALL risk in the non-DS population. Single CpGs and DMRs associated with DS-ALL risk in our Discovery Study require further investigation, including in additional ALL case-control studies in DS and non-DS populations. Disclosures Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding.

Identifying chemicals linked to lung cancer: Integrating genome-wide association studies with a chemical-gene interaction network

2020 ◽  
Author(s):  
Yutiantian Lei ◽  
Hanmin Tang ◽  
Liuyun Gong ◽  
Zhenzhen Luo ◽  
Xinyue Tan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Methylation ◽  
Association Study ◽  
Gene Interaction ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Methylation Data ◽  
Genome Wide ◽  
Summary Data

Abstract Background Lung cancer is the most common cancer and the leading cause of cancer-related mortality worldwide. Environmental chemicals play a significant role in tumorigenesis, it is necessary to explore the lung cancer-related chemicals and provide new clues for neoplastic prevention and treatment. Methods The genome-wide association study (GWAS) summary data of malignant neoplasm of bronchus and lung (C34) were downloaded from the UK Biobank. It includes 1,655 samples and 450,609 controls. DNA methylation profiles of non-small cell lung cancer were obtained from the GEO database (GSE75008). A transcriptome-wide association study was applied to detect genes significantly related to lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) by FUSION software. Comparative toxicogenomics database (CTD) enables the construction of chemical-gene-disease networks. We conducted a chemical-related gene set enrichment analysis (GSEA) based on GWAS summary data, DNA methylation data, and the CTD to explore the relationships between chemicals and two major histological subtypes of lung cancer. Venn analysis was used to identify the common related chemicals of the GWAS summary data and the DNA methylation data. Results We detected aluminum, naringenin, and 2-acetylaminofluorene as LUSC-related chemicals and antirheumatic agents, nickel monoxide, and 2-amino-2-methyl-1-propanol as LUAD-related chemicals. Conclusion By integrating GWAS and chemical-gene interaction networks, we made linkages between various chemicals and lung cancer on genetic basis. Moreover, this study provided new clues for exploring the etiology of lung cancer and a new method for finding the chemicals related to tumor or other complex disease.

scholarly journals Epigenome-Wide Association Study of Wellbeing

2015 ◽  
Vol 18 (6) ◽  
pp. 710-719 ◽  
Author(s):  
Bart M. L. Baselmans ◽  
Jenny van Dongen ◽  
Michel G. Nivard ◽  
Bochao D. Lin ◽  
BIOS Consortium ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Association Study ◽  
Satisfaction With Life ◽  
Strong Association ◽  
Complex Trait ◽  
Epigenetic Mechanisms ◽  
Scientific Disciplines ◽  
Genome Wide ◽  
Illumina Infinium Humanmethylation450 Beadchip ◽  
Future Work

Wellbeing (WB) is a major topic of research across several scientific disciplines, partly driven by its strong association with psychological and mental health. Twin-family studies have found that both genotype and environment play an important role in explaining the variance in WB. Epigenetic mechanisms, such as DNA methylation, regulate gene expression, and may mediate genetic and environmental effects on WB. Here, for the first time, we apply an epigenome-wide association study (EWAS) approach to identify differentially methylated sites associated with individual differences in WB. Subjects were part of the longitudinal survey studies of the Netherlands Twin Register (NTR) and participated in the NTR biobank project between 2002 and 2011. WB was assessed by a short inventory that measures satisfaction with life (SAT). DNA methylation was measured in whole blood by the Illumina Infinium HumanMethylation450 BeadChip (HM450k array) and the association between WB and DNA methylation level was tested at 411,169 autosomal sites. Two sites (cg10845147, p = 1.51 * 10−8 and cg01940273, p = 2.34 * 10−8) reached genome-wide significance following Bonferonni correction. Four more sites (cg03329539, p = 2.76* 10−7; cg09716613, p = 3.23 * 10−7; cg04387347, p = 3.95 * 10−7; and cg02290168, p = 5.23 * 10−7) were considered to be genome-wide significant when applying the widely used criterion of a FDR q value < 0.05. Gene ontology (GO) analysis highlighted enrichment of several central nervous system categories among higher-ranking methylation sites. Overall, these results provide a first insight into the epigenetic mechanisms associated with WB and lay the foundations for future work aiming to unravel the biological mechanisms underlying a complex trait like WB.

scholarly journals A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins

2020 ◽  
Vol 14 ◽  
Author(s):  
Mette Soerensen ◽  
Dominika Marzena Hozakowska-Roszkowska ◽  
Marianne Nygaard ◽  
Martin J. Larsen ◽  
Veit Schwämmle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cognitive Functioning ◽  
Association Study ◽  
Gene Expression Data ◽  
Monozygotic Twins ◽  
Later Life ◽  
Expression Data ◽  
Genome Wide ◽  
A Genome

scholarly journals Evaluation of affinity-based genome-wide DNA methylation data: Effects of CpG density, amplification bias, and copy number variation

2010 ◽  
Vol 20 (12) ◽  
pp. 1719-1729 ◽  
Author(s):  
M. D. Robinson ◽  
C. Stirzaker ◽  
A. L. Statham ◽  
M. W. Coolen ◽  
J. Z. Song ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number Variation ◽  
Copy Number ◽  
Methylation Data ◽  
Amplification Bias ◽  
Genome Wide ◽  
Number Variation

scholarly journals Integration of genome-wide mRNA and miRNA expression, and DNA methylation data of three cell lines exposed to ten carbon nanomaterials

Data in Brief ◽  
2018 ◽  
Vol 19 ◽  
pp. 1046-1057 ◽  
Author(s):  
Giovanni Scala ◽  
Veer Marwah ◽  
Pia Kinaret ◽  
Jukka Sund ◽  
Vittorio Fortino ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Mirna Expression ◽  
Carbon Nanomaterials ◽  
Methylation Data ◽  
Genome Wide

Abstract P098: An Epigenome-wide Study of Obesity in African American Youth and Young Adults: Novel Findings, Replication in Neutrophils and Relationship With Gene Expression

Circulation ◽  
2017 ◽  
Vol 135 (suppl_1) ◽  
Author(s):  
Xiaoling Wang ◽  
Yue Pan ◽  
Haidong Zhu ◽  
Guang Hao ◽  
Xin Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Older Adults ◽  
Dna Methylation ◽  
Young Adults ◽  
Methylation Data ◽  
Middle Aged ◽  
Cpg Sites ◽  
Genome Wide ◽  
Obesity Status ◽  
Youth And Young Adults

Background: Several large-scale epigenome wide association studies on obesity-related DNA methylation changes have been published and in total identified 46 CpG sites. These studies were conducted in middle-aged and older adults of Caucasians and African Americans (AAs) using leukocytes. To what extend these signals are independent of cell compositions as well as to what extend they may influence gene expression have not been systematically investigated. Furthermore, the high prevalence of obesity comorbidities in middle-aged or older population may hide or bias obesity itself related DNA methylation changes. Methods: In this study of healthy AA youth and young adults, genome wide DNA methylation data from leukocytes were obtained from three independent studies: EpiGO study (96 obese cases vs. 92 lean controls, aged 14-21, 50% females, test of interest is obesity status), LACHY study (284 participants from general population, aged 14-18, 50% females, test of interest is BMI), and Georgia Stress and Heart study (298 participants from general population, aged 18-38, 52% females, test of interest is BMI) using the Infinium HumanMethylation450 BeadChip. Genome wide DNA methylation data from purified neutrophils as well as genome wide gene expression data from leukocytes using Illumina HT12 V4 array were also obtained for the EpiGO samples. Results: The meta-analysis on the 3 cohorts identified 76 obesity related CpG sites in leukocytes with p<1х10 -7 . Out of the 46 previously identified CpG sites, 36 can be replicated in this AA youth and young adult sample with same direction and p<0.05. Out of the 107 CpG sites including the 36 replicated ones and the 71 newly identified ones, 71 CpG sites (66%) had their relationship with obesity replicated in purified neutrophils (p<0.05). The analysis on the cis regulation of the 107 CpG sites on gene expression showed that 59 CpG sites had at least one gene within 250kb having expression difference between obese cases and lean controls. Furthermore, out of the 59 CpG sites, 6 showed significantly negative correlations and 1 showed significantly positive correlation with the differentially expressed genes. These CpG sites located in SOCS3, CISH, ABCG1, PIM3 and PTGDS genes. Conclusion: In this study of AA youth and young adults, we identified novel CpG sites associated with obesity and replicated majority of the CpG sites previously identified in middle-aged and older adults. For the first time, we showed that majority of the obesity related CpG sites identified from leukocytes are not driven by cell compositions and provided the direct link between DNA methylation-gene expression-obesity status for 7 CpG sites in 5 genes.

scholarly journals Testing cell-type-specific mediation effects in genome-wide epigenetic studies

2020 ◽  
Author(s):  
Xiangyu Luo ◽  
Joel Schwartz ◽  
Andrea Baccarelli ◽  
Zhonghua Liu
Keyword(s):  
Dna Methylation ◽  
Mediation Analysis ◽  
Methylation Data ◽  
Cell Type ◽  
Multiple Testing Procedure ◽  
Mediation Effects ◽  
Cpg Sites ◽  
Genome Wide ◽  
A Cell ◽  
Cell Type Specific

Abstract Epigenome-wide mediation analysis aims to identify DNA methylation CpG sites that mediate the causal effects of genetic/environmental exposures on health outcomes. However, DNA methylations in the peripheral blood tissues are usually measured at the bulk level based on a heterogeneous population of white blood cells. Using the bulk level DNA methylation data in mediation analysis might cause confounding bias and reduce study power. Therefore, it is crucial to get fine-grained results by detecting mediation CpG sites in a cell-type-specific way. However, there is a lack of methods and software to achieve this goal. We propose a novel method (Mediation In a Cell-type-Specific fashion, MICS) to identify cell-type-specific mediation effects in genome-wide epigenetic studies using only the bulk-level DNA methylation data. MICS follows the standard mediation analysis paradigm and consists of three key steps. In step1, we assess the exposure-mediator association for each cell type; in step 2, we assess the mediator-outcome association for each cell type; in step 3, we combine the cell-type-specific exposure-mediator and mediator-outcome associations using a multiple testing procedure named MultiMed [Sampson JN, Boca SM, Moore SC, et al. FWER and FDR control when testing multiple mediators. Bioinformatics 2018;34:2418–24] to identify significant CpGs with cell-type-specific mediation effects. We conduct simulation studies to demonstrate that our method has correct FDR control. We also apply the MICS procedure to the Normative Aging Study and identify nine DNA methylation CpG sites in the lymphocytes that might mediate the effect of cigarette smoking on the lung function.

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