62 CONSISTENT DNA METHYLATION DIFFERENCES IN 46 GENOME-WIDE LOCI IN MONOZYGOTIC TWINS DISCORDANT FOR PRIMARY BILIARY CIRRHOSIS

The prevalence of hepatocellular carcinoma (HCC) is still high worldwide because liver diseases could develop into HCC. Recent reports indicate nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NAFLD&NASH) and primary biliary cirrhosis and primary sclerosing cholangitis (PBC&PSC) are significant of HCC. Therefore, understanding the cellular mechanisms of the pathogenesis and hepatocarcinogenesis from normal liver cells to HCC through NAFLD&NASH or PBC&PSC is a priority to prevent the progression of liver damage and reduce the risk of further complications. By the genetic and epigenetic data mining and the system identification through next-generation sequencing data and its corresponding DNA methylation profiles of liver cells in normal, NAFLD&NASH, PBC&PSC, and HCC patients, we identified the genome-wide real genetic and epigenetic networks (GENs) of normal, NAFLD&NASH, PBC&PSC, and HCC patients. In order to get valuable insight into these identified genome-wide GENs, we then applied a principal network projection method to extract the corresponding core GENs for normal liver cells, NAFLD&NASH, PBC&PSC, and HCC. By comparing the signal transduction pathways involved in the identified core GENs, we found that the hepatocarcinogenesis through NAFLD&NASH was induced through DNA methylation of HIST2H2BE, HSPB1, RPL30, and ALDOB and the regulation of miR-21 and miR-122, and the hepatocarcinogenesis through PBC&PSC was induced through DNA methylation of RPL23A, HIST2H2BE, TIMP1, IGF2, RPL30, and ALDOB and the regulation of miR-29a, miR-21, and miR-122. The genetic and epigenetic changes in the pathogenesis and hepatocarcinogenesis potentially serve as potential diagnostic biomarkers and/or therapeutic targets.

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International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Nature Communications ◽

10.1038/ncomms9019 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 147

Author(s):

Heather J. Cordell ◽

◽

Younghun Han ◽

George F. Mells ◽

Yafang Li ◽

...

Keyword(s):

Primary Biliary Cirrhosis ◽

Meta Analysis ◽

Biliary Cirrhosis ◽

Genome Wide

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Epigenome-Wide DNA Methylation Analysis of Monozygotic Twins Discordant for Diurnal Preference

Twin Research and Human Genetics ◽

10.1017/thg.2015.78 ◽

2015 ◽

Vol 18 (6) ◽

pp. 662-669 ◽

Cited By ~ 8

Author(s):

Chloe C. Y. Wong ◽

Michael J. Parsons ◽

Kathryn J. Lester ◽

Joe Burrage ◽

Thalia C. Eley ◽

...

Keyword(s):

Dna Methylation ◽

Circadian Clock ◽

Monozygotic Twins ◽

Enrichment Analysis ◽

Genome Wide ◽

Analysis Strategy ◽

Diurnal Preference ◽

Significant Enrichment ◽

Longitudinal Twin Study ◽

Mz Twins

Diurnal preference is an individual's preference for daily activities and sleep timing and is strongly correlated with the underlying circadian clock and the sleep-wake cycle validating its use as an indirect circadian measure in humans. Recent research has implicated DNA methylation as a mechanism involved in the regulation of the circadian clock system in humans and other mammals. In order to evaluate the extent of epigenetic differences associated with diurnal preference, we examined genome-wide patterns of DNA methylation in DNA from monozygotic (MZ) twin-pairs discordant for diurnal preference. MZ twins were selected from a longitudinal twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties. Fifteen pairs of MZ twins were identified in which one member scored considerably higher on the Horne–Ostberg Morningness–Eveningness Questionnaire (MEQ) than the other. Genome-wide DNA methylation patterns were assessed in twins’ buccal cell DNA using the Illumina Infinium HumanMethylation450 BeadChips. Quality control and data pre-processing was undertaken using the wateRmelon package. Differentially methylated probes (DMPs) were identified using an analysis strategy taking into account both the significance and the magnitude of DNA methylation differences. Our data indicate that DNA methylation differences are detectable in MZ twins discordant for diurnal preference. Moreover, downstream gene ontology (GO) enrichment analysis on the top-ranked diurnal preference associated DMPs revealed significant enrichment of pathways that have been previously associated with circadian rhythm regulation, including cell adhesion processes and calcium ion binding.

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Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

Nature Genetics ◽

10.1038/ng.789 ◽

2011 ◽

Vol 43 (4) ◽

pp. 329-332 ◽

Cited By ~ 330

Author(s):

George F Mells ◽

◽

James A B Floyd ◽

Katherine I Morley ◽

Heather J Cordell ◽

...

Keyword(s):

Primary Biliary Cirrhosis ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Biliary Cirrhosis ◽

Susceptibility Loci ◽

Genome Wide

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Genome-wide DNA methylation analysis of pulmonary function in middle and old-aged Chinese monozygotic twins

Respiratory Research ◽

10.1186/s12931-021-01896-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Tong Wang ◽

Weijing Wang ◽

Weilong Li ◽

Haiping Duan ◽

Chunsheng Xu ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Pulmonary Function ◽

Monozygotic Twins ◽

Linear Mixed Effect Model ◽

Sequencing Analysis ◽

Mixed Effect ◽

Cpg Sites ◽

Genome Wide ◽

Genomic Regions

Abstract Background Previous studies have determined the epigenetic association between DNA methylation and pulmonary function among various ethnics, whereas this association is largely unknown in Chinese adults. Thus, we aimed to explore epigenetic relationships between genome-wide DNA methylation levels and pulmonary function among middle-aged Chinese monozygotic twins. Methods The monozygotic twin sample was drawn from the Qingdao Twin Registry. Pulmonary function was measured by three parameters including forced expiratory volume the first second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Linear mixed effect model was used to regress the methylation level of CpG sites on pulmonary function. After that, we applied Genomic Regions Enrichment of Annotations Tool (GREAT) to predict the genomic regions enrichment, and used comb-p python library to detect differentially methylated regions (DMRs). Gene expression analysis was conducted to validate the results of differentially methylated analyses. Results We identified 112 CpG sites with the level of P < 1 × 10–4 which were annotated to 40 genes. We identified 12 common enriched pathways of three pulmonary function parameters. We detected 39 DMRs located at 23 genes, of which PRDM1 was related to decreased pulmonary function, and MPL, LTB4R2, and EPHB3 were related to increased pulmonary function. The gene expression analyses validated DIP2C, ASB2, SLC6A5, and GAS6 related to decreased pulmonary function. Conclusion Our DNA methylation sequencing analysis on identical twins provides new references for the epigenetic regulation on pulmonary function. Several CpG sites, genes, biological pathways and DMRs are considered as possible crucial to pulmonary function.

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EWAS of Monozygotic Twins Implicate a Role of mTOR Pathway in Pathogenesis of Tic Spectrum Disorder

Genes ◽

10.3390/genes12101510 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1510

Author(s):

Mathis Hildonen ◽

Amanda M. Levy ◽

Christine Søholm Hansen ◽

Jonas Bybjerg-Grauholm ◽

Axel Skytthe ◽

...

Keyword(s):

Dna Methylation ◽

Monozygotic Twins ◽

Neuropsychiatric Disorders ◽

Monozygotic Twin ◽

Mtor Pathway ◽

Spectrum Disorder ◽

Genetic Components ◽

Genome Wide ◽

Chronic Tic Disorder ◽

Mtor Signalling

Tic spectrum disorder (TSD) is an umbrella term which includes Gilles de la Tourette syndrome (GTS) and chronic tic disorder (CTD). They are considered highly heritable, yet the genetic components remain largely unknown. In this study we aimed to investigate disease-associated DNA methylation differences to identify genes and pathways which may be implicated in TSD aetiology. For this purpose, we performed an exploratory analysis of the genome-wide DNA methylation patterns in whole blood samples of 16 monozygotic twin pairs, of which eight were discordant and six concordant for TSD, while two pairs were asymptomatic. Although no sites reached genome-wide significance, we identified several sites and regions with a suggestive significance, which were located within or in the vicinity of genes with biological functions associated with neuropsychiatric disorders. The two top genes identified (TSC1 and CRYZ/TYW3) and the enriched pathways and components (phosphoinosides and PTEN pathways, and insulin receptor substrate binding) are related to, or have been associated with, the PI3K/AKT/mTOR pathway. Genes in this pathway have previously been associated with GTS, and mTOR signalling has been implicated in a range of neuropsychiatric disorders. It is thus possible that altered mTOR signalling plays a role in the complex pathogenesis of TSD.

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