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

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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Genome-Wide DNA Methylation Analysis Reveals Epigenetic Pattern of SH2B1 in Chinese Monozygotic Twins Discordant for Autism Spectrum Disorder

Frontiers in Neuroscience ◽

10.3389/fnins.2019.00712 ◽

2019 ◽

Vol 13 ◽

Cited By ~ 2

Author(s):

Shuang Liang ◽

Zhenzhi Li ◽

Yihan Wang ◽

Xiaodan Li ◽

Xiaolei Yang ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Dna Methylation ◽

Monozygotic Twins ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Methylation Analysis ◽

Genome Wide ◽

Dna Methylation Analysis ◽

Epigenetic Pattern

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Methylome modifications in monozygotic twins and in depression

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.854 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S30-S30

Author(s):

L. Fañanás ◽

A. Córdova-Palomera

Keyword(s):

Dna Methylation ◽

Monozygotic Twins ◽

Monozygotic Twin ◽

Epidemiological Studies ◽

P38 Map Kinase ◽

Biological Processes ◽

Genome Wide ◽

Glucocorticoid Signaling ◽

Analytical Strategies ◽

Competing Interest

Epigenetics is the study of gene expression changes that are produced by heritable, though potentially reversible, modifications of chromatin structure or DNA methylation. DNA methylation is interesting in epidemiological studies, due to its accessibility and since previous evidence indicates that large inter-individual differences in methylation levels at some loci may correlate with phenotypic plasticity in changing environments.Prior genome-wide methylomic research on depression has suggested that, together with differential DNA methylation changes, affected co-twins of monozygotic twin pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. However, the putative biological roots of this variability remain largely unexplored.This study evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their depressive status. Genome-wide DNA methylation levels were measured in peripheral blood of 34 twins (17 MZ pairs) using Illumina Infinium Human Methylation450 Beadchip. Two analytical strategies were used to identify differentially methylated probes (DMPs) and variably methylated probes (VMPs).The majority of the DMPs were located in genes previously related to neuropsychiatric phenotypes, such as WDR26, a GWAS hit for MDD whose expression levels have been found altered in blood of depressed individuals.VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling.The findings expand on previous research to indicate that both differential and variable methylation may play a role in the etiopathology of depression, and suggest specific genomic loci of potential interest in the epigenetics of depression.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Genome-wide analysis of DNA methylation in hypertension-discordant monozygotic twins

10.21203/rs.3.rs-16695/v1 ◽

2020 ◽

Author(s):

Zhentian Wu ◽

Wenjing Gao ◽

Weihua Cao ◽

Chunxiao Li ◽

Canqing Yu ◽

...

Keyword(s):

Blood Pressure ◽

Dna Methylation ◽

Empirical Bayes ◽

Vegetable Intake ◽

Monozygotic Twins ◽

Monozygotic Twin ◽

Main Function ◽

Genome Wide ◽

Replication Group ◽

Pressure Independent

Abstract Background: DNA methylation has great potential for identifying the aetiology of hypertension. The aim of this study was to explore the correlation between hypertension and DNA methylation using twins discordant for hypertension in China. Methods: In this study, 43 pairs of monozygotic twins discordant for hypertension (age 31.9-72.3 years; 67.4% male) from the Chinese National Twin Registry were recruited. Genome-wide DNA methylation was measured using the Illumina Human methylation EPIC Beadchip in whole-blood-derived DNA. Standardized questionnaires were used to collect twin data on the following variables: age, gender, socioeconomic level, lifestyle factors (including smoking, alcohol drinking, vegetable intake, and physical activity). Blood pressure, height, weight, and other anthropometric indicators were obtained by physical examination. Empirical Bayes paired moderated t-test was utilized to compare the methylation data within twin pairs. Results: Four suspected significant methylation sites, cg00950476, cg08041400, cg26733338, and cg08580087 were identified. All of these four sites locate on known loci, which were LINC01252, BDP1, SYT1, and ODZ4, respectively. The main function includes transcriptional regulation, learning and cognitive, neurodevelopment. The significant sites were further replicated among two different replication population, the first replication population contained 38 hypertension concordant monozygotic twin pairs and 38 non-hypertension concordant monozygotic twin pairs matched in age, sex, region, and birth order, and the second replication group included 21 MZ twin pairs discordant for hypertension . None of them, however, were significant. The methylation variation in the above sites may influence blood pressure, independent of genetic and early-life environmental factors. Conclusions: This study found four suspected methylation sites correlated with hypertension. However, all four sites failed the replication analysis. More hypertension-discordant monozygotic twin pairs are needed to replicate these findings in the future to explore the stability of the results.

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Increased DNA methylation variability in rheumatoid arthritis discordant monozygotic twins

10.1101/314963 ◽

2018 ◽

Author(s):

Amy P. Webster ◽

Darren Plant ◽

Simone Ecker ◽

Flore Zufferey ◽

Jordana T. Bell ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Dna Methylation ◽

Association Studies ◽

Monozygotic Twins ◽

Autoimmune Disorder ◽

Monozygotic Twin ◽

Autoimmune Disorders ◽

Healthy Population ◽

Genome Wide ◽

Discordant Twins

ABSTRACTBackgroundRheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may also be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease discordant monozygotic twin pairs.MethodsGenome-wide DNA methylation was assessed in 79 monozygotic twin pairs discordant for rheumatoid arthritis using the HumanMethylation450 BeadChip array (Illumina). Discordant twins were tested for both differential DNA methylation and methylation variability between RA and healthy twins. The methylation variability signature was then compared with methylation variants from studies of other autoimmune diseases and with an independent healthy population.ResultsWe have identified a differentially variable DNA methylation signature, that suggests multiple stress response pathways may be involved in the aetiology of the disease. This methylation variability signature also highlighted potential epigenetic disruption of multiple RUNX3 transcription factor binding sites as being associated with disease development. Comparison with previously performed epigenome-wide association studies of rheumatoid arthritis and type 1 diabetes identified shared pathways for autoimmune disorders, suggesting that epigenetics plays a role in autoimmunity and offering the possibility of identifying new targets for intervention.ConclusionsThrough genome-wide analysis of DNA methylation in disease discordant monozygotic twins, we have identified a differentially variable DNA methylation signature, in the absence of differential methylation in rheumatoid arthritis. This finding supports the importance of epigenetic variability as an emerging component in autoimmune disorders.

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Integrated analysis of the methylome and transcriptome of twin almonds (Prunus dulcis [Mill.] D.A.Webb) reveals genomic features associated with non-infectious bud failure

10.1101/2021.02.08.430330 ◽

2021 ◽

Author(s):

Katherine M. D’Amico-Willman ◽

Chad E. Niederhuth ◽

Matthew R. Willman ◽

Thomas M. Gradziel ◽

Wilburforce Z. Ouma ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Monozygotic Twin ◽

Prunus Dulcis ◽

Integrated Analysis ◽

Related Disorder ◽

Genomic Features ◽

Genetic Components ◽

Age Related ◽

Genome Wide

I.SummaryAlmond (Prunus dulcis [Mill.] D.A.Webb) exhibits an age-related disorder called non-infectious bud-failure (BF) affecting vegetative bud development and nut yield. The underlying cause of BF remains unknown but is hypothesized to be associated with heritable epigenetic mechanisms. To address this disorder and its epigenetic components, we utilized a monozygotic twin study model profiling genome-wide DNA methylation and gene expression in two sets of twin almonds discordant for BF-exhibition. Analysis of DNA methylation patterns show that BF-exhibition and methylation, namely hypomethylation, are not independent phenomena. Transcriptomic data generated from the twin pairs also shows genome-wide differential gene expression associated with BF-exhibition. After identifying differentially methylated regions (DMRs) in each twin pair, a comparison revealed 170 shared DMRs between the two twin pairs. These DMRs and the associated genetic components may play a role in BF-exhibition. A subset of 52 shared DMRs are in close proximity to genes involved in meristem maintenance, cell cycle regulation, and response to heat stress. Annotation of specific genes included involvement in processes like cell wall development, calcium ion signaling, and DNA methylation. Results of this work support the hypothesis that BF-exhibition is associated with hypomethylation in almond, and identified DMRs and differentially expressed genes can serve as potential biomarkers to assess BF-potential in almond germplasm. Our results contribute to an understanding of the contribution of epigenetic disorders in agricultural performance and biological fitness of perennials.II.SignificanceThis study examines epigenetic components underlying noninfectious bud failure, an aging-related disorder affecting almond. Results from this work contribute to our understanding of the implications of DNA methylation on agricultural production, namely perennial fruit and nut production, due to effects on growth, development, and reproduction. Describing the methylome of discordant, monozygotic twin almonds enables the study of genomic features underlying noninfectious bud failure in this economically important crop.

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

Frontiers in Neuroscience ◽

10.3389/fnins.2020.00233 ◽

2020 ◽

Vol 14 ◽

Cited By ~ 1

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

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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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DNA Methylation and Susceptibility to Autism Spectrum Disorder

Annual Review of Medicine ◽

10.1146/annurev-med-120417-091431 ◽

2019 ◽

Vol 70 (1) ◽

pp. 151-166 ◽

Cited By ~ 10

Author(s):

Martine W. Tremblay ◽

Yong-hui Jiang

Keyword(s):

Autism Spectrum Disorder ◽

Dna Methylation ◽

Causative Factor ◽

Autism Spectrum ◽

Postnatal Period ◽

Spectrum Disorder ◽

Regulation Of Transcription ◽

Peak Time ◽

Genome Wide ◽

Technical Advances

The prevalence of autism spectrum disorder (ASD) has been increasing steadily over the last 20 years; however, the molecular basis for the majority of ASD cases remains unknown. Recent advances in next-generation sequencing and detection of DNA modifications have made methylation-dependent regulation of transcription an attractive hypothesis for being a causative factor in ASD etiology. Evidence for abnormal DNA methylation in ASD can be seen on multiple levels, from genetic mutations in epigenetic machinery to loci-specific and genome-wide changes in DNA methylation. Epimutations in DNA methylation can be acquired throughout life, as global DNA methylation reprogramming is dynamic during embryonic development and the early postnatal period that corresponds to the peak time of synaptogenesis. However, technical advances and causative evidence still need to be established before abnormal DNA methylation and ASD can be confidently associated.

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