scholarly journals Increased DNA methylation variability in rheumatoid arthritis discordant monozygotic twins

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.

scholarly journals Role of Cytokines in Systemic Lupus Erythematosus: Recent Progress from GWAS and Sequencing

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
John J. Connolly ◽  
Hakon Hakonarson
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Association Studies ◽  
Monozygotic Twins ◽  
Autoimmune Disorder ◽  
Genome Wide Association Studies ◽  
Systemic Lupus ◽  
Genome Wide ◽  
Number Variation

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, known to have a strong genetic component. Concordance between monozygotic twins is approximately 30–40%, which is 8–20 times higher than that of dizygotic twins. In the last decade, genome-wide approaches to understanding SLE have yielded many candidate genes, which are important to understanding the pathophysiology of the disease and potential targets for pharmaceutical intervention. In this paper, we focus on the role of cytokines and examine how genome-wide association studies, copy number variation studies, and next-generation sequencing are being employed to understand the etiology of SLE. Prominent genes identified by these approaches includeBLK, FCγR3B,andTREX1. Our goal is to present a brief overview of genomic approaches to SLE and to introduce some of the key discussion points pertinent to the field.

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

Genes ◽  
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.

Methylome modifications in monozygotic twins and in depression

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.

scholarly journals Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Muhammad Muaaz Aslam ◽  
Peter John ◽  
Kang-Hsien Fan ◽  
Attya Bhatti ◽  
Wajahat Aziz ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Studies ◽  
Autoimmune Disorder ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Pakistani Population ◽  
Genome Wide ◽  
Genetic And Environmental Factors ◽  
European Populations

Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.

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

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.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

scholarly journals Association analysis of juvenile idiopathic arthritis genetic susceptibility factors in Estonian patients

2021 ◽  
Author(s):  
Tiit Nikopensius ◽  
Priit Niibo ◽  
Toomas Haller ◽  
Triin Jagomägi ◽  
Ülle Voog-Oras ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Juvenile Idiopathic Arthritis ◽  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Association Studies ◽  
Control Sample ◽  
Case Control ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. Genome-wide association studies have augmented the number of JIA-associated loci, particularly for non-HLA genes. The aim of this study was to identify new associations at non-HLA loci predisposing to the risk of JIA development in Estonian patients. Methods We performed genome-wide association analyses in an entire JIA case–control sample (All-JIA) and in a case–control sample for oligoarticular JIA, the most prevalent JIA subtype. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. After imputation, 16,583,468 variants were analyzed in 263 cases and 6956 controls. Results We demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. We replicated known JIA associations in CLEC16A and VCTN1 regions in the oligoarticular JIA sample. The strongest associations in the All-JIA analysis were identified at PRKG1 (P = 2,54 × 10−6), LTBP1 (P = 9,45 × 10−6), and ELMO1 (P = 1,05 × 10−5). In the oligoarticular JIA analysis, the strongest associations were identified at NFIA (P = 5,05 × 10−6), LTBP1 (P = 9,95 × 10−6), MX1 (P = 1,65 × 10−5), and CD200R1 (P = 2,59 × 10−5). Conclusion This study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that confer susceptibility to JIA in Estonian patients. Key Points• Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with heterogeneous presentation and genetic predisposition.• Present genome-wide association study for Estonian JIA patients is first of its kind in Northern and Northeastern Europe.• The results of the present study increase the knowledge about JIA risk loci replicating some previously described associations, so adding weight to their relevance and describing novel loci.• The study provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis.

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
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