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Extensive variation and low heritability of DNA methylation identified in a twin study

 

kristinaDisturbance of DNA methylation leading to aberrant gene expression has been implicated in the etiology of many diseases. Whereas variation at the genetic level has been studied extensively, less is known about the extent and function of epigenetic variation. To explore variation and heritability of DNA methylation, we performed bisulfite sequencing of 1760 CpG sites in 186 regions in the human major histocompatibility complex (MHC) in CD4+ lymphocytes from 49 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs. Individuals show extensive variation in DNA methylation both between and within regions. In addition, many regions also have a complex pattern of variation. Globally, there appears to be a bimodal distribution of DNA methylation in the regions, but a significant fraction of the CpG sites are also heterogeneously methylated. Classification of regions into CpG islands (intragenic and intergenic), 5’end of genes not associated with a defined CpG island, conserved non-coding regions and random CpG sites, show region-type differences in variation and heritability. Analyses revealed slightly lower intra-pair differences among MZ than among DZ pairs, suggesting some genetic influences on DNA methylation variation with most of the variance attributed to non-genetic factors. Overall, heritability estimates of DNA methylation were low. Our heritability estimates are, however, somewhat deflated due to the presence of batch effects that artificially inflate the estimates of shared environment.

 

Another relevant paper to the topic has been recently accepted for publication on PLoS Genetics.

'DNA Methylation and Gene Expression Changes in Monozygotic Twins Discordant for Psoriasis: Identification of Epigenetically Dysregulated Genes'

Monozygotic (MZ) twins do not show complete concordance for many complex diseases, for example, discordance rates for autoimmune diseases are 20-80%. MZ discordance indicates a role for epigenetic or environmental factors in disease. We used MZ twins discordant for psoriasis to search for genome-wide differences in DNA methylation and gene expression in CD4+ and CD8+ cells using Illumina’s HumanMethylation27 assay and HT-12 expression assays, respectively. Analysis of these data revealed no differentially methylated or expressed genes between co-twins when analyzed separately, although we observed a substantial amount of small differences. However, combined analysis of DNA methylation and gene expression identified genes where differences in DNA methylation between unaffected and affected twins were correlated with differences in gene expression. Several of the top ranked genes according to significance of the correlation in CD4+ cells are known to be associated with psoriasis. Gene ontology (GO) analysis revealed enrichment of biological processes associated with the immune response and clustering of genes in a biological pathway comprising cytokines and chemokines. These data suggest that DNA methylation is involved in an epigenetic dysregulation of biological pathways involved in the pathogenesis of psoriasis. This is the first study based on data from MZ twins discordant for psoriasis to detect epigenetic alterations, which potentially contributes to development of the disease.

 

Publications:

Gervin K, Hammerø M, Akselsen HE, Moe R, Nygård H, Brandt I, Gjessing HK, Harris JR, Undlien DE, Lyle R Extensive variation and low heritability of DNA methylation identified in a twin study. Genome Res. 2011 Nov;21(11):1813-21. Epub 2011 Sep 26.

Gervin K et al., DNA Methylation and Gene Expression Changes in Monozygotic Twins Discordant for Psoriasis: Identification of Epigenetically Dysregulated Genes PLoS Genetics (accepted).

 

 

December 2011
ENGAGE Young Investigator

Kristina Gervin is a PhD-student in Dag Undlienís group at the Department of Medical Genetics at Oslo University Hospita and Norwegian Institute of Public Health under supervision from Dr Robert Lyle and professor Dag Undlien. (Partner 14)


Kristina’s primary research interest is epigenetics and the role in development of autoimmune diseases. I am working on my PhD exploring epigenetic changes in monozygotic (MZ) twins discordant for autoimmune diseases. Within ENGAGE, I have been involved in two projects: exploring variation and heritability of DNA methylation in healthy MZ and DZ (Gervin et al, Genome Res, 2011) and identification of epigenetically dysregulated pathways in MZ twins discordant for psoriasis (Gervin et al., PLoS Genetics 2011, accepted)