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The relationship between DNA methylation and disease

By carrying out a genome-wide association study, researchers have uncovered novel mechanisms linking DNA methylation and disease. Their findings greatly advance our understanding of the relationship between genetic variation and gene expression.

Genetic variation and DNA methylation

DNA is often subjected to modification by environmental factors. These modifications, known as epigenetic changes, can alter gene expression. A major epigenetic change is DNA methylation, which involves the addition of methyl groups to DNA bases. Methylation often occurs at regions of DNA known as CpG sites.

DNA methylation plays a key role in determining genomic structure and function. For example, disturbances in DNA methylation have been associated with cancer and neuropsychiatric illness. However, it is not well understood how genetic variants influence DNA methylation. In the current study, published in Nature Genetics, researchers aimed to uncover more about the molecular mechanisms that link genetic variation to gene expression and ultimately disease susceptibility. 

DNA methylation sites in trans

Firstly, the team carried out a genome-wide association study (GWAS) of DNA methylation in peripheral blood of both European and South Asian populations. From this study, the team identified 11.2 million unique SNP-CpG associations.

Interestingly, not all the CpG sites were on the same chromosome as their associated SNP. These associations, known as trans associations, were of particular interest as previous studies have shown that they play a critical role in the coordination of genomic function.

To investigate this further, the researchers assessed whether there were causal relationships between trans SNP-CpG pairings and clinical phenotypes. They discovered that the gene NFKBIE, which encodes a transcription factor inhibitor, contained multiple SNPs associated with trans methylation sites. These were found to be associated with rheumatoid arthritis, which implies a role for NFKBIE in the disease. Additionally, the team found associations between trans SNP-CpG pairings and high blood pressure.

The effects of methylation in specific cell types

Finally, the team examined whether methylated DNA regions affected specific cell types. Interestingly, they found that an SNP in the gene FADS1, which encodes an enzyme that metabolises fatty acids,had a strong correlation with DNA methylation in CD8+ T cells. This SNP was also strongly associated with asthma. Therefore, the team suggest that DNA methylation affects genetic regulation of FADS1 in CD8+ T cells, which contributes to the development of asthma.


The findings of this study have greatly advanced our understanding of the relationships between DNA sequence variation and DNA methylation. It has also reported novel variants that underlie health conditions such as arthritis and high blood pressure.

In addition, the researchers have uncovered links between DNA methylation and asthma in white blood cells. Nonetheless, more work will need to be done to find the specific molecular mechanisms involved. The researchers hope that in the future, similar approaches to those applied here will help uncover such associations between methylation and disease in other cell types.

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