Epigenomic research sheds light on complex disease

US researchers have revealed how changes in regions of DNA that do not code for genes can affect disease. The majority of the human genome is composed of non-protein coding regions of DNA. Changes in these regions are associated with disease susceptibility, but precisely how these changes function is unclear. Using a new mapping technique, researchers have shown how chemical modifications in these regions are associated with the regulation of gene expression and correlate with disease-associated genetic mutations.

'Our ultimate goal is to figure out how our genome dictates our biology. But 98.5 percent of the genome is non-protein coding, and those non-coding regions are generally devoid of annotation', said Dr Manolis Kellis, co-author of the study at the Massachusetts Institute of Technology (MIT). The research was conducted in conjunction with colleagues at the Broad Institute of MIT and Harvard, and Massachusetts General Hospital.

Mutations called SNPs  (single nucleotide polymorphisms) have been linked to the likelihood of developing disease. The majority of disease associated SNPs occur in non-protein coding regions of DNA. Researchers analysed genetic data from ten genome-wide association studies (GWAS), which had previously identified disease associated SNPs, in order to identify other notable changes to the DNA.

Modifications to the genome that contribute to disease can occur at the level of the DNA sequence itself, as in the case of SNPs, and at the epigenomic level. Epigenomic changes involve chemical modifications to the DNA that do not alter the DNA sequence itself, such as chromatin marks. Chromatin marks occur throughout the genome and are able to regulate gene expression when present in areas outside of genes called control regions.

Chromatin marks in several different cell types were mapped, including blood cells, skin cells, embryonic cells and cancerous liver cells. Following identification of the control regions, the chromatin marks in these areas were specifically analysed. The chromatin marks were shown to map to regions that contained SNPs.

'Across ten association studies of various human diseases, we found a striking overlap between previously uncharacterised SNPs and the control region annotations [chromatin marks] in specific cell types', said Dr Kellis. 'This suggests that these DNA changes are disrupting important regulatory elements and thus play a role in disease biology'.

'GWAS has identified hundreds of non-coding regions of the genome that influence human disease, but a major barrier to progress is that we remain quite ignorant of the functions of these non-coding regions', said Professor David Altshuler deputy director at the Broad Institute of MIT and Harvard, but who was not involved in the study. 'This remarkable and much-needed resource is a major step forward in helping researchers address that challenge'.

This study sheds new light on previous GWAS analyses and the role of epigenomics in disease susceptibility. Future work will address how drugs can target components of this network of chromatin marks and SNPs, in order to help prevent and/or treat disease.

This study was published in Nature.