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Rare Epigenetic Variation May Contribute to Genetic Disease, Large-Scale Study Finds

NEW YORK – Epigenetic variation is more common in the human genome than previously suspected, a new study has found, and could contribute to disease.

There have already been hints that epigenetic changes could affect diseases like hereditary breast and colon cancer. Researchers led by Andrew Sharp at the Icahn School of Medicine sought to determine the prevalence of epivariations by analyzing methylation profiles of more than 23,000 people. As they reported in the American Journal of Human Genetics on Tuesday, they uncovered nearly 4,500 unique epivariations, some of which affected the promoters, and expression, of genes associated with human disease. This suggests epivariations are an overlooked contributor to genetic disease, they wrote.

"Because the epigenetic variants we identify would not be detected by genome sequencing, yet can lead to the dysregulation and silencing of genes known to be linked with heritable diseases, our work shows that some types of disease-causing mutations will be missed by standard genetic testing that only looks at DNA sequence," Sharp, an associate professor of genetics and genomic sciences at Mount Sinai, said in a statement.

He and his colleagues analyzed methylation data for 23,173 individuals from nearly two dozen cohorts that were initially generated for epigenome-wide association studies. About a third of those samples harbored one or more epivariation. In all, they identified 13,879 autosomal epivariations and 26 epivariations on the X chromosome. Most of these variants, they noted, were excess methylation. 

Slightly more than 60 percent of the epivariations overlapped with gene promoter regions. By analyzing gene expression data available on 7,786 samples, the researchers found that promoter hypomethylation was linked to increased gene expression, while promoter hypermethylation was associated with decreased gene expression.

In particular, the researchers noted that 499 of the epivariations overlapped with the promoter regions of disease genes from the Online Mendelian Inheritance in Man database and that hypermethylation epivariations at 384 OMIM genes could lead to allelic silencing. When the researchers homed in on four loci where they predicted methylation gains in the promoter regions of OMIM disease genes based on array data, they found those individuals also exhibited methylation gains by bisulfite sequencing, as compared to controls, confirming their prediction.

At the same time, the researchers investigated whether epivariations are driven by underlying genetic variation. By drawing on methylation and SNV data from the Women's Health Initiative, they uncovered 97 epivariations present in at least two people. About 70 percent of these epivariations were significantly associated with at least one SNV, suggesting some epivariations are shaped by their genetic environment. They further noted that rare epivariations were more likely to appear alongside rare SNVs and estimated about 8 percent of epivariations stem from the presence of a nearby rare SNV.

However, the researchers also found that monozygotic twins could be discordant for epivariations, which indicated that about a third of epivariations are somatic events. Underscoring that finding, they noted that the number of epivariations per individual increased with age, again suggesting some are somatic events. 

The findings, the researchers noted, suggest that epivariations can exert an effect on gene expression and act similarly to loss-of-function coding mutations. "Based on this observation, we anticipate that epigenetic profiling in patients with overt genetic disease, but who lack pathogenic sequence mutations in the gene(s) relevant to their phenotype, will lead to the identification of epivariants as a causative factor in some conditions, and potentially provide additional diagnostic yield compared to purely sequence-based approaches," they wrote in their paper.

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