Epigenetic circuits just got a little more complicated. They have been found to contain new components called outside variants, which are important because they can influence disease risk. Now that these components are no longer being overlooked, they may end up explaining at least some of the “missing heritability” for complex traits.

The outside variants, which have been identified by scientists based at Case Western Reserve University, are genetic variants in specific regions of DNA that physically interact with disease genes, even though they may seem relatively distant from the disease genes. Outside variants can come into close proximity with disease genes when DNA strands twist and fold. They suggest a new level of gene regulation and may help explain how identical single-nucleotide polymorphisms (SNPs) can lead to different clinical outcomes.

“Our previous work showed that there was more to the expression of a disease gene than just the nearby regulatory elements on the DNA strand, and it seemed logical to look at variants that are brought in close physical proximity to the gene when DNA is packaged in the cell,” said Peter Scacheri, Ph.D., associate professor of genetics and genome sciences. “By looking at these 'outside variants,' we can determine the risk associated with disease with better precision than by just looking at the known variants.”

Dr. Scacheri is the senior author of a new study (“Modeling Disease Risk through Analysis of Physical Interactions between Genetic Variants within Chromatin Regulatory Circuitry”) that appeared September 19 in the journal Nature Genetics. The study investigated SNPs associated with six autoimmune diseases—rheumatoid arthritis, systemic lupus, Crohn's disease, multiple sclerosis, ulcerative colitis, and celiac disease. The SNPs were previously identified through genome-wide association studies (GWASs), increasingly popular research tools that search DNA sequence data for regions associated with disease. The large-scale studies tend to zero in on SNPs in “enhancer clusters” of DNA, regions known to contort and interact with disease genes. The researchers identified outside variant DNA regions that seemed to be dependent on known disease SNPs, but were found far beyond enhancer clusters normally associated with the diseases.

Once the researchers discovered outside variants, they studied DNA samples to determine the impact of the regions on disease gene levels. The team used computer models to compare gene levels associated with their newly identified outside variants to those associated with previously identified SNPs. The team discovered outside variants physically interacted with known SNPs within the DNA samples, and both genetic elements joined forces to mediate disease risk. Through the models, Dr. Scacheri's team was able to use outside variants to predict disease risk better.

“The big surprise was when we crunched the numbers and compared the risk associated with the amount of heritability that could be explained by the outside variants,” explained Dr. Scaceri. “By our calculations, outside variants accounted for a whopping two to three times more of the heritability than explained by the current models. That was far more than we had expected.”

Further characterization of outside variants revealed they have much in common with enhancer clusters. Proteins that help activate disease genes commonly attach to both regions. In fact, 77% of outside variants identified by the researchers were located near protein attachment sites similar to those found in enhancer clusters. The similarities between outside variants and enhancer clusters support the team's conclusion that multiple elements work together to control disease genes.

“Imagine you have a light bulb hooked up to multiple dimmer switches in different places in a room,” said Olivia Corradin, Ph.D., fellow and principal investigator at Whitehead Institute for Biomedical Research, former graduate student in Dr. Scacheri's laboratory, and lead author of the study. “Instead of studying the effect of each switch, one at a time, we studied the light bulb, and asked 'how do the multiple switches combine to control the room's light?' This perspective allowed us to better determine the genetic risk associated with disease.”

The study provides a better understanding of how folded DNA employs distant genetic regions to control how genes are turned on or off. Three-dimensional models of DNA may therefore reveal other genetic elements that can help explain the complex processes of gene control, and ultimately disease heritability. The outside variants identified in the study may also provide additional biomarkers to assess a person's risk of disease.

“We found outside variants associated with several autoimmune-related disorders, including multiple sclerosis, Crohn's disease, and arthritis. The next step is to see if this extends to other common diseases, like heart disease and diabetes,” said Dr. Scacheri, indicating his research team plans to “determine whether we can use outside variants in a diagnostic or preventive medicine setting to better identify individuals who are most at risk for developing these diseases.”


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