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Genetic variants, gene regulation linked in common diseases
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In the past 10 years, researchers have conducted hundreds of studies to identify the regions in the human genome that are somehow linked to disease. In a recent study published in the journal Science, researchers said they have found the link between genetic variants and gene regulation in common diseases such as cancer, cardiovascular disease, diabetes and neurological diseases.
John A. Stamatoyannopoulos, MD, researcher and associate professor of genome sciences and medicine at the University of Washington, School of Medicine, told Endocrine Today that there are likely more genetic changes associated with diseases than previously thought.
John A. Stamatoyannopoulos
“Now we have a much broader view of what or how to potentially interpret the individual’s genome sequence. But the difficulty is that we don’t necessarily know how to connect that information with a particular diagnosis or treatment yet. However, now that we have some of these new tools in place, it’s going to greatly help our ability to do that,” Stamatoyannopoulos said.
DNA cartography
The NIH-supported study involved the examination of thousands of genome-wide association studies’ (GWAS) variants in non-coding regions of DNA to see how those variants could regulate gene expression. According to a press release issued by the NIH, regions of non-coding DNA that actively regulate gene expression are sensitive to DNasel, a protein that acts like molecular scissors to slice parts of DNA.
Using more than 400 cell and tissue samples, some from the NIH Common Fund’s Epigenomics program and the National Human Genome Research Institute’s Encyclopedia of DNA Elements, or ENCODE, project, Stamatoyannopoulos and colleagues created a map of DNA regions sensitive to the DNasel hypersensitivity sites.
Stamatoyannopoulos and colleagues found that more than 76% of non-coding GWAS variants were in or very near DNasel hypersensitivity sites, demonstrating that most non-coding GWAS variants in these samples were actively involved in regulating genes, according to the press release. Additionally, 88% of GWAS variants in regulatory DNA regions are active in fetal development, including those variants associated with adult-onset disease.
“In general, our ability to treat and diagnose disease has been connected to our understanding of the biology and the pathways that are involved in the disease. This has been shown over and over again,” Stamatoyannopoulos said. “Once we understand that, we can move forward.”
Until now, Stamatoyannopoulos said researchers have not understood the common disease pathways very well.
“What [the study] does is expose a lot of those pathways and many new pathways that can be used to try and make sense of what’s going on with these diseases. It’s not going to have an impact tomorrow, but what it’s going to do is greatly accelerate research efforts in a variety of areas,” he said.
Moreover, the findings could help clarify why some environmental exposures in utero or during early childhood development might increase the risk for diseases, which create symptoms many years later. Stamatoyannopoulos said one area of interest includes the finding that there is a specific group of genetic variants acting through regulatory DNA to influence the age of menarche.
A better understanding
Francis S. Collins, MD, PhD, director of the NIH, told Endocrine Today this landmark study is unique compared with previous studies. When combined with 36 papers from the ENCODE program, the data represent a major advance in the understanding of how the human genome functions in health and disease.
Francis S. Collins
“These findings point to millions of regulatory sites in the human genome that direct genes to turn on or off in particular cell types at particular moments in development,” Collins said. “These insights promise to shed new light on the mechanisms that underlie many common diseases, including cancer, cardiovascular disease, neurological conditions, and diabetes and other endocrine disorders.”
The study allowed researchers to look at the genome and identify which genes were regulated by hundreds of GWAS variants, including variants linked to blood platelet counts, amyotrophic lateral sclerosis, Crohn’s disease, breast and ovarian cancer and schizophrenia, according to the press release.
“… It took a far more comprehensive look at the regions of the human genome involved in regulating how, where and when genes are switched off or on,” Collins said. “This new knowledge will serve to accelerate efforts to identify targets for new therapeutics, as well as to develop better strategies for disease prevention. For example, the discovery that many regulatory variants associated with common, adult-onset diabetes are located in genomic regions active during fetal development suggests a major role for early environmental exposures in such diseases.”
Now that researchers have realized this effect, Stamatoyannopoulos said there will be additional work to increase the extent and the resolution of the data, and these findings have forced a re-evaluation of the existing GWAS that have been completed because many of these studies involved potentially hundreds of different variants that were previously missed. – by Samantha Costa
For more information
Maurano MT. Science. 2012;doi:10.1126/science.1222794.
Francis S. Collins, MD, PhD, can be reached at the Office of the Director, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892; email: collinsf@od.nih.gov.
John A. Stamatoyannopoulos, MD, can be reached at the Department of Genome Sciences, University of Washington, Foege Building S-310A, 3720 NE Pacific St., Box 355065, Seattle, WA 98195; email: jstam@uw.edu.
Disclosure: This study was supported by NIH grants. Collins and Stamatoyannopoulos report no relevant financial disclosures.