A genetic map for complex diseases
September 26, 2013
Although heavily studied, the specific genetic causes of “complex diseases,” a category of disorders which includes autism, diabetes and heart disease, are largely unknown due to byzantine genetic and environmental interactions.
Now, scientists from the University of Chicago have created one of the most expansive analyses to date of the genetic factors at play in complex diseases — by using disorders with known genetic causes to guide them. Analyzing more than 120 million patient records and identifying trends of co-occurrence among hundreds of diseases, they created a unique genetic map that has the potential to guide researchers and clinicians in diagnosing, identifying risk factors for and someday developing therapies against complex diseases. The work was published Sept. 26 in Cell.
“For the first time we’ve found that almost every complex disease has a unique set of associations with single-gene diseases. This essentially gives us ‘barcodes’ of specific gene loci, which we can use to help untangle the complex genetics of complex diseases,” said Andrey Rzhetsky, PhD, professor of genetic medicine and human genetics at the University of Chicago, who led the study.
The majority of human diseases are complex and caused by a combination of genetic, environmental and lifestyle factors. On the other end of the spectrum are Mendelian diseases such as cystic fibrosis and sickle-cell anemia, which are caused by abnormalities to a single gene. Some Mendelian disorders are known to predispose patients to certain complex diseases, but these co-occurrences have thus far only been studied on a small-scale basis.
To expose any underlying shared genetic structures between these disease categories, Rzhetsky and his team developed computational algorithms to parse more than 120 million patient billing records from hospitals systems across the U.S. and from nearly the entire population of Demark. They looked for trends in comorbidity, or the occurrence of both complex and Mendelian disease in the same patient, that were higher than expected from random chance. They studied these correlations in 65 complex diseases affecting almost every system in the body, including arthritis, depression and lung cancer, and in 95 Mendelian disease groups (representing 213 disorders).
The team uncovered 2,909 statistically significant associations, as well as corresponding levels of relative risk between every disease pair. Some comorbidities were well known, such as the strong link between lipoprotein deficiencies and heart attack, but the vast majority were previously unknown. For example, Marfan syndrome, a connective tissue disorder, was found to have significant comorbidities with neuropsychiatric diseases such as autism, bipolar disorder and depression.
Fragile X syndrome, an intellectual disability disorder, has significant associations with asthma, psoriasis and viral infection, highlighting a potential immune system dysfunction in these patients.
“Since the Mendelian diseases are associated with known genetic loci, we have essentially created a genetic map for complex disease using Mendelian disorders as markers,” said David Blair, a graduate student at the University of Chicago and first author on the study. “These loci represent great candidates for uncovering subtle genetic variations, some which might not directly cause Mendelian disease but still impact the risk for developing complex diseases.”
This genetic map is immediately useful for geneticists and clinicians as a gauge to the level of risk of developing complex disease among their patients with Mendelian diseases. But it also gives scientists a wealth of new data and a unique approach by which to better understand and develop therapeutics against complex diseases.
The team also discovered that genetic insults underlying Mendelian diseases do not appear to independently contribute to complex diseases but likely interact in a combinatorial way to ultimately cause the disorders.
“Individuals with multiple Mendelian disease-causing genetic variants end up having a much higher risk for a complex disease than we would predict given that the variants act in isolation,” Blair said.
The team hopes to expand their study to even more diseases and larger population data and to compare their predictions against the whole genome data of a broad population.
“Our work has the potential to open many new avenues of future research for complex diseases,” Rzhetsky said.
The work was supported by grants from the National Institutes of Health and by a Lever Award from the Chicago Biomedical Consortium.
Further Readings of Interest
The syndrome is carried by the gene FBN1, which encodes the connective protein fibrillin-1. Marfan syndrome is a dominant genetic trait, meaning that people who inherit only one copy of the Marfan FBN1 gene from either parent will develop Marfan syndrome and be able to transmit it to their children.
Marfan syndrome has a range of expressions, from mild to severe. The most serious complications are defects of the heart valves and aorta. It may also affect the lungs, the eyes, the dural sac surrounding the spinal cord, the skeleton and the hard palate.
In addition to being a connective protein that forms the structural support for tissues outside the cell, the normal fibrillin-1 protein binds to another protein, transforming growth factor beta (TGF-β). TGF-β has deleterious effects on vascular smooth muscle development and the integrity of the extracellular matrix. Researchers now believe, secondary to mutated fibrillin, excessive TGF-β at the lungs, heart valves, and aorta weakens the tissues and causes the features of Marfan syndrome. Since angiotensin II receptor antagonists (ARBs) also reduce TGF-β, ARBs (losartan, etc.) have been tested in a small sample of young, severely affected Marfan syndrome patients. In some patients, the growth of the aorta was indeed reduced.
Marfan syndrome is named after Antoine Marfan, the French pediatrician who first described the condition in 1896. The gene linked to the disease was first identified by Hal Dietz and Francesco Ramirez in 1991.
Transforming growth factor beta (TGFβ) plays an important role in Marfan syndrome. Fibrillin-1 directly binds a latent form of TGFβ, keeping it sequestered and unable to exert its biological activity. The simplest model of Marfan syndrome suggests reduced levels of fibrillin-1 allow TGFβ levels to rise due to inadequate sequestration. Although it is not proven how elevated TGFβ levels are responsible for the specific pathology seen with the disease, an inflammatory reaction releasing proteases that slowly degrade the elastin fibers and other components of the extracellular matrix is known to occur. The importance of the TGFβ pathway was confirmed with the discovery of the similar Loeys-Dietz syndrome involving the TGFβR2 gene on chromosome 3, a receptor protein of TGFβ. Marfan syndrome has often been confused with Loeys-Dietz syndrome, because of the considerable clinical overlap between the two pathologies.