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Twin Study Sheds Light on Utility of Whole-Genome Sequencing for Common and Rare Diseases


By Monica Heger

A recent study that assessed the utility of whole-genome sequencing for predicting disease risk could point the way toward effective strategies for personal genome sequencing for both common and rare diseases, and offers a "reality check" on sequencing's ability to predict a healthy individual's predisposition for common disease.

The study, published this week in Science Translational Medicine, found that sequencing healthy individuals may only provide limited information about the risk of developing common diseases, and will not become a substitute for traditional medicine.

Researchers from Johns Hopkins University developed an algorithm to assess the ability of whole-genome sequencing of healthy individuals to provide clinically relevant information on 24 common diseases including autoimmune diseases, cancer, cardiovascular diseases, genitourinary diseases, neurological disorders, and obesity.

They used data generated from previously published studies on twins to show that while many individuals could be alerted to a predisposition to at least one disease, for the majority, whole-genome sequencing would be uninformative for most diseases, and the risk of developing these diseases would be similar to that of the general population.

"For individuals with a strong family history of disease, whole-genome sequencing may become extremely valuable," assuming scientists understand the genetic variables, Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University and a senior author of the paper, said during a press briefing. "But, for the vast majority of individuals, whole-genome sequencing will never be a predictive tool."

Despite this apparent less-than-positive outlook, Euan Ashley, a cardiologist at Stanford University who was involved with one of the first published clinical interpretations of an individual's whole genome sequence (IS 5/4/2010), told Clinical Sequencing News that while he agrees with the majority of the authors' conclusion regarding common disease, the study does not address a few important points.

First, he said, whole-genome sequencing is already important for Mendelian disease, and there are multiple examples of the technology finding the molecular cause of a rare disease. Furthermore, many of the groups that have implemented it in this setting argue that not only is sequencing powerful enough to find the cause of a rare disease, but it can often do so in a more efficient manner than traditional testing.

The Hopkins team does acknowledge in its paper that sequencing has been "highly informative" for Mendelian disease, and stresses that the aim of the study was to focus on the use of the approach for predicting common diseases in the general population.

Whole-genome sequencing is also becoming important for pharmacogenomics, said Ashley. If nothing else, whole-genome sequencing can provide a host of useful information about what drugs may or may not be effective in treating an individual, as well as what drugs could cause adverse reactions.

The study focused on complex diseases, where the impact is likely to be "the least important and furthest away," he said.

Nevertheless, he said, the study is a "great approach to get at the maximum likely benefit from genetic testing in complex disease."

Predictive Power

The goal of the study was to quantitatively analyze the predictive power of whole-genome sequencing.

To do this, the Johns Hopkins researchers analyzed data from more than 53,000 pairs of identical twins, and for a set of 24 diseases determined whether a twin's genome increased or decreased his or her risk for developing disease.

The key to the analysis was the concept of a "genometype." The researchers did not know the individual sequences of the twins that they analyzed, but did know that the twins shared nearly identical genomes, so should have the same risks for developing genetic diseases.

"We can use twin 1 as a control, see what disease twin 1 gets, and then the prevalence of the disease in the other twin yields the genetic risk for that genome," explained Vogelstein.

Doing this in many twins gives a "good capacity of genome sequencing to determine risk, even though we don't know the genome sequence of any of these twins," he added.

One challenge in developing the model was determining what would constitute as clinically useful information, said Vogelstein. For instance, a result might indicate that a person has a 5 percent increase in risk over the baseline risk, but that may not always be useful information. If the risk for disease was initially 1 percent, and sequencing indicated a 5 percent increase over that baseline risk, than the individual would have a 1.05 percent risk of developing the disease — "not a significant difference," he said.

So, the team defined a positive test result as being at least a 10 percent risk for developing disease from all factors.

When applying these criteria to ovarian cancer, the researchers found that at maximum, 2 percent of women would find that they were at an increased risk for ovarian cancer. The test would be useful for these women because it would suggest that they would be candidates for intense surveillance. However, 98 percent of women would get a negative result, which would not be very informative, said Vogelstein, and would only mean that their risk of developing ovarian cancer would be around 1.3 percent, compared to the general population, which has a risk of 1.4 percent.

When the model was applied to other diseases, the results were similar, he said.

Additionally, he said that the model assumes "that we understand the functional significance of every variation," so it will not improve as scientists better understand the genome.

There were however, some outliers. For Alzheimer's disease, thyroid autoimmunity, type 1 diabetes, and coronary heart disease-related deaths in males, whole-genome sequencing could have the potential to identify 75 percent of patients who ultimately develop the disease.

Additionally, whole-genome sequencing could provide important information for individuals with rare diseases, or with a strong family history of disease, said Vogelstein.

Even though these are outliers, said Ashley, they are still important. As a patient, "the things you are really interested in are the much smaller number of diseases for which you are not in the main crowd," he said. "Identifying what those are could be really critical."

Vogelstein agreed and said that sequencing would be most useful in cases where, for example, an individual comes from a family with a strong history of Alzheimer's, and a whole-genome sequencing test showed that the individual did not carry alleles that predisposed him or her to Alzheimer's. Likewise, a woman whose aunt died from ovarian cancer could gain "solace from knowing she's not at an increased excessive risk."

Informed Consent and Interpretation

As sequencing becomes cheaper and more accessible, it will be important to make sure that patients and physicians understand the value of the test, and that patients who choose to have their genomes sequenced are adequately informed about the meaning of the results, Vogelstein said.

"Everyone who gets a positive test result is alerted to a disease that they are susceptible to," he said. "That can be useful, although there are certain downsides," he said.

It will be important to make sure that the results are delivered appropriately, so as not to cause undue distress, he said. For instance, an increased risk of getting a disease is not a guarantee that an individual will develop the disease, and often there are preventative measures that can be taken to counteract the genetic risk.

So, incorporating the test with both genetic counseling and traditional preventative medicine will be important for gaining the maximum benefit from the results, he said.

Similarly, he said, a test result indicating a decreased risk for a certain disease does not mean that there's no chance a patient will get that disease. For instance, a lowered risk for lung cancer does not give the patient free reign to start smoking, nor does it justify not quitting smoking, he said.

The study focused on the "actual quantitative limits" of whole-genome sequencing, said Vogelstein, and aimed to serve as a "reality check." He added that the actually utility of whole-genome sequencing will vary between individuals and will be "totally dependent on other points of family history and lifestyle."

Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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