Predisposition testing has arguably captured the most public attention, with Angelina Jolie Pitt becoming the poster child for how BRCA mutation testing can present wrenching but proactive choices to avoid disease. Jolie Pitt, whose mother died of ovarian cancer, had her breasts and ovaries removed in two separate surgeries over the past several years in an attempt to escape the same fate — a decision that generated national attention.
Pharmacogenomic testing to predict how patients will respond to specific medications depending on their genetic makeup is another way in which sequencing can be useful. Certain gene variants can indicate that a medication may be more effective for an individual, while others might increase the risk for severe side effects.
Of sequencing’s uses, Topol and Khoury contend that pharmacogenomic data may be the most valuable to the average healthy person. But the ability to actually access this data — all of which isn’t yet clinically useful — still lags.
“There are well over 100 drugs where the interaction between DNA and the drug [may determine] if there are serious side effects, if it will or won’t work, or if the dose has to be adjusted from the norm,” Topol says. “But that information is not really attainable by anyone today, because there’s no good, widespread service to get that information.”
Finally, whole genome sequencing can reliably determine a wide variety of traits that test subjects may find edifying, intriguing, or just plain odd. These include their blood type; whether they’re lactose intolerant, with dairy consumption causing digestive distress; or how quickly or slowly they metabolize caffeine or alcohol.
While some feel drug-specific genomic data isn’t yet, as Khoury puts it, “ready for prime time,” the same is true of many common gene variants thus far identified by scientists for common diseases like diabetes, schizophrenia, and heart disease. These variants tend to increase a person’s risk of disease only slightly, so knowing about them doesn’t help a physician to treat or prevent illness. And geneticists don’t yet know the best way to compile the subtle health risks posed by many variants predisposing people to everyday disorders in a way that accurately predicts a person’s overall risk.
This is one of the reasons the Food and Drug Administration (FDA) shut down 23andMe’s initial $99 kit that tested for hundreds of genetic markers. According to a letter the FDA sent to 23andMe in November 2013, the agency had serious concerns “if test results are not adequately understood by patients or if incorrect test results are reported.” While the FDA approved 23andMe’s new $199 test kit in October 2015, the new kit offers a fraction of the tests in the original kit.
The complexity of these diseases is brought on by a mysterious interplay of genetic, environmental, and lifestyle triggers, says Isaac Kohane, chair of the Department of Biomedical Informatics at Harvard Medical School in Boston. “For most common diseases, the measure of your risk due to heredity is about 50 percent,” Kohane says. “Even with perfect omniscience about the genome, for common diseases like heart attacks, strokes, diabetes, Alzheimer’s, and so on, a big chunk of risk is still determined by other factors.”
Greater use of DNA sequencing tests is also serving to illuminate other increasingly glaring glitches in scientists’ ability to correctly forecast rare disorders. Some genetic variants originally identified in people with rare diseases and thought to be highly penetrant — bestowing a high likelihood of developing the condition — are now being found in healthy people as well.
This means the variants aren’t as accurate at predicting disease as once believed. “It turns out,” Kohane observes, “that we are riddled with abnormalities that will not kill us.”
Snyder experienced this shortcoming firsthand, when his WGS results indicated mutations suggesting he should have aplastic anemia, a rare and life-threatening condition in which the bone marrow shuts down blood cell production. Fortunately, however, that warning was wrong. “There’s no single gene that’s 100 percent predictive of getting something,” Snyder says, though he adds that some results are more alarming than others.
To Sequence, Or Not to Sequence
Snyder is a self-described “believer in the whole enterprise” of genome sequencing. He doesn’t share the deep worries of those who fear the potential psychological ramifications of learning what’s encoded in their genes. Indeed, the technology can open a Pandora’s box — both enlightening people about their genetic variations and spurring emotional distress as well as concerns about how others might use the information.
Michael Linderman, an assistant professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City, and a member of Genome’s advisory board, led research published in June 2015 in the European Journal of Human Genetics. The research focused on the motivations, concerns, and preferences of 35 healthy people who chose to have their whole genomes sequenced. The majority expressed interest in learning personal disease risk or health-related information, with one-quarter mentioning concerns about the adverse psychological impact of potential results. Nearly 6 in 10 endorsed concerns related to potential privacy issues about their data, and an equal number gave permission for their data to be used by researchers elsewhere.
Indeed, legislation is still catching up to the rising availability of genetic information. The federal Genetic Information Nondiscrimination Act forbids discrimination based on genetic information with regard to health insurance or employment, but doesn’t cover life, disability, or long-term care insurance.
Aside from privacy concerns, experts fret that a deluge of personal genetic data may create a class of “worried well” who engage in ultimately unnecessary diagnostic tests and treatments based on information that’s still of questionable value.
“Until we develop the knowledge, I think we have to be ‘buyer beware,’ ” Kohane says. “Just as critical as we should be of any test, the whole genome presents us with literally millions of tests and each will do something potentially helpful or harmful to you. If you’re healthy, you have more to lose. If you’re not healthy, you have less to lose.”
Despite the current drawbacks of the technology for genome sequencing, Kohane and others in the field contend that the more healthy people who take part, the more valid the data will become, with widespread benefits to society. “There will be a day,” says Kohane, “when we’ll have sequenced thousands of individuals with a variety of diseases who were healthy for a very long time, and we’ll understand the meaning of these variants.”