If a crystal ball could reveal your personal risk for developing heart disease or breast cancer or Alzheimer's disease, would you pay to take a look? Would you believe what it predicted and would you be willing to change your behavior to prevent or reduce the risk of this disease taking over your body? These may sound like abstract philosophical questions—but for us they are not.
Two years ago, as I (Rahul Desikan) completed my final year of training as an M.D.-Ph.D. neuroscientist and neuroradiologist, and spent my afternoons rushing back and forth between the hospital and the lab, I was oblivious to the fact that I had a high risk of dying soon. A year later, I was diagnosed with amyotrophic lateral sclerosis or ALS—the same disease that killed Lou Gehrig and Stephen Hawking. If I had any hint that I would develop ALS, which has locked me inside my body as though inside a cell, unable to move or breath normally on my own, I can tell you without hesitation that I would have done anything and everything to stop or slow the devastation this disease has visited on my life. If only I could have glimpsed into my future …
Today, thanks to the mapping of the human genome and subsequent efforts to make sense of the resulting blueprint of As and Ts, Gs and Cs, we are close to being able to predict your future health from your DNA. Using advanced computer models, scientists are adding together the influence of the hundreds, even thousands, of DNA variants associated with a given disease into what is called a “polygenic score.”
The influence that each genetic variant exerts on a person’s disease risk may be tiny, but by distilling all of this complex genetic information into a single number that quantifies an individual person’s particular genetic risk of disease, polygenic scores pack powerful risk prediction into a single number. The hope is that your personalized polygenic score could help you prevent disease, live longer and plan for your future.
Can a genetic test really predict your health? Do you want to know today that you are at high risk of a disease whose onset may be three decades from now? And if the genetic test comes out positive for a terminal disease that has no cure, what would you do? These are the kinds of tough questions that we need to start discussing as we enter this new age of genomic medicine.
As we embark on this discussion, the most important thing to know is that polygenic scores are not diagnostic tests. Even doctors and other health professionals get this wrong. Polygenic scores measure your risk for developing a disease, not whether you do or don't have the disease, or even whether you will ever get that disease. Given your combination of genetic risk factors, these scores estimate the probability that you will develop a particular disease over time.
Like the probability of rain in next week’s weather forecast, polygenic scores have inherent uncertainty. Appreciating this uncertainty is key because the uncertainty in polygenic scores leaves room for action. We know that for many complex diseases behavior is just as important as genes in setting the stage for what is to come. If disease onset isn't solely determined by genes, then lifestyle or therapeutic interventions can prevent or modify the trajectory of disease.
Polygenic scores will need to undergo rigorous evaluation by the medical community before being incorporated into clinical practice. However, companies are already offering these tests direct to consumers. Myriad Genetics has launched a commercial polygenic test that estimates breast cancer risk for women. HealthLytix and Dash Genomics have developed a polygenic test for Alzheimer's disease available to anyone who already has their DNA data from Ancestry.com or 23andMe—upload your data and for $99 an app on your smartphone will tell you when you are at greatest risk for developing dementia.
These easy to understand scores are being hailed as a breakthrough technology. But how might these scores actually help you? First, polygenic risk can inform treatment decisions and lifestyle modifications. For example, aggressively lowering cholesterol in individuals with a high polygenic score for heart disease may lead to a much greater reduction in the risk of a heart attack than doing so in people with a low polygenic score.
Polygenic scores may also influence disease-screening strategies. Recently, it was shown that a polygenic score can predict risk for aggressive prostate cancer, suggesting that it could identify men who would benefit most from PSA screening. Finally, knowledge of polygenic risk can be useful in planning for the future. For example, although we don’t yet have effective treatment for dementia, knowing that you are at high risk for Alzheimer's disease can help you make informed decisions about changing your behavior—keeping heart and brain healthy through diet and exercise, and, of course, paying more attention to your future finances and plans for long-term care.
In our laboratory at the University of California, San Francisco, we are experimenting with and developing molecular pathway-specific polygenic scores. We have found that different molecular processes appear to underlie and drive brain diseases like Alzheimer’s and ALS in different patients. The implication is that a subset of people with Alzheimer's may be genetically susceptible to immune dysfunction whereas another group of Alzheimer's patients may have genetic abnormalities in that make them susceptible to cardiovascular disease. We are building an online platform for people at risk for or living with Alzheimer's and ALS: upload your DNA and the website will send you a cardiovascular and immune polygenic report card that you can take to your doctor.
Today we have unprecedented access to information. Our genetic information will soon be added to the global libraries of digital information to which we have almost instant access, and the use of genetic risk scores will soon become commonplace in our lives. As a society, we need to understand what this genetic knowledge does and does not mean, and become comfortable with the prognostic uncertainty inherent in these genetic risk scores. As an individual, you should know that your polygenic risk profile has the potential to tell you which interventions are likely to have the biggest positive impact on your long-term health.
Armed with knowledge about the capabilities and limitations of polygenic scores, you can make informed decisions and choose exactly how a genetic test will shape your future.