How polygenic risk scores can reveal a predisposition for diseases
Reprinted courtesy of Next Avenue.
by George Lorenzo
Two framed displays adorn the walls at the American Medical Association main office. One is a replica of the June 27, 2000 New York Times front page, with the banner headline “Genetic Code of Human Life Cracked by Scientists.” The other is a quote pulled from an accompanying article on the same front page, sub-headlined “A Pearl and a Hodgepodge: Human DNA.” The article featured a variety of complex opinions from leading scientists about the human genome. The framed quote is from Nobel Laureate David Baltimore, who said, “We’ve got another century of work ahead of us, to figure out how all these things relate to each other.”
Nineteen years since, forward-thinking, precision-medicine-oriented advances related to human DNA sequencing have been developed around mountains of information analyzed around all parts of our genes — the whole genome — and how these genes relate to each other. Referred to as polygenic, this work is different than the more common utilization of gene-based information referred to as monogenic. The monogenic research considers the identification of single, specific gene mutations (or variants).
Today’s health-oriented genetic tests are mostly monogenic-oriented. But a growing number of DNA experts believe using polygenic information through polygenic risk scores (PRS) is the wave of the future. However, just as in 2000, there’s a scientific “hodgepodge” of opinions and viewpoints.
An April 2019 Journal of the American Medical Association (JAMA) Insights article on polygenic risk scores explains how PRS “reflect a mathematical aggregate of risk conferred by many DNA variants to estimate the likelihood of a specific outcome, such as disease onset in an individual.” In short, PRS will offer a prediction about whether a patient is at low, average or high risk for a variety of medical conditions and diseases.
In his October 2018 article on the power of PRS, Matthew Warren (a Nature News reporter) stressed that “polygenic scores add together the small — sometimes infinitesimal — contributions of tens to millions of spots on the genome, to create some of the most powerful genetic diagnostics to date.”
“Genetic risk information can focus your good habits on your risk.”
PRS entered the world of DNA advances sometime during the early 2000s. Initially, the scores were not well accepted. But in the past two years, they have been increasingly documented by geneticists and biostatisticians as a viable approach to enhance the use of monogenic information for forecasting disease.
While genetic tests that recognize monogenic mutations are “highly predictive of disease,” writes UC Berkeley trained genetic epidemiologist Jeanette McCarthy in a paper on PRS, “the genetic underpinning of most cases of common diseases is not monogenic, but polygenic.” However, “questions remain about whether they (PRS) are predictive or broadly relevant or useful,” McCarthy adds.
PRS are culled from large repositories of data analyzed from what are known as genome-wide association studies or GWAS. “A genome-wide association study is an approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease,” according to the National Genome Research Institute.
As reported by Nature, an extraordinarily large and unprecedented genome-wide association study generated by the UK Biobank, for example, is frequently used to develop a variety of studies that create PRS. The UK Biobank consists of data generated from 500,000 UK citizens who donated urine, saliva and blood samples for genetic analysis and evaluated for known biomarkers of disease.
In addition to the UK Biobank, there are several thousand such studies. And the number is growing, worldwide. But most genome-wide association studies are based on biomarkers from white Northern Europeans. This means there’s a great need for ones based on other races and ethnicities, such as Africans, Asians and Hispanics.
How does this all relate to older adults who may be thinking about getting a health-oriented genetic test?
“If you are talking about genetics, in general, for older adults, polygenic risk is actually more relevant to you than monogenic risk,” says Ali Torkamani, director of genomics and genome informatics at Scripps Research Translational Institute.
Torkamani explains that monogenic risk related to early-onset disease identification typically cuts off around our mid-50s. So, for example, a coronary artery disease PRS can be “much more relevant to older individuals than monogenic risk, because you sort of aged out of monogenic risk,” he says.
But getting a PRS, even from a reputable lab that offers genetic-testing results to clinics, has not yet taken off in any significant manner.
“PRS are not widely commercialized right now because they are still new,” McCarthy says. And getting an interpretation from an erudite genetic counselor and primary care physician for any kind of PRS is still in its early stages.
Even so, there are ways to get some PRS. For instance, Ambry Genetics, a biotech company in Aliso Viejo, Calif., offers PRS for breast cancer and prostate cancer, called AmbryScore, that patients can obtain through their health care providers.
In March 2019, an MIT Technology Review article reviewed 23andMe’s recent announcement of a new type 2 diabetes test based on PRS that “evaluates 1,244 locations in a person’s genome, each with a small bearing on the overall risk of diabetes.” A Harvard University epidemiologist quoted in the article calls the new PRS-oriented test results “a huge experiment.”
In December 2018, Myriad Genetics, a molecular diagnostic company in Salt Lake City, announced that it had validated new PRS that “predict breast cancer risk in women of Hispanic ancestry who test negative for hereditary cancer mutations.”
A May 2019 article in STAT+ reported that Sekar Kathiresan, director of the center for genomic medicine at Massachusetts General Hospital, and his colleagues, have developed PRS “based on multiple genes for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease and breast cancer identified through recent genome-wide association studies.” None are yet available to the public in a clinical setting, and it’s difficult to predict when they will be.
You can also get PRS by uploading raw data from genetic health reports provided by 23andMe and other genetic health testing services in a service that will deliver reporting based on detailed descriptions and links between your personal DNA variants and a growing database of genome-wide association studies about them, says Bertalan Meskó, a geneticist and director of The Medical Futurist Institute.
In his book, The 40 Most Exciting Questions About the Future of Healthcare, Meskó explains how he had his whole genome sequenced by Dante Labs, a global genome sequencing and data analysis company with offices in Europe and the U.S., and then uploaded the raw data into a DNA interpretation service called Promethease.
“I upload my data to Promethease regularly,” (as more genome-wide association studies are added to the service) he says. “I learned a bit more about the potential medical issues I might have in the future.”
However, using this method is not for most of us who know little about DNA sequencing and data analysis. And, regardless of your knowledge base, you’ll need a professional to review the report with you.
Meskó has the benefit of being a geneticist himself, and he works with his primary care physician and a genetic counselor to review the results of his PRS. He believes the common use of PRS in a clinical setting is at least five to 10 years away.
“I can tell you your risk for lung cancer based on the top 20 studies in the world, but even knowing your PRS for lung cancer would mean that the best advice I can give to you is not to smoke, or maybe get a low-dose CT scan once or twice every few years,” he says. “That is the absolute best advice I can provide with or without me sequencing your DNA. And for most medical conditions, that is the case.”
“Genetic risk information can focus your good habits on your risk,” adds Torkamani, who estimates that PRS will become commonly available in clinical settings (similar to a blood test) within five years. “That is the power that polygenic risk brings to people if they embrace it and use it to guide their health practice.”