Next step is to design Web portal offering low-cost ‘polygenic risk score’ to people willing to upload genetic data received from DNA testing companies such as 23andMe

Pathologists and other medical professionals have long predicted that multi-gene diagnostics tests which examine thousands of specific gene sequences might one day hold the key to assessing disease risk, diagnosing diseases, and guiding precision medicine treatment decisions. Now, a research team from the Broad Institute, Massachusetts General Hospital (MGH) and Harvard Medical School have brought that prediction closer to reality.

Their study, published last month in Nature Genetics, found that a genome analysis called polygenic risk scoring can identify individuals with a high risk of developing one of five potentially deadly diseases:

  • Coronary artery disease;
  • Atrial fibrillation;
  • Type 2 diabetes;
  • Inflammatory bowel disease; and,
  • Breast cancer.

Polygenic Scoring Predicts Risk of Disease Among General Population

To date, most genetic testing has been “single gene,” focusing on rare mutations in specific genes such as those causing sickle cell disease or cystic fibrosis. This latest research indicates that polygenic predictors could be used to discover heightened risk factors in a much larger portion of the general population, enabling early interventions to prevent disease before other warning signs appear. The ultimate goal of precision medicine.

“We’ve known for long time that there are people out there at high risk for disease based just on their overall genetic variation,” senior author Sekar Kathiresan, MD, co-Director of the Medical and Population Genetics Program at the Broad Institute, and Director, Center for Genomic Medicine at Massachusetts General Hospital, said in a Broad Institute news release. “Now, we’re able to measure that risk using genomic data in a meaningful way. From a public health perspective, we need to identify these higher-risk segments of the population, so we can provide appropriate care.”

“What I foresee is in five years, each person will know this risk number—this ‘polygenic risk score’—similar to the way each person knows his or her cholesterol,” Sekar Kathiresan, MD (above), Co-Director of the Medical and Population Genetics Program at the Broad Institute, and Director, Center for Genomic Medicine at Massachusetts General Hospital, told the Associated Press (AP). He went on to say a high-risk score could lead to people taking other steps to lower their overall risk for specific diseases, while a low-risk score “doesn’t give you a free pass” since an unhealthy lifestyle can lead to disease as well. (Photo copyright: Massachusetts General Hospital.)

The researchers conducted the study using data from more than 400,000 individuals in the United Kingdom Biobank. They created a risk score for coronary artery disease by looking for 6.6 million single-letter genetic changes that are more prevalent in people who have had early heart attacks. Of the individuals in the UK Biobank dataset, 8% were more than three times as likely to develop the disease compared to everyone else, based on their genetic variation.

In absolute terms, only 0.8% of individuals with the very lowest polygenic risk scores had coronary artery disease, compared to 11% for people with the highest scores, the Broad Institute news release stated.

“The results should be eye-opening for cardiologists,” Charles C. Hong, MD, PhD, Director of Cardiovascular Research at the University of Maryland School of Medicine, told the AP. “The only disappointment is that this score applies only to those with European ancestry, so I wonder if similar scores are in the works for the large majority of the world population that is not white.”

In its news release, the Broad Institute noted the need for additional studies to “optimize the algorithms for other ethnic groups.”

The Broad Institute’s results suggest, however, that as many as 25 million people in the United States may be at more than triple the normal risk for coronary artery disease. And millions more may be at similar elevated risk for the other conditions, based on genetic variations alone.

Reanalyzing Data from DNA Testing Companies

The researchers are building a website that would enable users to receive a low-cost polygenic risk score—such as calculating inherited risk score for many common diseases—by reanalyzing data users previously receive from DNA testing companies such as 23andMe.

Kathiresan told Forbes his goal is for the 17 million people who have used genotyping services to submit their data to the web portal he is building. He told the magazine he’s hoping “people will be able to get their polygenic scores for about as much as the cost of a cholesterol test.”

Some Experts Not Impressed with Broad Institute Study

But not all experts believe the Broad Institute/MGH/Harvard Medical School study deserves so much attention. Ali Torkamani, PhD, Director of Genomics and Genome Informatics at the Scripps Research Translational Institute, offered a tepid assessment of the Nature Genetics study.

In an article in GEN that noted polygenic risk scores were receiving “the type of attention reserved for groundbreaking science,” Torkamani said the recent news is “not particularly” a big leap forward in the field of polygenic risk prediction. He described the results as “not a methodological advance or even an unexpected result,” noting his own group had generated similar data for type 2 diabetes in their analysis of the UK dataset.

Nevertheless, Kathiresan is hopeful the study will advance disease treatment and prevention. “Ultimately, this is a new type of genetic risk factor,” he said in the news release. “We envision polygenic risk scores as a way to identify people at high or low risk for a disease, perhaps as early as birth, and then use that information to target interventions—either lifestyle modifications or treatments—to prevent disease.”

This latest research indicates healthcare providers could soon be incorporating polygenic risking scoring into routine clinical care. Not only would doing so mean another step forward in the advancement of precision medicine, but clinical laboratories and pathology groups also would have new tools to help diagnose disease and guide treatment decisions.

—Andrea Downing Peck

Related Information:

Genome-wide Polygenic Scores for Common Diseases Identify Individuals with Risk Equivalent to Monogenic Mutations

Predicting Risk for Common Deadly Diseases from Millions of Genetic Variants

Multigene Test May Find Risk for Heart Disease and More

A Harvard Scientist Thinks He Has a Gene Test for Heart Attack Risk. He Wants to Give It Away Free

Why Do Polygenic Risk Scores Get So Much Hype?