Will Polygenic Risk Scoring Change Medicine in the Future?

By Dike Drummond, MD | Published 9/4/2018 1


Imagine a world where each of us knows our exact genetic fingerprint of disease risk. Your doctor will provide precisely tailored medical advice and preventive medicine to match your specific DNA sequence.

  • Will the new technique known as Polygenic Risk Scoring usher this new and universal age of precision medicine?
  • Will each of us soon carry our fully-sequenced genome in our cell phone, giving your physician instant access to your exact disease risk profile rather than having to rely on the blunt instrument of a family history?

A paper on Polygenic Risk Scoring was recently published in Nature Genetics.[1] It hints at a breakthrough in genetic diagnosis that appears to be both universally applicable and universally beneficial. I have no doubt, your genome will be a very important part of the doctor-patient relationship in the very near future.

Why is this important? I’ll get there, but first, let me provide some historical perspective.

B.G. Before Genomics

Back in the good old days, a doctor would calculate your risk of common diseases by your family history. If you have first degree relatives with coronary heart disease, breast cancer, diabetes and such, you would be declared at higher risk as well. General advice was then dispensed like don’t smoke, watch your weight, get regular mammograms.

On rare occasion, we knew your family disease history was caused by your genes, directly inheritable and a clear and present danger to you. The classic example is Huntington’s Disease, a fatal degenerative neurologic disease inherited in an autosomal dominant fashion that puts the children of HD victims at a 50% risk of having the disease themselves. It was only in those obvious circumstances that we could guess at the genetic origin of your personal risk of disease.

Gene sequencing and specific mutations

In the infancy of the study of the human genome, scientists discovered individual gene mutations that put individual people at dramatically increased risk for specific diseases. The most widely known example is probably the BRCA1 gene mutation that increases risk of breast cancer. Angelina Jolie is just one of the thousands of women who choseĀ bilateral prophylactic mastectomy to mitigate the increased risk of the BRCA1 mutation.

There are hundreds of examples of known mutations putting individuals at increased risk of specific diseases. Sometimes that person also has an obvious family history of the same disease, but often spontaneous mutations or de novo gene combinations can cause new genetic abnormalities in the absence of a family history. Sometimes we don’t find the genes until after you have the disease.

Ā Your genetic fingerprint and polygenic risk

Enter this week’s paper. Unfortunately, the full paper is behind aĀ paywall, but here are the highlights:

Researchers analyzed 400,000 individual genomes to “identify genetic variants associated with coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, or breast cancer.”Ā They identifiedĀ all the variations that produced even a small bump in disease risk, not just the major mutations like BRCA1 or the gene for Huntington’s Disease. Beneath the major mutations are a large number of minor variations that add up to increase in disease risk in individuals with multiple “hits”. This pattern of increased risk can cause disease in the absence of an obvious family history.

This allows the scientists to take anyone’s genome and calculate your aggregate risk for these diseases even if you don’t have one of the known major mutations. They call it Polygenic Risk Scoring (poly = more than one and genic = gene). Polygenic Risk Scoring is your total score of all the minor gene variations that increase disease risk

This is a powerful upgrade to your doctor’s ability to predict disease in any given patient. We are no longer in the darkness of the B.G. age with only the family history to guide us. And, we aren’t just looking for major, single gene mutations.

Polygenic Risk Scoring allows researchers to take a deep, wide look into your risks at the level of your individual DNA.

It is a fingerprint and a method of risk stratification that is relevant to every single human on the planet, not just those with a significant family history of a specific disease.

Dr. Amit V. Khera, a cardiologist and lead author of the study said:

“These individuals, who are at several times the normal risk for having a heart attack just because of the additive effects of many variations, are mostly flying under the radar.Ā If they came into my clinical practice, I wouldn’t be able to pick them out as high risk with our standard metrics. There’s a real need to identify these cases so we can target screening and treatments more effectively, and this approach gives us a potential way forward.”

Sekar KathiresanĀ  MD, a co-author of the study and Director of the Center for Genomic Medicine (CGM) at Massachusetts General Hospital predicts:

“Ultimately, this is a new type of genetic risk factor. 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.”

It’s only the beginning of this diagnostic revolution

It’s only the beginning of this diagnostic revolution. I expect this technology will advance very rapidly in the years ahead. This study only had 400,000 genomes worth of disease association and predictive ability out of the current 7.6 billion humans on earth (= 0.005%). Over time, researchers will expand the number of genomes in the analysis, improve the accuracy and expand the scope of diseases they can predict. I suggest all of us keep an eye on this technology and research going forward.


Amit V. Khera, et alĀ Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.Ā Nature Genetics, 2018; DOI:Ā 10.1038/s41588-018-0183-z [Paywall]



Dike Drummond, MD

Website: http://www.thehappymd.com

Dike Drummond, M.D. is a Mayo trained family practice doctor, executive coach, trainer, and consultant specializing in the prevention of physician burnout and physician leadership development. His comprehensive resource hub is online at www.TheHappyMD.com.


  • My work with overstressed and burned out physicians has me wondering what effect this advance in diagnostic ability will have on the STRESS on doctors of the future. This is clearly an advance for the patients. Is it also an advance for the doctor at the same time – meaning does it make the doctor’s life easier too. Time will tell.

    Dike Drummond MD

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