Understanding PRS

Polygenic risk scoring is what makes BioCertica different. It’s what makes us better. But what is it? How does it work and why is it something to get excited about?

Let’s start with the definition: A polygenic risk score (PRS) is obtained from a comprehensive method used to estimate the relative genetic risks of being affected by a certain condition or inheriting a certain trait.

Basically, what PRS allows us to do differently:

Instead of giving the results of single genes which have been identified to contribute towards certain traits, we test all the known genes that contribute to a trait or risk towards a condition and disease.  Then, instead of separately reporting on each of these genes, we provide the result of the full/overall relative risk (genetic risk/contribution) for the trait. 

What is a trait? Anything (physical attribute, condition, disease) that is, at least in part, genetically determined.  Some traits or diseases, such as cystic fibrosis, are caused by single genes. By testing for these specific genes, a diagnosis can be made.  

In most cases, though, a combination of genetic and environmental (lifestyle mostly) contribute towards the expression or presence of certain traits or disease risks. An example of one of these traits is obesity. 

There are a very large number of genes that have been found to be associated with the development of obesity.  Thus, a combination of many genes contribute to your inclination to being overweight.  Your genes, however, do not cause you to be overweight.  They may make it much easier or harder, but your lifestyle still determines your weight in combination with your genetics. 

Continuing with obesity as an example, we have two options when it comes to the testing your genetics: 

1. Identify a couple of specific genes that have been identified in physiological pathways that explain why someone may have an increased or decreased risk for obesity.  Test and give the results for these specific genes.  Give recommendations which are focussed on up- or down-regulating these genes. 
2. Use established complex calculations based on all the known genes associated with a trait, whether they can be physiologically explained or not, taking the interactions and weights of the gene effects into account. Give the overall result of the relative (genetic) risk for a trait - the polygenic risk score. Lower the lifestyle factors that contribute to obesity in order to decrease the absolute risk thereof as much as possible.

Option 1 above makes a lot of sense and allows for very specific gene-focussed recommendations. This method is, however, over-simplistic in a way as it ignores too many genes and gene interactions.  How effective is it really to focus on up or down-regulating a single gene amongst hundreds that contribute to the genetic/relative risk of a disease or condition?

Even for a trait which is highly impacted by your genetic make-up, let’s say 50%, if it is a complex trait, as the majority are, single genes tell us a very small part of the story.  We need the results of all the genes put together to get the full 50% picture.  Identifying single genes may each, for example, only give us 1% of the picture.  So although the results and recommendations may be accurate and specific, we don’t have all the information. 

A too small portion of the full picture may not be enough and could lead to wrongful conclusions. Not all the genes contributing to a given trait will impact it in the same way.  With obesity as an example again, of the genes related to obesity, 70% may predispose you to obesity while the remaining may protect against obesity.  Overall, you have an increased genetic risk for obesity.  Let’s say we were to cherry-pick 5 of the >100 genes, we could just as well end up with 4 protective genes and only one predisposing gene. See the problem here if we don’t take all the factors into consideration to get the full picture?

Taking it together - PRS is a complex methodology in genetic testing and provides a comprehensive overview of the narrative of how your genes form the basis of who you are. If we can compare genetic testing to a puzzle, single gene analysis is like trying to complete the puzzle with only a few pieces. However, PRS would be completing the puzzle with all the pieces meaning we get the full picture.