Why are some people short and others tall? Why do some have blue eyes, some brown and others green? Genes, right?
Of course, but there’s not only one gene that influences the colour of your eyes or your height, there are many. For example, there are two major eye colour genes, but at least 14 other genes that play roles in determining a person’s exact eye colour and thousands of genetic variants determining a person's height.
Such features that are affected by many genes are called polygenic traits. When they are inherited, we talk about polygenic inheritance.
Unfortunately, genetic variations do not affect only various traits but also various diseases.
Fortunately, our knowledge and technology have come far enough to analyze various genetic variants and see if a certain combination increases the risk of developing certain diseases.
The result is a polygenic risk score, which we’re going to explore and explain in this article.
Let’s start with the foundations.
In this article:
What are genetic variants?
We all have near-identical DNA sequences. What makes us unique are slight differences in our DNA that are called genetic variants.
Our DNA’s code is made out of 4 chemical building blocks - A (adenine), T (thymine), C (cytosine) and G (guanine). A genetic variance occurs in a location within the DNA where that code differs among people.
For example, if Person #1 has a “A” in the same location in the DNA code where Person #2 has a “T”, that’s a genetic variant.
There are roughly 4 to 5 million genetic variants in an individual’s genome. Not all of them are unique, some of them occur in others as well.
Some variants increase the risk of developing diseases, while others may reduce such risk. Others have no effect on disease risk at all. Let’s take a closer look at possible connections between genetic variants and diseases.
Polygenic vs monogenic diseases
When somebody says they have a “genetic disease”, it usually means a monogenic disease. Some diseases occur in multiple family members in several generations. Among such diseases are inborn deafness, Duchenne muscular dystrophy, cystic fibrosis, haemophilia, colour blindness, etc.
Monogenic diseases can be caused by a single pathogenic (disease-causing) genetic variant (a.k.a. mutation) in a single, specific, and important gene. If you inherit the mutation, you will get the disease, and in most cases, nothing can prevent it. The environmental factors usually have negligible effects.
Pathogenic variants are rare as they convey an evolutionary disadvantage and often mean individuals cannot lead a normal life due to the disease. However, many different mutations can cause the same disease. There are over 5000 known monogenic diseases, meaning that collectively they affect about 1 in 100 live births globally. They account for 20% of infant mortality and 18% of paediatric hospitalizations.
Genetic testing is widely used to diagnose monogenic diseases, such as cystic fibrosis or sickle cell disease, caused by mutations in a single gene. These tests can also identify unaffected carriers of disease-associated genes, allowing them to make informed family planning decisions or, in cases like Huntington’s disease, to make plans in case they develop the condition in the future.
Every disease is, to some extent, influenced by our genetic makeup. However, common diseases, such as hypertension, coronary artery disease, type 2 diabetes, multiple sclerosis are only partly heritable. But this heritability is on account of many genetic variants in many genes and thus “polygenic”.
Polygenic diseases differ from monogenic diseases in two major ways:
- The individual genetic variants that cause them have an almost negligible effect on disease risk, but there are a lot of them. Some people have more, some have fewer unfavourable variants, and this determines whether their risk of the disease is somewhat increased or decreased compared to an average individual. As these variants are individually harmless, they can be passed from parents to children through generations and are thus common.
- Even all these variants combined cannot determine whether one will get the disease or not with certainty. Environmental factors such a diet, sleep, stress and smoking also contribute to the risk, thus a more general term for polygenic diseases is “multifactorial diseases".
It is important to know that the risk for some diseases is determined by both monogenic AND polygenic components. A notable example is cancer. BRCA1 gene causes breast cancer when it is affected by rare pathogenic mutations. However, only around 5% of breast cancers are caused by mutations in BRCA and similar genes. The rest of the cases are the consequence of the environmental factors and risk posed by common genetic variants.
Polygenic risk scores (PRS) combine the small effects of individual variants into a single parameter. The PRS tells you if the overall effect of your common genetic variants is negative or positive compared to the average in your population, and by how much.
Before we further discuss PRS, let’s take one more quick, yet necessary detour.
Polygenic diseases and the environment
You might have a genetic predisposition for being tall. But prolonged lack of nutrients in your childhood will cause you to grow up shorter despite a favourable genetic basis.
This interplay between genes and the environment is also expressed in polygenic diseases. You might have a genetic predisposition for a higher risk of developing a particular disease. Still, your overall risk depends on both your genetic makeup and your exposure to environmental factors. The contribution of each differs among diseases. For example:
PRS does not take environmental factors into account, but most PRS test results do offer personal recommendations that will help you reduce the risk of developing diseases influenced by both genetics and the environment.
Understanding the polygenic risk score
Over the last decade, genome-wide association studies (GWAS) have uncovered the contribution of inherited variants to common complex disorders. The concept of a polygenic risk score (PRS) had been circulating among researchers for several years. It wasn’t until 2018, however, that these polygenic scores were shown to have the potential for broad-scale clinical utility. A health research study at the Cardiovascular Disease Initiative of the Broad Institute in Cambridge identified people at high risk for five common diseases, based on their genome.
When the team tested their polygenic predictor for heart disease on 290,000 participants in the UK Biobank, they found that 8% of the population had 3-times the normal risk of a heart attack. Those wouldn’t know about the increased risk if not for genetic testing and PRS.
PRS is a result of new genomic technologies that allow researchers to rapidly and inexpensively sequence the entire genome, providing a complete survey of a person’s genetic make-up.
The enormous amount of genomic data now available enables researchers to calculate which variants tend to be found more frequently in groups of people with a given disease. There can be hundreds or even thousands of variants per disease.
Researchers use statistics and modern software to estimate how the collection of a person’s variants affect their risk for a certain disease.
The result is a polygenic risk score, an objective and easy to understand risk assessment.
PRS gives you valuable information which can help you address this risk and take timely preventive measures. It also addresses the vital issue of chronic diseases: their onset is often overlooked. If they are discovered early, patients can expect more effective treatment and a better outcome.
Benefits of a PRS test
Basically, PRS identifies your “genetic weak points” and helps you to address them.
The PRS test results can help you:
- Identify the diseases for which you have an increased risk.
- Focus on diseases with an increased risk. Knowing your risk and what you can do about it gives you control.
- Address your increased risks by altering your lifestyle with the help of personalised recommendations.
- Get medical advice and screening tests at a younger age, if necessary.
PRS includes calculations and detailed information which help users determine if and when should they perform screening tests for individual diseases. As such, the PRS is increasingly recognised in clinical medicine and is already incorporated in some clinical decision-making algorithms aimed at assessing cancer risk and patient stratification.
How does a PRS test report look like?
What kind of information and results do you get once you perform a PRS test? Let’s see what GenePlanet’s personalised PRS test report includes:
Your PRS results are presented as:
Relative risk (RR)
Estimates your risk compared to the average risk in the population. RR depends only on your genetics and identifies your genome's "weak spots" and "strong points". It is the most personalised result available.
However, your actual risk of getting the disease also depends on how common is the disease in general – this is taken into account by the two measures of absolute risk.
Five-year absolute risk (5yAR)
Estimates your probability of developing the disease during the next five years. While relative risk estimation enables you to compare your genetic predisposition to that of other people, your 5yAR additionally considers your age, sex, and how common is the disease in general in your population.
Lifetime absolute risk
Lifetime risk considers the same factors as the 5-year absolute risk, but it estimates your probability of developing the disease until you reach 85 years of age.
Most importantly, based on your results, a PRS test gives you personalised recommendations for early detection and prevention.
Screening tests are performed on healthy individuals to detect the disease early (before the symptoms appear), which enables better treatment options and disease outcome.
They are recommended when it is reasonably likely doctors can detect the disease, which depends on the presence of genetic and environmental risk factors (including the person’s age). Early detection methods are specific for each disease, e.g. colonoscopy for colon cancer, mammography for breast cancer, etc.
There is a generally recommended age for screening. But if your 5-year absolute risk is increased, you can benefit from performing it earlier.
Genes determine only a part of the disease, and the rest depends on the environment. You can influence your risk by altering your lifestyle with the recommendations you receive in the report.
Use the PRS test results to focus your time and effort on addressing diseases for which your risk is increased. Adapt your lifestyle to best address the relevant environmental risk factors and consider taking screening tests early.
3. ABOUT THE DISEASE
We explain each disease in detail to help you understand where and how it develops, what are the possibilities of its detection and therapy, which factors influence it, and more.
Your DNA test results and personalised recommendations are always within easy reach – on the computer or smartphone through our safe online GenePlanet app.
How to use your PRS results?
You should consider altering your lifestyle in a way to address your increased risks. If you’re at an increased risk, you should also consider medical advice and screening tests at a younger age. If you’re proactive, a PRS test can potentially have a huge positive impact.
However, you should not take comfort in decreased risk. Unfortunately, a PRS result is not a definitive risk score and your risk might be higher due to undetected mutations.
That’s why you also should not postpone the established screening programmes, even if your risk is decreased.
As said, your PRS results are not a definitive risk prediction. Think of increased risk as a valuable tool to help you take timely preventive measures and protect your health in the future.
Keep in mind that the PRS test is not a diagnostic test, does not discover diseases and the result is not a diagnosis. It should never be used instead of a visit to the doctor.
The difference between a PRS Cancer and Cancer Screen tests
So what is the difference? PRS deals with the polygenic component of the disease only, and rare pathogenic cancer-causing mutations are detected with our Cancer Screen test.
Cancer Screen can detect rare mutations which drastically increase the risk of cancer. Their detection can have a profound impact on someone's life and medical/clinical interventions are always indicated.
However, for the vast majority of people, the results will simply be negative. The result offers only an absence of bad news but no further information regarding risk (what is the actual risk for different cancers etc.).
The test is mostly sought by (and recommended to) people who have reason to believe that their risk is increased due to the presence of the disease in the family (1st-degree relatives, multiple affected members on the same side of the family) or other reasons. The test can provide relief associated with a negative result.
As the PRS test does not detect rare mutations, even a low PRS cannot guarantee a low risk of disease. Thus customers should not take refuge in a low PRS score for individual diseases.
We’ve addressed this problem by grouping similar diseases into bundles – eg. PRS Cancer. It analyses the risk for many cancers simultaneously and highlights those with an increased risk. This helps you to focus additional attention on these diseases and enables you to mitigate these increased risks by implementing preventive and early detection measures.
The amount of bad (or good) news you can get with the PRS test results is not comparable to Cancer Screen. Whereas Cancer Screen can identify a mutation that gives you cancer with near certainty, PRS only speaks in terms of increased/decreased risks.
While PRS can indicate you have a reduced risk for a particular type of cancer, you cannot be sure of it unless you exclude the possibility of rare pathogenic variants (detected by Cancer Screen).
That is why PRS Cancer and Cancer Screen tests are complementary and both recommended.
Want to learn more about PRS or take a PRS test?
This article introduced and explained some PRS basics. Yet knowledge is power and being proactive is key to living a better life! So if you want to learn even more about PRS or if you want to take one of GenePlanet’s PRS tests, click here.