Common diseases, such as cardiovascular disease or diabetes, are complex. This means that their onset depends as much on environmental factors as on diverse genetic factors. Establishing the genetic component associated with these diseases has been challenging. However, with a new approach call Polygenic Risk Score (PRS), now it is possible to detect a greater number of patients at risk, which is a key factor for preventing the onset of disease.
A brief review of genetics
Before we enter the world of the Polygenic Risk Score or PRS test, let’s review some basic notions about genetics.
As you may have read in other articles on our blog, DNA is an abbreviation that we use when talking about the complex molecule known as Deoxyribonucleic Acid. DNA is the molecule that constitutes our genetic code, the complete set of all our genetic information is known as the genome. We could define the genome as our body’s instruction manual consisting of a coding region and a non-coding region. In the coding region, we find the genes that contain the information required to make proteins, our body’s molecular executors.
The genome contains all the information it needs to create and maintain life, and it determines everything, from the colour of our hair to the onset or susceptibility to present with different diseases. Therefore, it plays a fundamental role in our health. The small changes in this instruction manual may have advantages or disadvantages for the body to carry out specific functions, which may increase the risk of developing a disease.
An interesting point about the genome is that only differs by 0.1% among humans, that is, our genome is 99.9% the same.
As we mentioned above, the genetic variants in our instruction manual may cause health problems, but this depends on many factors, among them, the type of genetic variant produced. In our article Genetic alterations: causes and types we explain what types of alterations may be produced in the DNA.
It is important to point out that a genetic variant does not always have a negative meaning. In other words, depending on the type of effect and where it is within the genome, it may have a negative or positive impact or no effect at all. When a variant alters the manufacture of a protein and has a significant effect on the development of a disease, this is defined as a mutation. Generally, mutations are located in the coding region of the genome and they are rare within the population.
Other types of variants are frequent within the population and don’t alter the activity of a protein. These are called Polymorphisms or SNPs (Single Nucleotide Polymorphisms or variants of a single nucleotide); we all have millions of polymorphisms that differentiate us from each other and it is precisely these variations that make us unique.
Millions of SNPs are described throughout the length of the genome and the majority of these do not have a direct effect on health. However, many of them, despite not causing diseases by themselves, provide advantages or disadvantages in carrying out specific functions in the body which may increase the risk of developing a disease. The Polygenic Risk Score test is based on the study of these types of variants.
The difference between monogenic and multifactorial diseases
As we mentioned earlier, complex diseases, that is, multifactorial diseases, are the most common and their onset depends as much on genetic factors as environmental ones such as diet, lifestyle, the consumption of toxic substances, etc.
Until recently, genetics focussed on the diagnosis of monogenic diseases, also known as Mendelian diseases, since they are simply diseases that appear due to the presence of mutations in a single gene. Some examples of monogenic diseases are cystic fibrosis, haemophilia, and Marfan syndrome.
In contrast, the genetics associated with multifactorial diseases involve the study of many common genetic variants which do not all have the same effect, but which together, may lead to having the same level of impact on the development of a disease as the mutations in monogenic diseases. This type of genetic risk is known as a polygenic risk.
The mutation = disease rule does not exist in the development of multifactorial diseases, but each genetic variant carries a small risk that can either increase or reduce susceptibility to presenting with a disease and, combined with other non-genetic factors, this implies a greater or lesser risk of disease.
Until very recently, this complexity has been an obstacle for the study of polygenic risk related to multifactorial diseases. Today, with the emergence of Polygenic Risk Score (PRS) testing, it is now possible.
What is a polygenic risk score (PRS)?
The Polygenic Risk Score test determines a person’s polygenic risk factor in relation to multifactorial diseases by studying thousands to millions of SNPs distributed throughout the whole genome. Until today, this genetic risk was an unperceived risk that we were incapable of measuring.
To calculate the PRS, the effect of all the variants analysed is added up and a score is generated that indicates the risk presented by that person in relation to the general population. This is what is known as a percentile.
To establish the percentiles of a population, this is divided by 100 in groups of similar size, which enables the creation of a distribution of risk. If the PRS is in the 95% percentile, it does not mean that the person has a 95% possibility of developing a disease, but that out of 100 people, their polygenic score is higher than that of 95 people and equal to, or lower than, that of 5 people. The highest percentiles are those that involve the highest level of risk.
If the risk for a disease within the general population is known, the percentile may become an absolute risk for presenting with the pathology, as well as its progression throughout one’s lifetime, which results in key information for influencing modifiable factors and reducing the risk of presenting with the disease.
The importance of biobanks and GWAS
PRS were developed due to the existence of biobanks, which contain quality genetic data from genome sequencing as well as clinical data from large cohorts of people. This has created a perfect ecosystem for research and the development of bioinformatics tools that enable a large quantity of genomic data to be analysed. The association studies or GWAS (Genome Wide Association Studies), whose objective is to establish the relationship between genetic variants and the presence of specific diseases or characteristics through the comparison of large databases with cases and controls, has enabled the development of the PRS, bringing them closer to current clinical practice.
Risk and diseases associated to PRS
The development of PRS plays a key role in the personalised medicine of the future, as it is able to study common diseases whose genetic risk was previously impossible to calculate.
It has been demonstrated that, for some diseases, such as coronary artery disease, the involvement of thousands to millions of SNPs throughout the genome, the risk of presenting with the disease may have a comparable effect to the monogenic variants that are only present in a small percentage of the population.
Evidence exists within publications of the great potential for increasing detection in patients at risk of common diseases. Very significant discoveries were made in a study published by Nature, whose objective was to calculate the polygenic risk for different diseases in over 250,000 people. Of the population analysed, 8% had a risk that was three times greater than the general population for presenting with coronary artery disease. The study also identified 20 times more people with a high risk of family hypercholesterolemia than those identified with the genetic tests for mutations. Lastly, it identified that 3% of the people in the study had 3 times greater risk of presenting with diabetes than the general population.
Through PRS, it is possible to detect more people with a risk of presenting with these multifactorial diseases. For example, we know that 1 in every 4 people that present with coronary artery disease are not able to be detected through the conventional evaluation of clinical factors. In fact, there are studies that have demonstrated that people that present with an LDL cholesterol level that falls within the acceptable range, but present a high risk PRS, have a similar risk of coronary artery disease than people with a high level of LDL cholesterol that is considered to be high risk.
Equally, PRS is a useful tool for detecting people with a greater risk of cancer. Only between 5-10% of breast cancer cases are considered to be hereditary, while the remaining percentage is known as sporadic breast cancer. Women who present with a high risk percentile for breast cancer may have up to twice the risk of presenting with breast cancer than women with an average PRS. This makes it possible to detect up to an additional 24% of women with a high risk of presenting with breast cancer.
Genetic risk: monogenic + polygenic
The advances in genetics allow new screening tools to be available such as PRS testing which is a new and powerful tool for risk segmentation of common diseases.
PRS testing can also be integrated in the clinical practice together with traditional testing for monogenic risk, achieving a more comprehensive assessment of the genetic risk allowing the detection of a larger number of patients at risk, which represents a big step in personalised preventive medicine. PRS is increasingly being positioned as a test to support clinical decision making based on other clinical factors and the patient’s family.
Current evidence and publications suggest that, in people with a mutation related to a low penetrance monogenic disease, the study of PRS may provide additional information related to the risk of developing the disease, although there is still a long way to go.
At Veritas, we are always spearheading innovation. We offer myHealthScore, a polygenic risk score genetic testing that provides information regarding patient risk for different common multifactorial diseases such as breast cancer, prostate cancer, diabetes and cardiovascular pathologies, among others. myHealthScore is a screening test that evaluates millions of common variants throughout the genome. If you would like further information, please don’t hesitate to contact us.
Maria Moreno - Medical Science Liaison Manager
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