Understanding Polygenic Risk Scores

Many individuals have one or more illnesses influenced by changes in their genes, often in conjunction with environmental factors. Researchers are examining these genetic changes to comprehend the role of genetics in diseases across various populations. A "polygenic risk score" helps people understand their risk of developing a disease based on the cumulative number of genetic changes related to that disease.

What is a Genomic Variant?
Humans have almost identical DNA sequences across their approximately 6 billion-letter genome. However, slight differences, known as genomic variants, exist and make each individual unique. These variants occur at specific DNA locations. DNA is read as a code made up of four chemical building blocks: adenine (A), thymine (T), cytosine (C), and guanine (G). A genomic variant occurs where this code differs among people. For example, one person might have a "C" base at a certain location, while another person has a "T" (reference, reference).

There are around 4 to 5 million genomic variants in an individual's genome. These variants can be unique to an individual or shared with others. Some variants increase the risk of developing diseases, others reduce it, and some have no effect on disease risk (reference, reference).

Single-Gene vs. Complex Diseases Genetic diseases are often categorized into two types: single-gene diseases and complex diseases influenced by multiple genes and environmental factors. Many diseases fall somewhere between these extremes.

Single-Gene Diseases
Many inherited diseases are due to variants in a single gene. For instance, cystic fibrosis, a progressive genetic disorder causing long-term lung infections and breathing difficulties, results from variants in the CFTR gene on chromosome 7 (reference).

Complex Diseases
Complex diseases arise from many genomic variants combined with environmental influences (such as diet, sleep, stress, and smoking). These are known as "polygenic" diseases. Coronary artery disease is an example, with around 60 genomic variants more frequently found in affected individuals. These variants are spread across the genome, not clustered on one chromosome (reference, reference).

Calculating Polygenic Risk Scores
Researchers identify genomic variants associated with complex diseases by comparing the genomes of people with and without those diseases. The vast amount of genomic data available today allows researchers to determine which variants are more common in groups with a specific disease. This process can involve hundreds or thousands of variants (reference, reference).

Using statistical methods, researchers input this data into computers to estimate how a person's collection of variants affects their risk for a certain disease. This calculation produces polygenic risk scores. Importantly, this can be done even without knowing the specific genes involved in the disease (reference, reference).

Interpreting a Polygenic Risk Score
A polygenic risk score explains the relative risk of a disease, comparing an individual's risk to others with different genetic makeups. These scores, derived from large-scale genomic studies, show correlations rather than causations and do not provide a baseline or timeframe for disease progression (reference, reference).

For instance, two individuals with high polygenic risk scores for coronary heart disease, one aged 22 and the other 98, will have different lifetime risks despite having the same score. Unlike absolute risk, which indicates the likelihood of disease occurrence (e.g., women with a BRCA1 mutation having a 60-80% absolute risk of breast cancer), polygenic risk scores offer a relative perspective (reference, reference).