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Polygenic background modifies penetrance of monogenic variants

Researchers have found that polygenic background can modify penetrance of disease in tier 1 genomic conditions.

Monogenic variants

Monogenic variants are rare and lead to a large increase in disease risk. Recently, researchers have been looking at polygenic risk scores and the impact common genetic variants have on disease risk. While individually these variants have a small effect, collectively they can have a large effect. Now, researchers are considering how monogenic and polygenic risks interact. Can these monogenic variants which have large effects be modified by polygenic risk factors that could impact disease progression?  

For example, recent work has suggested that common background variants can modify the age of onset among carriers of high-risk variants. These include carriers of trinucleotide repeats that predispose individuals to Huntington’s disease.

Interplay between polygenic and monogenic variants

In a study published in Nature on Thursday 20 August 2020, researchers expanded on previous work on common background variants by looking at the three tier 1 genomic conditions. These conditions are highlighted by the U.S. Centers for Disease Control and Prevention and include familial hypercholesterolemia, hereditary breast and ovarian cancer and Lynch syndrome. Furthermore, it has been estimated that around 1% of adults carry asymptomatic pathogenic or likely pathogenic variants, which are associated with increased risk of disease. Nevertheless, it has been suggested that these variants have incomplete penetrance and variable expressivity. The researchers hypothesised that this incomplete penetrance could partly be explained by polygenic background.

The team studied 80,928 individuals to determine the interplay between polygenic background and monogenic variants. During their investigation, they found based on polygenic background, carriers of monogenic risk variants had substantial gradients in disease risk. The probability of disease by age 75 ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer and 11% to 80% for colon cancer.

These results show that risk conferred by monogenic variants which perturb specific molecular pathways can be modified by polygenic background. They also highlight that accounting for polygenic background is important to increase accuracy of risk estimates for individuals who inherit a monogenic risk variant. Evidently, refined risk estimates have significant implications for genetic counselling and clinical decision-making.

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