Polygenic risk score as a possible tool for identifying familial monogenic causes of complex diseases

The study aimed to evaluate whether polygenic risk scores could be helpful in addition to family history for triaging individuals to undergo deep-depth diagnostic sequencing for identifying monogenic causes of complex diseases.

Among 44,550 exome-sequenced European ancestry UK Biobank participants, we identified individuals with a clinically reported or computationally predicted monogenic pathogenic variant for breast cancer, bowel cancer, heart disease, diabetes, or Alzheimer disease. We derived polygenic risk scores for these diseases. We tested whether a polygenic risk score could identify rare pathogenic variant heterozygotes among individuals with a parental disease history.

Monogenic causes of complex diseases were more prevalent among individuals with a parental disease history than in the rest of the population. Polygenic risk scores showed moderate discriminative power to identify familial monogenic causes. For instance, we showed that prescreening the patients with a polygenic risk score for type 2 diabetes can prioritize individuals to undergo diagnostic sequencing for monogenic diabetes variants and reduce needs for such sequencing by up to 37%.

Among individuals with a family history of complex diseases, those with a low polygenic risk score are more likely to have monogenic causes of the disease and could be prioritized to undergo genetic testing.