Calculating maternal polygenic risk scores from prenatal screening by cell-free DNA data

Area of Science:

• Genetics
• Genomics
• Prenatal Diagnostics

Background:

• Polygenic Risk Scores (PRS) are crucial for quantifying genetic predisposition to complex traits.
• Current methods for PRS calculation often require high-coverage genomic DNA, limiting their application in prenatal settings.

Purpose of the Study:

• To develop and validate a novel method for estimating maternal PRS using low-coverage cell-free DNA (cfDNA) obtained during routine prenatal screening.
• To assess the accuracy of PRS derived from cfDNA compared to PRS derived from high-coverage genomic DNA.

Main Methods:

• A prospective study involving 455 pregnant women undergoing cfDNA-based prenatal screening.
• Isolation of cfDNA from maternal plasma and genomic DNA from buffy coat.
• Low-coverage (∼0.25x) sequencing of cfDNA and high-coverage (∼15x) sequencing of genomic DNA.
• Genotype imputation and PRS calculation for paired cfDNA and genomic DNA samples.

Main Results:

• A high correlation (average ≈ 0.9) was observed between PRS calculated from cfDNA and PRS from matched genomic DNA.
• The accuracy was consistent across various PRS panels and sizes.
• Demonstrated feasibility of maternal PRS estimation from low-coverage cfDNA sequencing data.

Conclusions:

• Maternal PRS can be accurately calculated from low-coverage cfDNA sequencing data acquired during standard prenatal screening.
• This approach offers a promising avenue for integrating genetic risk assessment into routine prenatal care.
• Highlights the potential of cfDNA for non-invasive genomic analyses beyond aneuploidy screening.