High-Resolution Genotyping of Formalin-Fixed Tissue Accurately Estimates Polygenic Risk Scores in Human Diseases

Area of Science:

• Genomics
• Molecular Biology
• Biobanking

Background:

• Formalin-fixed paraffin-embedded (FFPE) tissues are abundant in biobanks but underutilized for molecular studies.
• FFPE samples preserve genetic information comparable to blood, yet DNA quality concerns limit their use.
• Germline variants and polygenic risk scores (PRS) are crucial for disease risk assessment.

Purpose of the Study:

• To demonstrate the feasibility and accuracy of genotyping DNA from FFPE normal tissues (FFPE-NT) for genomic analysis.
• To establish and validate a protocol for FFPE-NT DNA genotyping on a genome-wide array.
• To assess the utility of FFPE-NT DNA for identifying disease-predisposing variants and calculating PRS.

Main Methods:

• Optimized FFPE-NT DNA performance on a genome-wide array (657,675 variants).
• Conducted testing and validation phases to establish a genotyping protocol.
• Compared FFPE-NT genotyping results with matching blood samples for call rate and concordance.
• Imputed FFPE-NT genotype data and calculated genome-wide PRS for multiple diseases and risk variables.

Main Results:

• Achieved high median call rate (99.85%) and concordance (99.79%) for FFPE-NT genotyping compared to blood.
• Successfully identified a rare pathogenic PALB2 variant predisposing to cancer in FFPE-NT samples.
• Demonstrated high concordance (Pearson's r > 0.95) between FFPE-NT and blood-derived PRS for 3 diseases and 4 risk variables.

Conclusions:

• Genotyping FFPE-NT DNA on genome-wide arrays is accurate and reliable, overcoming previous quality concerns.
• Archived FFPE-NT samples are a valuable resource for translational genomics, enabling large-scale PRS studies.
• This approach facilitates linking genomic data from FFPE samples to clinical phenotypes and longitudinal health records.