Polygenic Risk and Rare Variants in Endotypes of Idiopathic Pulmonary Fibrosis

Area of Science:

• Genetics
• Pulmonary Medicine
• Bioinformatics

Background:

• Idiopathic pulmonary fibrosis (IPF) is linked to rare and common genetic variations.
• Shortened telomere length (TL) may be a causal factor in IPF.
• The interplay between rare and common genetic variants in IPF risk is not well understood.

Purpose of the Study:

• To investigate the combined effects of rare and common genetic variants on IPF risk.
• To assess the utility of a telomere length polygenic risk score (TL-PRS) in predicting IPF.
• To explore genetic heterogeneity in IPF through endotype stratification.

Main Methods:

• Utilized whole genome sequencing (WGS) data from three large cohorts (Columbia, TOPMed, UKBB).
• Identified rare damaging variants and computed polygenic risk scores for IPF (IPF-PRS) and TL (TL-PRS).
• Assessed associations between genetic risk scores, IPF risk, and genetic endotypes.

Main Results:

• Replicated associations of rare variants, MUC5B SNP, and polygenic scores with IPF risk across cohorts.
• The TL-PRS independently improved IPF prediction, comparable to IPF-PRS-no MUC5B, and enhanced AUC.
• TL-PRS explained additional IPF liability (8-13%) and was crucial in specific endotypes (rare variant carriers, short TL).

Conclusions:

• Common and rare genetic variations interact to confer context-specific IPF risk.
• TL-PRS represents a significant, previously unrecognized genetic risk factor, particularly in certain IPF endotypes.
• Understanding genetic heterogeneity, including polygenic modifiers, is key for precision medicine in IPF.