# Assessment of mosaic loss of chromosome Y in pulmonary fibrosis reveals limited association with susceptibility or disease severity

## TL;DR

This study finds that mosaic loss of chromosome Y is present in pulmonary fibrosis patients but is not a major cause of the disease and may be linked to telomere shortening.

## Contribution

The study provides new evidence that mLOY is not a primary driver of IPF but may be causally linked to telomere shortening.

## Key findings

- mLOY is found in PF patients but has minimal effect compared to age-matched populations.
- mLOY is associated with age and shorter telomere length, not PF severity.
- Mendelian randomisation suggests telomere shortening may cause both IPF and mLOY.

## Abstract

Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and biological mechanisms. Mosaic loss of chromosome Y (mLOY) has been reported to be associated with increased risk of fibrotic diseases. However, the exact role of mLOY in the development of PF remains to be elucidated.

Copy number on chromosome Y was used to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from the PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. Mendelian randomisation was performed to examine the causal relationship between mLOY, idiopathic pulmonary fibrosis (IPF) and telomere length.

The genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (p=0.00316, median: 0.288 vs 0.291). mLOY is related to age (p=0.000214) and shorter telomere length (p=0.00815) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY.

Our study confirms the existence of mLOY in PF patients, suggests that mLOY is not a major driver of IPF, and might support a triangulation model where telomere shortening leads to both IPF and mLOY.