University of Leicester
Browse
PIIS2352396422005382.pdf (2.17 MB)

Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk

Download (2.17 MB)
journal contribution
posted on 2023-10-12, 10:18 authored by Ali-Reza Mohammadi-Nejad, Richard Allen, Luke Kraven, Olivia Leavy, R. Gisli Jenkins, Louise Wain, Dorothee P. Auer, Stamatios N. Sotiropoulos

Background: Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung parenchyma. It has a known polygenetic risk, with at least seventeen regions of the genome implicated to date. Growing evidence suggests linked multimorbidity of IPF with neurodegenerative or affective disorders. However, no study so far has explicitly explored links between IPF, associated genetic risk profiles, and specific brain features.

Methods: We exploited imaging and genetic data from more than 32,000 participants available through the UK Biobank population-level resource to explore links between IPF genetic risk and imaging-derived brain endophenotypes. We performed a brain-wide imaging-genetics association study between the presence of 17 known IPF risk variants and 1248 multi-modal imaging-derived features, which characterise brain structure and function.

Findings: We identified strong associations between cortical morphological features, white matter microstructure and IPF risk loci in chromosomes 17 (17q21.31) and 8 (DEPTOR). Through co-localisation analysis, we confirmed that cortical thickness in the anterior cingulate and more widespread white matter microstructure changes share a single causal variant with IPF at the chromosome 8 locus. Post-hoc preliminary analysis suggested that forced vital capacity may partially mediate the association between the DEPTOR variant and white matter microstructure, but not between the DEPTOR risk variant and cortical thickness.

Interpretation: Our results reveal the associations between IPF genetic risk and differences in brain structure, for both cortex and white matter. Differences in tissue-specific imaging signatures suggest distinct underlying mechanisms with focal cortical thinning in regions with known high DEPTOR expression, unrelated to lung function, and more widespread microstructural white matter changes consistent with hypoxia or neuroinflammation with potential mediation by lung function.

Funding

This study was supported by the NIHR Nottingham Biomedical Research Centre and the UK Medical Research Council.

History

Citation

eBioMedicine; 2022; 86: 104356

Author affiliation

Department of Health Sciences

Version

  • VoR (Version of Record)

Published in

EBioMedicine

Volume

86

Publisher

Elsevier

issn

2352-3964

Acceptance date

2022-10-24

Copyright date

2022

Available date

2023-10-12

Language

en

Usage metrics

    University of Leicester Publications

    Categories

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC