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Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk

Mohammadi-Nejad, Ali Reza; Allen, Richard J.; Kraven, Luke M.; Leavy, Olivia C.; Jenkins, R. Gisli; Wain, Louise V.; Auer, Dorothee P.; Sotiropoulos, Stamatios N.

Authors

Richard J. Allen

Luke M. Kraven

Olivia C. Leavy

R. Gisli Jenkins

Louise V. Wain



Abstract

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.

Citation

Mohammadi-Nejad, A. R., Allen, R. J., Kraven, L. M., Leavy, O. C., Jenkins, R. G., Wain, L. V., …Sotiropoulos, S. N. (2022). Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk. EBioMedicine, 86, Article 104356. https://doi.org/10.1016/j.ebiom.2022.104356

Journal Article Type Article
Acceptance Date Oct 25, 2022
Online Publication Date Nov 19, 2022
Publication Date Dec 1, 2022
Deposit Date Oct 26, 2022
Publicly Available Date Nov 19, 2022
Journal eBioMedicine
Electronic ISSN 2352-3964
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 86
Article Number 104356
DOI https://doi.org/10.1016/j.ebiom.2022.104356
Public URL https://nottingham-repository.worktribe.com/output/12895516
Publisher URL https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00538-2/fulltext

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