Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk

<p>Background: <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/idiopathic-pulmonary-fibrosis" target="_blank">Idiopathic pulmonary fibrosis</a> (IPF) is a serious disease of the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/lung-parenchyma" target="_blank">lung parenchyma</a>. It has a known polygenetic risk, with at least seventeen regions of the genome implicated to date. Growing evidence suggests linked <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/multiple-chronic-conditions" target="_blank">multimorbidity</a> of IPF with neurodegenerative or affective disorders. However, no study so far has explicitly explored links between IPF, associated <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/genetics" target="_blank">genetic</a> risk profiles, and specific brain features.</p> <p>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 <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/endophenotype" target="_blank">endophenotypes</a>. 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.</p> <p>Findings: We identified strong associations between cortical morphological features, white matter microstructure and IPF risk loci in <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/chromosome-17" target="_blank">chromosomes 17</a> (<em>17q21.31</em>) and 8 (<a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/deptor" target="_blank"><em>DEPTOR</em></a>). 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 <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/chromosome-8" target="_blank">chromosome 8</a> locus. Post-hoc preliminary analysis suggested that <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/forced-vital-capacity" target="_blank">forced vital capacity</a> may partially mediate the association between the <em>DEPTOR</em> variant and white matter microstructure, but not between the <em>DEPTOR</em> risk variant and cortical thickness.</p> <p>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 <em>DEPTOR</em> expression, unrelated to lung function, and more widespread microstructural white matter changes consistent with <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hypoxia" target="_blank">hypoxia</a> or <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/neuroinflammation" target="_blank">neuroinflammation</a> with potential mediation by lung function.</p>