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Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer's Disease

Bledsoe, X.; Wang, T.-C.; Wu, Y.; Archer, D. B.; Chen, H.-H.; Naj, A. C.; Bush, W.; Hohman, T. J.; Dumitrescu, L.; Below, J. E.; Gamazon, E.

2025-09-19 genetic and genomic medicine
10.1101/2025.09.18.25336095 medRxiv
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INTRODUCTIONNeuroimaging genetics have advanced Alzheimers disease (AD) research, yet frameworks mechanistically connecting genes to neurological outcomes via functional genomics are needed to elucidate genetic associations. To address this challenge, we assessed relationships between AD-associated variants and disease via their impact on gene expression and neuroimaging phenotypes. METHODSWe mapped established AD genes to neuroimaging traits using NeuroimaGene atlas and predicted transcript-driven AD neurological features by comparing gene-derived neuroimaging features to clinical neuroimaging data. Genetic correlation and covariance analyses characterized shared genetic architecture between AD endophenotypes and neuroimaging features and identified neuroimaging features associated with dementia family history. RESULTSOur analyses implicate PSMC3 expression as a strong contributor to AD pathophysiology and indicate AD endophenotypes, including dementia family history, linked to frontal cortex thickness, volume, and cerebrospinal fluid volume changes. DISCUSSIONOur findings prioritize AD genes whose regulation is associated with vulnerable brain regions, offering a potential mechanistic framework for downstream functional validation.

Published in Alzheimer's & Dementia · not in our set (fewer than 10 published preprints to learn from) · training set

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