# Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer's disease

## TL;DR

This study identifies PSMC3 as a gene involved in Alzheimer's disease and links it to brain structure and cognitive outcomes.

## Contribution

The study introduces a framework combining neuroimaging and functional genomics to identify AD-related genes and their effects on brain morphology.

## Key findings

- PSMC3 is implicated in Alzheimer's disease pathophysiology and is associated with brain morphology and cognition.
- AD-associated genetic variants affect frontal cortex thickness, cerebrospinal fluid volume, and cingulate isthmus gyrus.
- Genetic covariance reveals shared architecture between hippocampus traits and AD risk.

## Abstract

Neuroimaging genetics has advanced our understanding of Alzheimer's disease (AD); however, frameworks using functional genomics are needed to elucidate mechanisms connecting loci to neurological outcomes. To address this need, we explored relationships between AD‐associated variants and disease via their impact on gene expression and neuroanatomical phenotypes.

We mapped established AD genes to neuroimaging traits using the NeuroimaGene Atlas and predicted transcript‐driven neurological features of AD by comparing gene‐derived neuroimaging features with clinical neuroimaging data. Genetic covariance analyses were performed to characterize shared genetic architecture between AD endophenotypes and neuroimaging features, and to identify neuroimaging features associated with a family history of dementia.

Our analyses implicate PSMC3 as a contributor to AD pathophysiology and identify AD endophenotypes, including dementia family history, linked to frontal cortex thickness and volume, as well as changes in cerebrospinal fluid volume.

Our findings prioritize AD genes whose regulation is associated with vulnerable brain regions, offering a potential mechanistic framework for downstream functional validation.

Alzheimer's disease (AD) genes relate to brain regions key to memory and cognition via genetic regulation of expression.
PSMC3, involved in protein degradation, is linked to AD and brain morphology.Increased PSMC3 levels associate with better cognition and lower amyloid beta levels.Genetic covariance shows shared genetic architecture between hippocampus traits and AD risk.AD‐associated genetic variants affect the frontal cortex, cerebrospinal fluid volume, and cingulate isthmus gyrus.

Alzheimer's disease (AD) genes relate to brain regions key to memory and cognition via genetic regulation of expression.

PSMC3, involved in protein degradation, is linked to AD and brain morphology.

Increased PSMC3 levels associate with better cognition and lower amyloid beta levels.

Genetic covariance shows shared genetic architecture between hippocampus traits and AD risk.

AD‐associated genetic variants affect the frontal cortex, cerebrospinal fluid volume, and cingulate isthmus gyrus.