Both clinically informed and brain region agnostic approaches identify neuroimaging derived phenotypes associated with genetically regulated gene expression of late‐onset Alzheimer’s disease genes
Ting‐Chen Wang, Xavier Bledsoe, Douglas Shaw, Hung‐Hsin Chen, Adam C. Naj, William S. Bush, Eric J Gamazon, Jennifer E. Below,- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Genetically regulated gene expression (GReX) data leverages expression quantitative trait loci to investigate the genetic mechanism of Alzheimer’s disease (AD). This study utilized the GReX‐mediated neuro‐imaging derived phenotypes (NIDPs), summary features derived from brain imaging modalities, as an endophenotype to identify brain regions associated with late‐onset AD (LOAD) via gene expression.
Method
This study contained brain region‐agnostic and region‐informed approaches. Both approaches utilized a set of 25 genes causally associated with LOAD in our previous cross‐tissue transcriptome‐wide association studies (TWAS) (Chen et al., 2021) to identify LOAD‐associated GReX‐mediated NIDPs. We leveraged the UK Biobank (UKBB) neuroimaging TWAS resource to provide GReX‐mediated NIDP information.
A Benjamini‐Hochberg FDR p‐value threshold of 0.05 was used to establish statistical significance, and causal inference testing on associations between GReX of LOAD genes and NIDPs was conducted by implementing MR‐JTI in both approaches.
Result
Conclusion
Our study shows the highly significant causal association between the GReX of ZNF296 and the right pars opercularis on LOAD through the region‐agnostic approach and the strong causal association between the GReX of PSMC3 and the ventral diencephalon on LOAD in AD‐associated region‐informed analyses. Our methodologies provide opportunities to explore brain regions associated with LOAD that are mediated by GReX of AD‐associated genes illuminating the impact of LOAD‐associated genes on gene expression and brain physiology.