Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative...

Area of Science:

• Genetics
• Neuroscience
• Immunology

Background:

• Verbal declarative memory (VDM) decline is a significant concern in aging and dementia.
• Genome-wide association studies (GWAS) offer insights into the genetic underpinnings of VDM.
• Functional interpretation of GWAS results is crucial for developing interventions.

Purpose of the Study:

• To explore the functional relevance of VDM GWAS findings using multi-omics and pathway analyses.
• To investigate the relationship between genetic associations and molecular mechanisms like gene expression and regulation.
• To identify specific pathways and genes contributing to VDM performance in older adults.

Main Methods:

• Performed multi-omics and pathway enrichment analyses on VDM GWAS data from 29,076 individuals.
• Assessed associations with expression quantitative trait loci (eQTLs) and methylation quantitative trait loci (meQTLs).
• Analyzed gene expression, TF and microRNA regulation, and differential expression in brain tissues.

Main Results:

• VDM genetic associations showed linkage disequilibrium with eQTLs and meQTLs.
• Gene associations correlated with reduced expression in brain tissues and were linked to immune system components.
• Six pathways, including type I diabetes and involving MHC genes, were significantly associated with VDM, with varied expression patterns.

Conclusions:

• Genetic associations for VDM impact gene expression regulation through eQTLs and meQTLs.
• Transcription factors, microRNAs, MHC genes, and immune pathways are integral to VDM performance in aging.
• Findings provide a foundation for understanding VDM and developing strategies against cognitive decline.