Quantifying Personalized Shift-Work Molecular Portraits Underlying Alzheimer's Disease through Computational Biology

Area of Science:

• Neuroscience
• Genetics
• Chronobiology

Background:

• Shift work is a known circadian rhythm disruptor.
• Previous research suggests a link between shift work and increased Alzheimer's disease (AD) risk.
• The precise causal relationship and underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the causal effect of shift work on Alzheimer's disease (AD) risk.
• To identify specific circadian-related genes involved in shift work-induced AD.
• To develop a metric for quantifying circadian rhythm disruption (CRD) and its association with AD.

Main Methods:

• Mendelian randomization (MR) analysis to assess causality between shift work and AD.
• Integration of expression quantitative trait loci (eQTEs) and transcriptome data to identify candidate genes.
• In vitro validation of target gene expression.
• Development of a novel integrative program using 4,077 samples to calculate clock deviation level (CDL) for CRD assessment.

Main Results:

• Shift work was found to causally increase AD risk (OR = 2.49).
• Seven circadian-related genes (CCS, CDS2, MYRIP, NRP1, PLEKHA5, POLR1D, PPP4C) were identified as being causally associated with AD.
• Elevated CDL was observed in shift work, sleep restriction, and AD patient groups compared to controls.
• CDL showed significant correlation with AD clinical biomarkers.

Conclusions:

• This study provides evidence for the causal role of circadian rhythm disruption (CRD) in Alzheimer's disease (AD).
• Identified target genes offer potential therapeutic avenues for shift work-induced AD.
• The developed CDL metric can characterize CRD status, aiding in disease prevention and intervention strategies.