Rare Variant Analysis and Molecular Dynamics Simulation in Alzheimer's Disease Identifies Exonic Variants in FLG

Area of Science:

• Genetics
• Neuroscience
• Computational Biology

Background:

• Genome-wide association studies have identified common variants for Alzheimer's disease (AD), but these explain less than half of its heritability.
• Rare variant association studies (RVAS) are crucial for explaining the remaining genetic risk and trait variability in AD.

Purpose of the Study:

• To identify potential rare variants contributing to Alzheimer's disease (AD) risk.
• To investigate the functional impact of identified variants on AD-related pathways, specifically interactions with BACE1.

Main Methods:

• Screened 70,209 rare variants from AD and cognitively normal cohorts using the Alzheimer's Disease Neuroimaging Initiative database.
• Applied MIRARE, a novel RVAS method, and ANNOVAR annotation to 232 non-synonymous variants.
• Utilized molecular docking and molecular dynamics (MD) simulations to verify variant interactions with BACE1.

Main Results:

• MIRAGE analysis identified significant associations between AD and six potential pathogenic genes: PREX2, FLG, DHX16, NID2, ZnF585B, and ZnF875.
• Molecular docking and MD simulations confirmed interactions between FLG (wild type and rs3120654(SER742TYR)) and BACE1.
• The interaction between the FLG(SER742TYR) variant and BACE1 was stronger than that of wildtype FLG.

Conclusions:

• Non-synonymous rare variants in six genes, with a notable emphasis on FLG(rs3120654), are implicated in Alzheimer's disease (AD).
• These findings, supported by bioinformatics and molecular simulations, suggest a key role for these variants in AD pathogenesis.