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

Weixue Xiong; Jiahui Cai; Ruijia Li; Canhong Wen; Haizhu Tan; On Behalf Of The Alzheimer's Disease Neuroimaging Initiative Adni Database

doi:10.3390/genes13050838

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

Genes (Basel). 2022 May 7;13(5):838. doi: 10.3390/genes13050838.

Authors

Weixue Xiong¹, Jiahui Cai¹, Ruijia Li², Canhong Wen², Haizhu Tan¹, On Behalf Of The Alzheimer's Disease Neuroimaging Initiative Adni Database

Affiliations

¹ Department of Preventive Medicine, Shantou University Medical College, Shantou 515000, China.
² Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei 230000, China.

Abstract

Background: Although an increasing number of common variants contributing to Alzheimer's disease (AD) are uncovered by genome-wide association studies, they can only explain less than half of the heritability of AD. Rare variant association studies (RVAS) has become an increasingly important area to explain the risk or trait variability of AD.

Method: To investigate the potential rare variants that cause AD, we screened 70,209 rare variants from two cohorts of a 175 AD cohort and a 214 cognitively normal cohort from the Alzheimer's Disease Neuroimaging Initiative database. MIRARE, a novel RVAS method, was performed on 232 non-synonymous variants selected by ANNOVAR annotation. Molecular docking and molecular dynamics (MD) simulation were adopted to verify the interaction between the chosen functional variants and BACE1.

Results: MIRAGE analysis revealed significant associations between AD and six potential pathogenic genes, including PREX2, FLG, DHX16, NID2, ZnF585B and ZnF875. Only interactions between FLG (including wild type and rs3120654(SER742TYR)) and BACE1 were verified by molecular docking and MD simulation. The interaction of FLG(SER742TYR) with BACE1 was greater than that of wildtype FLG with BACE1.

Conclusions: According to the literature search, bio-informatics analysis, and molecular docking and MD simulation, we find non-synonymous rare variants in six genes, especially FLG(rs3120654), that may play key roles in AD.

Keywords: ADNI; Alzheimer’s disease; MIRAGE; rare variants.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Amyloid Precursor Protein Secretases / genetics
Aspartic Acid Endopeptidases / genetics
Filaggrin Proteins / genetics*
Genome-Wide Association Study
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Polymorphism, Single Nucleotide / genetics

Substances

FLG protein, human
Filaggrin Proteins
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases

Grants and funding

Our research was supported by the National Key Research and Development Program of China (Reference: 2018YFC1315400); the Science and Technology Planning Project of Guangdong Province (Reference: 2017A010101030); the Third Medical Technology Projects of Shantou in 2018 (Reference: 41368043); the Natural Science Foundation of China (References: 11771462, 71991474, 72171216), the National Key Research, the Key Research and Development Program of Guangdong, China (Reference: 2019B020228001), the Science and Technology Program of Guangzhou, China (Grant No. 202002030129), and the Natural Science Foundation of Anhui (Reference: BJ2040170017).