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Volume 13
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10.3390/genes13050838
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Article

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

by
Weixue Xiong
1,†,
Jiahui Cai
1,†,
Ruijia Li
2,
Canhong Wen
2,*,
Haizhu Tan
1,* and
on behalf of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Database
‡
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
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
The ADNI was launched by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the Food and Drug Administration (FDA), private pharmaceutical companies and non-profit organizations. A complete listing of ADNI investigators can be found in the acknowledgments part.
Genes 2022, 13(5), 838; https://doi.org/10.3390/genes13050838
Submission received: 22 April 2022 / Revised: 3 May 2022 / Accepted: 4 May 2022 / Published: 7 May 2022
(This article belongs to the Special Issue Bioinformatics and Genetics of Human Diseases)
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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: Alzheimer’s disease; rare variants; ADNI; MIRAGE Alzheimer’s disease; rare variants; ADNI; MIRAGE

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MDPI and ACS Style

Xiong, W.; Cai, J.; Li, R.; Wen, C.; Tan, H.; on behalf of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Database. Rare Variant Analysis and Molecular Dynamics Simulation in Alzheimer’s Disease Identifies Exonic Variants in FLG. Genes 2022, 13, 838. https://doi.org/10.3390/genes13050838

AMA Style

Xiong W, Cai J, Li R, Wen C, Tan H, on behalf of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Database. Rare Variant Analysis and Molecular Dynamics Simulation in Alzheimer’s Disease Identifies Exonic Variants in FLG. Genes. 2022; 13(5):838. https://doi.org/10.3390/genes13050838

Chicago/Turabian Style

Xiong, Weixue, Jiahui Cai, Ruijia Li, Canhong Wen, Haizhu Tan, and on behalf of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Database. 2022. "Rare Variant Analysis and Molecular Dynamics Simulation in Alzheimer’s Disease Identifies Exonic Variants in FLG" Genes 13, no. 5: 838. https://doi.org/10.3390/genes13050838

APA Style

Xiong, W., Cai, J., Li, R., Wen, C., Tan, H., & on behalf of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Database. (2022). Rare Variant Analysis and Molecular Dynamics Simulation in Alzheimer’s Disease Identifies Exonic Variants in FLG. Genes, 13(5), 838. https://doi.org/10.3390/genes13050838

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