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Computational analysis of functional SNPs in Alzheimer's disease-associated endocytosis genes.

ABSTRACT: Background:From genome wide association studies on Alzheimer's disease (AD), it has been shown that many single nucleotide polymorphisms (SNPs) of genes of different pathways affect the disease risk. One of the pathways is endocytosis, and variants in these genes may affect their functions in amyloid precursor protein (APP) trafficking, amyloid-beta (A?) production as well as its clearance in the brain. This study uses computational methods to predict the effect of novel SNPs, including untranslated region (UTR) variants, splice site variants, synonymous SNPs (sSNPs) and non-synonymous SNPs (nsSNPs) in three endocytosis genes associated with AD, namely PICALM, SYNJ1 and SH3KBP1. Materials and Methods:All the variants' information was retrieved from the Ensembl genome database, and then different variation prediction analyses were performed. UTRScan was used to predict UTR variants while MaxEntScan was used to predict splice site variants. Meta-analysis by PredictSNP2 was used to predict sSNPs. Parallel prediction analyses by five different software packages including SIFT, PolyPhen-2, Mutation Assessor, I-Mutant2.0 and SNPs&GO were used to predict the effects of nsSNPs. The level of evolutionary conservation of deleterious nsSNPs was further analyzed using ConSurf server. Mutant protein structures of deleterious nsSNPs were modelled and refined using SPARKS-X and ModRefiner for structural comparison. Results:A total of 56 deleterious variants were identified in this study, including 12 UTR variants, 18 splice site variants, eight sSNPs and 18 nsSNPs. Among these 56 deleterious variants, seven variants were also identified in the Alzheimer's Disease Sequencing Project (ADSP), Alzheimer's Disease Neuroimaging Initiative (ADNI) and Mount Sinai Brain Bank (MSBB) studies. Discussion:The 56 deleterious variants were predicted to affect the regulation of gene expression, or have functional impacts on these three endocytosis genes and their gene products. The deleterious variants in these genes are expected to affect their cellular function in endocytosis and may be implicated in the pathogenesis of AD as well. The biological consequences of these deleterious variants and their potential impacts on the disease risks could be further validated experimentally and may be useful for gene-disease association study.

SUBMITTER: Tey HJ

PROVIDER: S-EPMC6776068 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Computational analysis of functional SNPs in Alzheimer's disease-associated endocytosis genes.

Tey Han Jieh HJ Ng Chong Han CH

PeerJ 20190930

<h4>Background</h4>From genome wide association studies on Alzheimer's disease (AD), it has been shown that many single nucleotide polymorphisms (SNPs) of genes of different pathways affect the disease risk. One of the pathways is endocytosis, and variants in these genes may affect their functions in amyloid precursor protein (APP) trafficking, amyloid-beta (Aβ) production as well as its clearance in the brain. This study uses computational methods to predict the effect of novel SNPs, including ...[more]

PMID: 31592138

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Project description:Developing Alzheimer's disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

Dataset Information

Computational analysis of functional SNPs in Alzheimer's disease-associated endocytosis genes.

Publications

Computational analysis of functional SNPs in Alzheimer's disease-associated endocytosis genes.

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