Functional annotation of Alzheimer's disease associated loci revealed by GWASs

Han, Zengpeng; Huang, Han Yao; Gao, Yue; Huang, Qingyang

doi:10.1371/journal.pone.0179677

Cited by 34 publications

(28 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Under other genetic models, rs2333227 SNP slightly elevated the risk of AD. This result was accorded with previous studies [ 31 – 33 ]. But Combarros and Usui had reported that rs2333227 SNP was not related to AD risk [ 34 , 35 ].…”

Section: Discussionsupporting

confidence: 94%

The association of MPO gene promoter polymorphisms with Alzheimer’s disease risk in Chinese Han population

2017

Oncotarget

View full text Add to dashboard Cite

AimThe objective of this study was to explore the genetic association of myeloperoxidase (MPO) gene polymorphisms with risk of Alzheimer's disease (AD).MethodsBlood samples were collected from 116 AD patients and 134 age and gender matched healthy individuals. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was utilized to confirm MPO polymorphisms in promoter region. Plasma concentration of MPO was detected by enzyme-linked immuno sorbent assay. Genotype distributions of MPO polymorphisms were compared by χ2 test between the two groups. The status of linkage disequilibrium between MPO two polymorphisms was detected using Haploview. MPO concentrations were analyzed by non-parametric test.ResultsMPO rs2333227 polymorphism was positively associated with AD risk, especially under the AA+GA vs. GG and A vs. G genetic models (P=0.042, OR=1.719, 95%CI=1.017-2.906; P=0.041, OR=1.582, 95%CI=1.016-2.463). While, rs34097845 polymorphism significantly decreased the risk of AD, particularly GA and AA+GA genotypes (P=0.048, OR=0.555, 95%CI=0.308-0.998; P=0.042, OR=0.552, 95%CI=0.310-0.983). In addition, rs2333227 genotypes affected the plasma concentration of MPO. But for rs34097845 polymorphism, only GA genotype exhibited significant association with MPO concentration.ConclusionPolymorphisms in the promoter region of MPO distinctly contribute to AD risk possibly through regulating MPO concentration. Present results should be confirmed by further studies.

show abstract

Section: Discussionsupporting

confidence: 94%

The association of MPO gene promoter polymorphisms with Alzheimer’s disease risk in Chinese Han population

2017

Oncotarget

View full text Add to dashboard Cite

show abstract

“…Using genome‐wide association studies (GWASs), Han, Huang, Gao, and Huang () identified functions of the genes and categorized these functions as “regulation of beta‐amyloid formation,” “regulation of neurofibrillary tangle assembly,” “leukocyte‐mediated immunity,” and “protein‐lipid complex assembly” signaling pathways. With the protein–protein interaction network and functional module analyses, they also identified “hub” genes and “bottleneck” genes indicating three subnetworks.…”

Section: Thirteen Among 37 Genes On the Human Ad Genetic Risk Loci Armentioning

confidence: 99%

“…With the protein–protein interaction network and functional module analyses, they also identified “hub” genes and “bottleneck” genes indicating three subnetworks. The hub genes included APOE, PICALM, BIN1, ABCA7, CD2AP, CLU, CR1, MS4A4E, and MS4A6A, while the bottleneck genes included APOE, TOMM40, NME8, PICALM, CD2AP, ZCWPW1, FAM180B, GAB2, and PTK2B (Han et al, ). However, as of 2019, not all genes are well characterized, as indicated by the limited number of publications listed in Table .…”

Section: Thirteen Among 37 Genes On the Human Ad Genetic Risk Loci Armentioning

confidence: 99%

See 1 more Smart Citation

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

View full text Add to dashboard Cite

The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

show abstract

“…Computational analyses represent a starting point to guide the functional research. Our group has previously characterized the GWAS SNPs and genes by computational approaches for osteoporosis [ 3 ], T2D [ 4 ] and Alzheimer's disease [ 5 ]. Here, we used computational approaches to comprehensively analyze obesity GWAS identified SNPs and genes, including functional annotation using RegulomeDB and 3DSNP, effects on miRNAs binding and protein phosphorylation for obesity associated SNPs, and protein-protein interaction network, gene ontology and pathway enrichment analyses for obesity associated genes, in order to identify functional SNPs for follow-up experimental assays, and to provide guidance for future study with regard to the pathogenesis and etiology of obesity.…”

Section: Introductionmentioning

confidence: 99%

Computational analyses of obesity associated loci generated by genome-wide association studies

et al. 2018

Self Cite

View full text Add to dashboard Cite

ObjectivesGenome-wide association studies (GWASs) have discovered associations of numerous SNPs and genes with obesity. However, the underlying molecular mechanisms through which these SNPs and genes affect the predisposition to obesity remain not fully understood. Aims of our study are to comprehensively characterize obesity GWAS SNPs and genes through computational approaches.MethodsFor obesity GWAS identified SNPs, functional annotation, effects on miRNAs binding and impact on protein phosphorylation were performed via RegulomeDB and 3DSNP, miRNASNP, and the PhosSNP 1.0 database, respectively. For obesity associated genes, protein-protein interaction network construction, gene ontology and pathway enrichment analyses were performed by STRING, PANTHER and STRING, respectively.ResultsA total of 445 SNPs are significantly associated with obesity related phenotypes at threshold P < 5×10−8. A number of SNPs were eQTLs for obesity associated genes, some SNPs located at binding sites of obesity related transcription factors. SNPs that might affect miRNAs binding and protein phosphorylation were identified. Protein-protein interaction network analysis identified the highly-interconnected “hub” genes. Obesity associated genes mainly involved in metabolic process and catalytic activity, and significantly enriched in 15 signal pathways.ConclusionsOur results provided the targets for follow-up experimental testing and further shed new light on obesity pathophysiology.

show abstract

Functional annotation of Alzheimer's disease associated loci revealed by GWASs

Cited by 34 publications

References 41 publications

The association of MPO gene promoter polymorphisms with Alzheimer’s disease risk in Chinese Han population

The association of MPO gene promoter polymorphisms with Alzheimer’s disease risk in Chinese Han population

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

Computational analyses of obesity associated loci generated by genome-wide association studies

Contact Info

Product

Resources

About