Dataset Information

Genetic and Expression Analysis of COPI Genes and Alzheimer's Disease Susceptibility.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly and the leading cause of dementia in humans. Evidence shows that cellular trafficking and recycling machineries are associated with AD risk. A recent study found that the coat protein complex I (COPI)-dependent trafficking in vivo could significantly reduce amyloid plaques in the cortex and hippocampus of neurological in the AD mouse models and identified 12 single-nucleotide polymorphisms in COPI genes to be significantly associated with increased AD risk using 6,795 samples. Here, we used a large-scale GWAS dataset to investigate the potential association between the COPI genes and AD susceptibility by both SNP and gene-based tests. The results showed that only rs9898218 was associated with AD risk with P = 0.017. We further conducted an expression quantitative trait loci (eQTLs) analysis and found that rs9898218 G allele was associated with increased COPZ2 expression in cerebellar cortex with P = 0.0184. Importantly, the eQTLs analysis in whole blood further indicated that 11 of these 12 genetic variants could significantly regulate the expression of COPI genes. Hence, these findings may contribute to understand the association between COPI genes and AD susceptibility.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6761859 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic and Expression Analysis of COPI Genes and Alzheimer's Disease Susceptibility.

Yang Yu Y Wang Xu X Ju Weina W Sun Li L Zhang Haining H

Frontiers in genetics 20190919

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly and the leading cause of dementia in humans. Evidence shows that cellular trafficking and recycling machineries are associated with AD risk. A recent study found that the coat protein complex I (COPI)-dependent trafficking <i>in vivo</i> could significantly reduce amyloid plaques in the cortex and hippocampus of neurological in the AD mouse models and identified 12 single-nucleotide polymorphisms in COPI genes t ...[more]

PMID: 31608112

Similar Datasets

Project description:BackgroundCognitive problems have been reported in breast cancer patients after chemotherapy. A small group of older breast cancer survivors carrying the APOE4 gene, receiving chemotherapy, was at increased risk of long-term impairment of brain function. We have analyzed the expression of APOE and the next 23-ranked Alzheimer's disease (AD) susceptibility genes in malignant breast tumors. We wished to determine if these 24 genes might be related to breast cancer.MethodsTo identify the most important AD susceptibility genes, we consulted the ALZGENE database (www.alzgene.org/) which displays this information and regularly updates it. To analyze the effect of AD susceptibility genes on breast cancer, we used The Cancer Genome Atlas (TCGA). We analyzed TCGA data with cBioPortal for Cancer Genomics. cBioPortal provides visualization, analysis, and download of large-scale cancer genomic data sets. cBioPortal can analyze APOE in breast tumors but cannot distinguish its three alleles: E2, E3, and E4.ResultsAbout 1.6% of the tumors had APOE amplification (copy number alteration). Two percent of the tumors had CD33 alterations. None of the tumors had APOE mutations. Two tumors had CD33 missense mutations of unknown significance. Expression heatmap shows that over- or underexpression of APOE and CD33 was correlated in most of the tumors. APOE alteration significantly co-occurred with CD33 and CD2AP.ConclusionAlterations of certain cancer genes tend to co-occur, indicating that they may work in tandem to drive tumor formation and development. This may be the case with the co-occurring alterations of APOE, CD33, and CD2AP. It would be important to know which APOE allele(s) were co-occurrent with CD33 and CD2AP and whether co-occurrence in the tumor predicted increased risk of AD. This information could help in identification of specific risk factors for breast cancer-related cognitive decline in older women, which has important implications for oncology care.

Project description:IntroductionAlthough the heritability of sporadic Alzheimer's disease (AD) is estimated to be 60-80%, addressing the genetic contribution to AD risk still remains elusive. More specifically, it remains unclear whether genetic variants are able to affect neurodegenerative brain features that can be addressed by in vivo imaging techniques.MethodsTargeted sequencing analysis of the coding and UTR regions of 132 AD susceptibility genes was performed. Neuroimaging data using 11C-Pittsburgh Compound B positron emission tomography (PET), 18F-fluorodeoxyglucose PET, and MRI that are available from the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's disease) cohort were acquired. A total of 557 participants consisted of 336 cognitively normal (CN) adults, 137 mild cognitive impairment (MCI), and 84 AD dementia (ADD) groups.ResultsWe called 5391 high-quality single nucleotide variants (SNVs) on AD susceptibility genes and selected significant associations between variants and five in vivo AD pathologies: (1) amyloid β (Aβ) deposition, (2) AD-signature region cerebral glucose metabolism (AD-Cm), (3) posterior cingulate cortex (PCC) cerebral glucose metabolism (PCC-Cm), (4) AD-signature region cortical thickness (AD-Ct), and (5) hippocampal volume (Hv). The association analysis for common variants (allele frequency (AF) > 0.05) yielded several novel loci associated with Aβ deposition (PIWIL1-rs10848087), AD-Cm (NME8-rs2722372 and PSEN2-rs75733498), AD-Ct (PSEN1-rs7523) and, Hv (CASS4-rs3746625). Meanwhile, in a gene-based analysis for rare variants (AF < 0.05), cases carrying rare variants in LPL, FERMT2, NFAT5, DSG2, and ITPR1 displayed associations with the neuroimaging features. Exploratory voxel-based brain morphometry between the variant carriers and non-carriers was performed subsequently. Finally, we document a strong association of previously reported APOE variants with the in vivo AD pathologies and demonstrate that the variants exert a causal effect on AD susceptibility via neuroimaging features.ConclusionsThis study provides novel associations of genetic factors to Aβ accumulation and AD-related neurodegeneration to influence AD susceptibility.

Project description:Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ?1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated.

Dataset Information

Genetic and Expression Analysis of COPI Genes and Alzheimer's Disease Susceptibility.

Publications

Genetic and Expression Analysis of COPI Genes and Alzheimer's Disease Susceptibility.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets