Genetic and Expression Analysis of COPI Genes and Alzheimer's Disease Susceptibility.
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ABSTRACT:
SUBMITTER: Yang Y
PROVIDER: S-EPMC6761859 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Project description:BackgroundAlzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.Principal findingsIn addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.SignificanceThe additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
| S-EPMC4055488 | biostudies-literature
Project description:Background:Cognitive 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. Methods:To 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. Results:About 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. Conclusion:Alterations 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.
| S-EPMC6709700 | biostudies-literature
Project description:Familial Alzheimer's disease (AD), mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1, and PSEN2) involved in the production of the amyloid ? peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies there is a mounting list of genetic risk factors associated with common genetic variants that have been associated with sporadic AD. Besides apolipoprotein E, that presents a strong association with the disease (OR?4), the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated with AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways, and networks rather than the contribution of specific genes.
| S-EPMC4391239 | biostudies-literature
Project description:Cellular trafficking and recycling machineries belonging to late secretory compartments have been associated with increased Alzheimer's disease (AD) risk. We have shown that coat protein complex I (COPI)-dependent trafficking, an early step in Golgi-to-endoplasmic reticulum retrograde transport, affects amyloid precursor protein subcellular localization, cell-surface expression, as well as its metabolism. We present here a set of experiments demonstrating that, by targeting subunit ?-COP function, the moderation of the COPI-dependent trafficking in vivo leads to a significant decrease in amyloid plaques in the cortex and hippocampus of neurological 17 mice crossed with the 2xTg AD mouse model. Remarkably, an improvement of the memory impairments was also observed. Importantly, human genetic association studies of different AD cohorts led to the identification of 12 SNPs and 24 mutations located in COPI genes linked to an increased AD risk. These findings further demonstrate in vivo the importance of early trafficking steps in AD pathogenesis and open new clinical perspectives.
| S-EPMC4868486 | biostudies-literature
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.
| S-EPMC7678113 | biostudies-literature
Project description:Alzheimer's disease (AD) is a neurodegenerative disease mostly occurred in the elderly. Genetic mutation is one of well-established risk factors for AD. Several polymorphisms on chromosome 11q were reported to be associated with AD susceptibility. Hence we performed a meta-analysis to systematically assess the association between the most-reported polymorphisms on chromosome 11q (rs10793294, rs7115850, rs7101429, rs4945261, rs2373115, rs670142, rs610932, rs541458 and rs3851179) and AD risk. A comprehensive literature search in the electronic databases was performed to identify all eligible studies. The pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the association between 11q variants and AD risk by using the allelic model. Sensitivity analysis was carried out to analyze the influence of single study on the overall results. Begg's funnel plots and Egger's test were used to assess the publication biases among studies. All the statistical analyses were conducted by using STATA 12.0 Software (Stata Corp, College Station, TX, USA). A total of 35 eligible articles were included in our meta-analysis. Our data showed that the polymorphism of rs610932 were significantly associated with lower AD risk with a pooled OR of 0.88 (95% CI: 0.84-0.92, P=0.005). The other SNPs of rs494526 (OR=0.83, 95% CI: 0.65-1.00, P<0.001), rs2373115 (OR=0.85, 95% CI: 0.75-0.95, P<0.001) and rs670139 (OR=1.09, 95% CI: 1.05-1.12, P=0.554) were shown to be correlated with lower AD risk. Subgroup analysis revealed a similar result in Caucasians. But only the rs610932 polymorphism was found to be associated with lower AD risk in Asians. The polymorphism of rs610932 was shown to be a risk factor for AD while the other three genetic variants (rs494526, rs2373115 and rs610932) may act as protective factors against AD.
| S-EPMC4694325 | biostudies-literature
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.
| S-EPMC4666664 | biostudies-literature
Project description:Late onset Alzheimer's disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.
| S-EPMC3511432 | biostudies-literature
Project description:Complement receptor 1 (CR1) plays an important role in the development of sporadic Alzheimer's disease (SAD) in Caucasians. However, the influence of CR1 (rs6656401A/G and rs3818361T/C) genetic polymorphisms on the risk of SAD remains controversial. A meta-analysis of 18 case-control studies was performed to derive a more precise association of CR1 (rs6656401A/G or rs3818361T/C) genetic polymorphism with the risk of SAD in Caucasians. A statistical difference was found in the dominant model (odds ratio (OR): 1.23, 95% confidence interval (CI): 1.16-1.30, P=0.00), recessive model (OR: 1.28, 95% CI: 1.05-1.56, P=0.02), homozygote comparison (OR: 1.36, 95% CI: 1.12-1.66, P=0.002) or heterozygote comparison (AG versus GG) (OR: 1.21, 95% CI: 1.15-1.29, P=0.00) of CR1 rs6656401A/G. For CR1 rs3818361T/C, a statistical difference was observed in the dominant model (OR: 1.21, 95% CI: 1.13-1.31, P=0.00), recessive model (OR: 1.28, 95% CI: 1.07-1.53, P=0.006), homozygote comparison (OR: 1.35, 95% CI: 1.13-1.62, P=0.001) or heterozygote comparison (TC versus CC) (OR: 1.20, 95% CI: 1.11-1.29, P=0.00). In summary, despite some limitations, the present meta-analysis indicated that rs6656401A/G or rs3818361T/C polymorphism was related to SAD risk. Moreover, a carrier of rs6656401A/G or T carrier of rs3818361T/C in CR1 genetic polymorphism might be an increased factor for SAD in Caucasians.
| S-EPMC7268259 | biostudies-literature
Project description:The relationships between genome wide association study-identified and replicated genetic variants associated with Alzheimer's disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. Seven hundred and one AD patients with at least 3 different cognitive evaluations and genotypic information for APOE and 6 genome wide association study-significant single-nucleotide polymorphisms were selected for this study. Mean differences in Global Deterioration Score and Mini Mental State Examination (MMSE) were evaluated using nonparametric tests, general linear model and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor, memantine, or both. Relationships between therapeutic protocols, genetic markers, and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared with GG carriers at the end of the follow-up (MMSE mean difference = -0.57; 95% confidence interval, -1.145 to 0.009; p = 0.047). This observation remained unaltered after covariate adjustments although it did not achieve predefined multiple testing significance threshold. The PICALM single-nucleotide polymorphism also displayed a significant effect protecting against rapid progression during pharmacogenetic assays although its observed effect displayed heterogeneity among AD therapeutic protocols (p = 0.039). None of the studied genetic markers were convincingly linked to AD progression or drug response. However, by using different statistical approaches, the PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes.
| S-EPMC4097044 | biostudies-literature