Frontotemporal Dementia Caused by the P301L Mutation in the MAPT Gene: Clinicopathological Features of 13 Cases from the Same Geographical Origin in Barcelona, Spain

2017 ◽  
Vol 44 (3-4) ◽  
pp. 213-221 ◽  
Author(s):  
Sergi Borrego-Écija ◽  
Joana Morgado ◽  
Leire Palencia-Madrid ◽  
Oriol Grau-Rivera ◽  
Ramón Reñé ◽  
...  
Keyword(s):  
Disease Onset ◽  
Memory Loss ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Mutation Carriers ◽  
Mapt Gene ◽  
Initial Symptoms ◽  
The Mean ◽  
P301l Mutation ◽  
Mapt Mutation

Background/Aims: We identified and studied 13 patients carrying the P301L mutation in the MAPT gene from the same area (Baix Llobregat County) in Barcelona, Spain. Methods: The demographic and clinical features were reviewed retrospectively. Detailed neuropathological characterization was obtained in 9 subjects. To investigate the origin of the P301L mutation in these families, 20 single nucleotide polymorphisms (SNPs) in the MAPT gene were analyzed. Results: The mean age at disease onset was 51 years and the mean disease duration was 7 years. The most common initial symptoms were behavioral changes (54%), followed by language disturbances (31%) and memory loss (15%). 46% developed parkinsonism. Neuropathology showed an extensive neuronal and glial 4-repeat (4R) tauopathy with “mini-Pick”-like bodies in the dentate gyrus as the characteristic underlying pathology in all cases. In 1 subject, additional 4R globular glial inclusions were observed. All the mutation carriers showed the same haplotype for the SNPs analyzed, suggesting a common ancestor. Conclusion: These findings suggest a relative homogeneous clinicopathological phenotype in P301L MAPT mutation carriers in our series. This phenotype might help in the differential diagnosis from other tauopathies and be a morphological hint for genetic testing. The haplotype analysis results suggest a founder effect of the P301L mutation in this area.

Assessing single nucleotide polymorphism selection methods for the development of a low-density panel optimized for imputation in South African Drakensberger beef cattle

2021 ◽  
Author(s):  
Simon F Lashmar ◽  
Donagh P Berry ◽  
Rian Pierneef ◽  
Farai C Muchadeyi ◽  
Carina Visser
Keyword(s):  
South African ◽  
Clustering Algorithm ◽  
Imputation Accuracy ◽  
Developed Countries ◽  
Genotype Imputation ◽  
Selection Strategy ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Single Nucleotide Polymorphism Selection ◽  
The Mean

Abstract A major obstacle in applying genomic selection (GS) to uniquely adapted local breeds in less-developed countries has been the cost of genotyping at high densities of single nucleotide polymorphisms (SNP). Cost reduction can be achieved by imputing genotypes from lower to higher densities. Locally adapted breeds tend to be admixed and exhibit a high degree of genomic heterogeneity thus necessitating the optimization of SNP selection for downstream imputation. The aim of this study was to quantify the achievable imputation accuracy for a sample of 1,135 South African (SA) Drakensberger using several custom-derived lower-density panels varying in both SNP density and how the SNP were selected. From a pool of 120,608 genotyped SNP, subsets of SNP were chosen 1) at random, 2) with even genomic dispersion, 3) by maximizing the mean minor allele frequency (MAF), 4) using a combined score of MAF and linkage disequilibrium (LD), 5) using a partitioning-around-medoids (PAM) algorithm, and finally 6) using a hierarchical LD-based clustering algorithm. Imputation accuracy to higher density improved as SNP density increased; animal-wise imputation accuracy defined as the within-animal correlation between the imputed and actual alleles ranged from 0.625 to 0.990 when 2,500 randomly selected SNP were chosen versus a range of 0.918 to 0.999 when 50,000 randomly selected SNP were used. At a panel density of 10,000 SNP, the mean (standard deviation) animal-wise allele concordance rate was 0.976 (0.018) versus 0.982 (0.014) when the worst (i.e., random) as opposed to the best (i.e., combination of MAF and LD) SNP selection strategy was employed. A difference of 0.071 units was observed between the mean correlation-based accuracy of imputed SNP categorized as low (0.01<MAF≤0.1) versus high MAF (0.4<MAF≤0.5). Greater mean imputation accuracy was achieved for SNP located on autosomal extremes when these regions were populated with more SNP. The presented results suggested that genotype imputation can be a practical cost-saving strategy for indigenous breeds such as the South African Drakensberger. Based on the results, a genotyping panel consisting of approximately 10,000 SNP selected based on a combination of MAF and LD would suffice in achieving a less than 3% imputation error rate for a breed characterized by genomic admixture on the condition that these SNP are selected based on breed-specific selection criteria.

scholarly journals The German Shorthair Pointer Dog Breed (Canis lupus familiaris): Genomic Inbreeding and Variability

Animals ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 498 ◽  
Author(s):  
Antonio Boccardo ◽  
Stefano Paolo Marelli ◽  
Davide Pravettoni ◽  
Alessandro Bagnato ◽  
Giuseppe Achille Busca ◽  
...  
Keyword(s):  
Canis Lupus ◽  
Inbreeding Coefficient ◽  
Nucleotide Polymorphisms ◽  
Canis Lupus Familiaris ◽  
Runs Of Homozygosity ◽  
Single Nucleotide ◽  
The Mean ◽  
Dog Breed ◽  
Genomic Inbreeding ◽  
Genealogical Information

The German Shorthaired Pointer (GSHP) is a breed worldwide known for its hunting versatility. Dogs of this breed are appreciated as valuable companions, effective trackers, field trailers and obedience athletes. The aim of the present work is to describe the genomic architecture of the GSHP breed and to analyze inbreeding levels under a genomic and a genealogic perspective. A total of 34 samples were collected (24 Italian, 10 USA), and the genomic and pedigree coefficients of inbreeding have been calculated. A total of 3183 runs of homozygosity (ROH) across all 34 dogs have been identified. The minimum and maximum number of Single Nucleotide Polymorphisms (SNPs) defining all ROH are 40 and 3060. The mean number of ROH for the sample was 93.6. ROH were found on all chromosomes. A total of 854 SNPs (TOP_SNPs) defined 11 ROH island regions (TOP_ROH), in which some gene already associated with behavioral and morphological canine traits was annotated. The proportion of averaged observed homozygotes estimated on total number of SNPs was 0.70. The genomic inbreeding coefficient based on ROH was 0.17. The mean inbreeding based on genealogical information resulted 0.023. The results describe a low inbred population with quite a good level of genetic variability.

PDGF-B gene single-nucleotide polymorphisms are not predictive for disease onset or progression of IgA nephropathy

2007 ◽  
Vol 67 (02) ◽  
pp. 65-72 ◽  
Author(s):  
B. Bicanski ◽  
M. Wenderdel ◽  
Peter R. Mertens ◽  
J. Senderek ◽  
U. Panzer ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Iga Nephropathy ◽  
Disease Onset ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Association Between Two Single-nucleotide Polymorphism of TAAR1 Gene and Suicide Attempts

2017 ◽  
Vol 41 (S1) ◽  
pp. S103-S103
Author(s):  
A. Zdanowicz ◽  
A. Sakowicz ◽  
E. Kusidel ◽  
P. Wierzbinski
Keyword(s):  
Suicide Attempts ◽  
Statistical Tests ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Hardy Weinberg Equilibrium ◽  
The Mean ◽  
Competing Interest ◽  
G Protein Coupled ◽  
The Brain

IntroductionTAAR1 is a G protein-coupled receptor expressed broadly throughout the brain. Recently, TAAR1 has been demonstrated to be an important modulator of the dopaminergic, serotonergic and glutamatergic activity.AimsAssessment of the relation between two single-nucleotide polymorphisms of TAAR1 gene, suicide attempts and alcohol abuse.MethodsA total of 150 Polish patients were included, 59 subjects after suicide attempt vs. 91 controls. The chosen SNPs (rs759733834 and rs9402439) were studied using RFLP-PCR methods. The Hardy-Weinberg equilibrium was tested in control group.Statistical testsChi2 or Yeates Chi2 Test were used.ResultsThe mean age of study subjects and controls was: 38 ± 12.3 and 42 ± 12.8 respectively; 49% study males vs. 54% male controls. We did not observe the association between the carriage of the genotypes GG, GA and AA of rs759733834 polymorphisms in either of the groups. The distribution of genotypes in respect to rs9402439 polymorphism (CC, CG, GG) was also insignificant. Among patients with alcohol dependence, the frequency G allele of rs9402439 polymorphism was lower compared to non-addicted ones (27 vs. 47%) P < 0.01.ConclusionsTAAR1 polymorphisms rs759733834 and rs9402439 are not related to suicide attempts. The carriage of allele G of rs9402439 polymorphism is related to lower risk of alcohol addiction OR 0.40 95%Cl 0.20–0.81. To our knowledge, this is the first study on the TAAR1 receptor and the risk of suicide and it might offer a new insight into genetic etiology of TAAR1 receptor.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals THE EFFECT OF SINGLE NUCLEOTIDE POLYMORPHISM (SNP) IN GLIOBLASTOMA MULTIFORME

2021 ◽  
Author(s):  
Asmita Ghosh ◽  
Dattatreya Mukherjee ◽  
Parth Patel ◽  
Debraj Mukhopadhyay
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Glioblastoma Multiforme ◽  
Association Studies ◽  
Disease Onset ◽  
Genetic Alterations ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide

Single nucleotide polymorphism is a genetic substitution of a base pair at a single position of the genome. SNPs are a common phenomenon and influence mRNA expression. Half of the SNPs occur in the non-coding region with 25% being mis-sense mutation and 25% being silent mutations. SNPs belong to the last generation of molecular markers which is identified through SNP mapping. SNPs are extensively studied to distinguish genetic expression and protein synthesis. These genetic differences are a major source of diseases in humans like cancers. One of the most common types of cancer of the brain is the Glioblastoma Multiforme that accounts for more than 80% of the malignant primary brain tumors (PBT). Researchers have found out a potential role of various SNPs in the genome to have a strong relation with Glioma formation and proliferation. Most SNPs are either not discovered, or their biological mechanisms are unknown, making it difficult to link putative associations with disease onset. The given review aims to identify some of the most common SNPs associated with GBM and classify the genetic basis along with future prospects. These SNPs are pioneer in Genome Wide Association studies to help in cancer research and identification of specific genetic alterations liked to GBM. Single Nucleotide Polymorphisms in a gene can be used as genetic biomarkers to aid better understanding of the mechanism of cancer formation, its aetiology, progression and metastatic behaviour.

scholarly journals Reverse transcriptase-related enzymes are associated with horizontal chromosome transfer in an asexual pathogen

2015 ◽  
Author(s):  
Xiaoqiu Huang ◽  
Anindya Das ◽  
Binod B Sahu ◽  
Subodh K Srivastava ◽  
Leonor F Leandro ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Root Rot ◽  
Supernumerary Chromosome ◽  
Open Reading Frames ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Chromosome Transfer ◽  
Supernumerary Chromosomes ◽  
The Mean ◽  
Reading Frames

Supernumerary chromosomes have been shown to transfer horizontally from one isolate to another. However, the mechanism by which horizontal chromosome transfer (HCT) occurs is unknown. In this study, we compared the genomes of 11 isolates comprising six Fusarium species that cause soybean sudden death syndrome (SDS) or bean root rot (BRR), and detected numerous instances of HCT in supernumerary chromosomes. We also identified a statistically significant number (21 standard deviations above the mean) of single nucleotide polymorphisms (SNPs) in the supernumerary chromosomes between isolates of the asexual pathogen F. virguliforme. Supernumerary chromosomes carried reverse transcriptase-related genes (RVT); the presence of long RVT open reading frames (ORFs) in the supernumerary chromosome was correlated with the presence of two or more chromosome copies with a significant number of SNPs between them. Our results suggest that supernumerary chromosomes transfer horizontally via an RNA intermediate. Understanding the mechanism by which HCT occurs will have a profound impact on understanding evolution and applying biotechnology as well as accepting HCT as a natural source of genetic variation.

Implications On Drug Resistance and Survival of ABCB1 Single Nucleotide Polymorphisms in Normal Karyotype De Novo AML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2648-2648
Author(s):  
Christer Paul ◽  
Henrik Green ◽  
Ingrid Jakobsen Falk ◽  
Kourosh Lotfi ◽  
Esbjorn Paul ◽  
...  
Keyword(s):  
Drug Sensitivity ◽  
De Novo ◽  
Normal Karyotype ◽  
University Hospital ◽  
Leukemic Cells ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
The Mean ◽  
De Novo Aml

Abstract Abstract 2648 Poster Board II-624 Background: Multidrug resistance and expression of the ATP-dependent drug transporting protein ABCB1 is a clinically relevant problem in the treatment of acute myeloid leukaemia. Several single nucleotide polymorphisms (SNPs) in the ABCB1 have been associated with altered P-glycoprotein expression and phenotype. These SNPs might influence the clinical outcome in AML and predict individual differences in response to therapy with ABCB1 substrates. Aims: To investigate the impact of the ABCB1 SNPs in exon 11, 12, 21 and 26 on treatment response, survival and in vitro drug sensitivity in AML patients. Methods: PCR and Pyrosequencing were used to determine the genotype of the SNPs G1199T/A, C1236T, A1308G, G2677T/A and C3435T in 100 de novo AML patients with normal karyotype treated at Linköping University Hospital or Karolinska University Hospital. Almost all patients were treated with one anthracycline and Ara-C during the induction regime. The affect of the genetic variants in ABCB1 on survival were analysed by Kaplan-Meier Log-rank tests and multivariant analysis by Cox regression. Patients receiving transplantation were censored at that point in the analysis. A Nordic reference material of 400 healthy volunteers of equal age and sex distribution was also included. NPM1 and FLT3-ITD mutations were determined by PCR. Leukemic cells were isolated and drug sensitivity was measured after 4 days culturing by a bioluminescence ATP-assay. Results: The survival of the AML patients was significantly correlated to the ABCB1 genotypes C1236T (P=0.02) and G2677T (P=0.02), with a borderline significance for G1199A (p=0.06). For the C1236T SNP the mean survival was 0.7, 1.3 and 1.8 years for the wild type, heterozygous and homozygous variants, respectively. The mean survival for patients with G/G, G/T and T/T genotype of SNP G2677T/A was 0.7, 1.2 and 1.7 years, respectively. Only the wild type of A1308T was found in the material and C3435T did not correlate to survival. Multivariate analysis showed that 1236T/T and 2677T/T were independent factors for survival (hazard ratio 0.24 and 0.22). Comparison of allele frequencies between AML patients and healthy volunteers showed no significant difference. In vitro testing showed that leukemic cells from patients carrying 1236T/T or 2677T/T were significantly more susceptible for mitoxantrone and borderline susceptible to daunorubicine and etoposide, substrates for Pgp but not to Ara-C. Conclusions: Our findings suggest that ABCB1 SNPs do not affect the development of the disease but the survival after chemotherapy possibly by impact on drug sensitivity. The correlation between ABCB1 genotype and the overall survival of AML patients might provide useful information for treatment strategies and individualized chemotherapy. Disclosures: Paul: Aprea AB: Consultancy, Research Funding.

scholarly journals What are the Prevalence and Risk Factors of Alzheimer’s Disease in China and the United States?

2020 ◽  
Vol 185 ◽  
pp. 03031
Author(s):  
Yiyang Xu
Keyword(s):  
United States ◽  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Activity ◽  
Disease Onset ◽  
The United States ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Desk Research

Dementia, especially Alzheimer’s dementia, which occupies more than 60% of total dementia cases, has become one of the most significant health problems in the world due to its increasing global prevalence, irreversible pathology, and rising social and economic costs. In this research, the author compared Alzheimer’s disease (AD) prevalence in China and the United States and found the common pattern of its epidemiology. Apart from the quantitative analysis, this research also identifies the pathophysiological, socioenvironmental, and other risk factors of Alzheimer’s disease by qualitative desk research. It was found that the risk factors related to or controlled by genes such as Single Nucleotide Polymorphisms (SNPs) have more influential effects on Alzheimer’s disease onset than the socio-environmental factors. Some socioenvironmental factors such as level of education reflecting the brain activity of a person are also correlated with Alzheimer’s disease prevalence. This disease is caused by an interplay of numerous factors, so there needs to be further investigations into its mechanisms as well as the combination therapy.

scholarly journals Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

2016 ◽  
Vol 6 (2) ◽  
pp. 330-340 ◽  
Author(s):  
Lieke H.H. Meeter ◽  
Holger Patzke ◽  
Gordon Loewen ◽  
Elise G.P. Dopper ◽  
Yolande A.L. Pijnenburg ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Single Nucleotide Polymorphisms ◽  
Frontotemporal Dementia ◽  
Coefficient Of Variation ◽  
Treatment Monitoring ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Therapeutic Trials ◽  
Mutation Carriers ◽  
Pathogenic Mutations

Background: Pathogenic mutations in the granulin gene (GRN) are causative in 5-10% of patients with frontotemporal dementia (FTD), mostly leading to reduced progranulin protein (PGRN) levels. Upcoming therapeutic trials focus on enhancing PGRN levels. Methods: Fluctuations in plasma PGRN (n = 41) and its relationship with cerebrospinal fluid (CSF, n = 32) and specific single nucleotide polymorphisms were investigated in pre- and symptomatic GRN mutation carriers and controls. Results: Plasma PGRN levels were lower in carriers than in controls and showed a mean coefficient of variation of 5.3% in carriers over 1 week. Although plasma PGRN correlated with CSF PGRN in carriers (r = 0.54, p = 0.02), plasma only explained 29% of the variability in CSF PGRN. rs5848, rs646776 and rs1990622 genotypes only partly explained the variability of PGRN levels between subjects. Conclusions: Plasma PGRN is relatively stable over 1 week and therefore seems suitable for treatment monitoring of PGRN-enhancing agents. Since plasma PGRN only moderately correlated with CSF PGRN, CSF sampling will additionally be needed in therapeutic trials.

scholarly journals Comparing low-pass sequencing and genotyping for trait mapping in pharmacogenetics

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Kaja Wasik ◽  
Tomaz Berisa ◽  
Joseph K. Pickrell ◽  
Jeremiah H. Li ◽  
Dana J. Fraser ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Sequencing Data ◽  
Single Nucleotide ◽  
Genotyping Array ◽  
Trait Mapping ◽  
Mean Imputation ◽  
Hla Genotypes ◽  
Low Pass ◽  
The Mean

Abstract Background Low pass sequencing has been proposed as a cost-effective alternative to genotyping arrays to identify genetic variants that influence multifactorial traits in humans. For common diseases this typically has required both large sample sizes and comprehensive variant discovery. Genotyping arrays are also routinely used to perform pharmacogenetic (PGx) experiments where sample sizes are likely to be significantly smaller, but clinically relevant effect sizes likely to be larger. Results To assess how low pass sequencing would compare to array based genotyping for PGx we compared a low-pass assay (in which 1x coverage or less of a target genome is sequenced) along with software for genotype imputation to standard approaches. We sequenced 79 individuals to 1x genome coverage and genotyped the same samples on the Affymetrix Axiom Biobank Precision Medicine Research Array (PMRA). We then down-sampled the sequencing data to 0.8x, 0.6x, and 0.4x coverage, and performed imputation. Both the genotype data and the sequencing data were further used to impute human leukocyte antigen (HLA) genotypes for all samples. We compared the sequencing data and the genotyping array data in terms of four metrics: overall concordance, concordance at single nucleotide polymorphisms in pharmacogenetics-related genes, concordance in imputed HLA genotypes, and imputation r2. Overall concordance between the two assays ranged from 98.2% (for 0.4x coverage sequencing) to 99.2% (for 1x coverage sequencing), with qualitatively similar numbers for the subsets of variants most important in pharmacogenetics. At common single nucleotide polymorphisms (SNPs), the mean imputation r2 from the genotyping array was 0.90, which was comparable to the imputation r2 from 0.4x coverage sequencing, while the mean imputation r2 from 1x sequencing data was 0.96. Conclusions These results indicate that low-pass sequencing to a depth above 0.4x coverage attains higher power for association studies when compared to the PMRA and should be considered as a competitive alternative to genotyping arrays for trait mapping in pharmacogenetics.

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