Microtubule Associated Protein Tau (MAPT) forms proteopathic aggregates in several diseases. The G273R tau mutation, located in the first repeat region, was found by exome sequencing in a patient who ...presented with dementia and parkinsonism. We herein return to pathological examination which demonstrated tau immunoreactivity in neurons and glia consistent of mixed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) features. To rationalize the pathological findings, we used molecular biophysics to characterize the mutation in more detail in vitro and in Drosophila. The G273R mutation increases the aggregation propensity of 4-repeat (4R) tau and alters the tau binding affinity towards microtubules (MTs) and F-actin. Tau aggregates in PSP and CBD are predominantly 4R tau. Our data suggest that the G273R mutation induces a shift in pool of 4R tau by lower F-actin affinity, alters the conformation of MT bound 4R tau, while increasing chaperoning of 3R tau by binding stronger to F-actin. The mutation augmented fibrillation of 4R tau initiation in vitro and in glial cells in Drosophila and showed preferential seeding of 4R tau in vitro suggestively causing a late onset 4R tauopathy reminiscent of PSP and CBD.
•G273R tau mutation was found in a patient with dementia and parkinsonism.•Tau pathology in neurons and glia resembled mixed PSP and CBD.•The G273R mutation increased the aggregation of 4R tau in vitro &Drosophila model.•The 4R tau G273R mutation selectively seeded 4R tau in vitro.
In May 2008, PulseNet detected a multistate outbreak of Salmonella enterica serotype Saintpaul infections. Initial investigations identified an epidemiologic association between illness and ...consumption of raw tomatoes, yet cases continued. In mid-June, we investigated two clusters of outbreak strain infections in Texas among patrons of Restaurant A and two establishments of Restaurant Chain B to determine the outbreak's source.
We conducted independent case-control studies of Restaurant A and B patrons. Patients were matched to well controls by meal date. We conducted restaurant environmental investigations and traced the origin of implicated products. Forty-seven case-patients and 40 controls were enrolled in the Restaurant A study. Thirty case-patients and 31 controls were enrolled in the Restaurant Chain B study. In both studies, illness was independently associated with only one menu item, fresh salsa (Restaurant A: matched odds ratio mOR, 37; 95% confidence interval CI, 7.2-386; Restaurant B: mOR, 13; 95% CI 1.3-infinity). The only ingredient in common between the two salsas was raw jalapeño peppers. Cultures of jalapeño peppers collected from an importer that supplied Restaurant Chain B and serrano peppers and irrigation water from a Mexican farm that supplied that importer with jalapeño and serrano peppers grew the outbreak strain.
Jalapeño peppers, contaminated before arrival at the restaurants and served in uncooked fresh salsas, were the source of these infections. Our investigations, critical in understanding the broader multistate outbreak, exemplify an effective approach to investigating large foodborne outbreaks. Additional measures are needed to reduce produce contamination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Introduction We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative ...variants. Methods We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. Results We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLOD max = 4.7, P joint = 6.6 × 10−6 ), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLOD max = 4.9, P joint = 1.2 × 10−5 ), a region harboring genes associated with the nervous system ( GARS , GHRHR, and NEUROD6 ). Discussion Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.
Abstract Introduction Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. Methods We performed genome-wide linkage and ...identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. Results Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2–11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2–14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds LOD* ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177 , and the microRNA Mir_320 , whereas IBD analyses implicates an additional gene BCL11B , a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. Discussion Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.
A number of countries have estimated the prevalence of acute gastroenteritis by asking survey respondents to recall past episodes of diarrhea; however, the recall period used varies between studies. ...We conducted a survey to examine the effects of 7-day and 1-month recall periods on the estimated annual episodes of acute gastroenteritis. Further, we examine whether asking first about illness in the previous 7 days affects a person's response to a 1-month recall period.
The Foodborne Diseases Active Surveillance Network (FoodNet) conducted a population-based telephone survey that included asking respondents about the occurrence of gastrointestinal symptoms. From February through April 2007, we randomly split respondents into two groups to examine effect of recall periods and question order. One group was first asked about symptoms in the 7 days before interview and then asked about symptoms in the month before interview. The other group was asked only about symptoms in the month before interview.
Overall, the monthly prevalence of acute diarrheal illness (≥3 loose stools in 24-hours, lasting >1 day, or restricting daily activities) was 7.7%. This proportion was consistent among the respondents who were first asked about a 7-day recall period (n=1436) and those asked only about symptoms in the past month (n=2132). Extrapolation from the reported 7-day prevalence of 3.1% to an annual rate of 1.6 episodes per person, however, was almost twice the rate of episodes estimated when extrapolating from the month recall period. Similar findings were found with acute gastroenteritis (acute diarrheal illness or vomiting without respiratory symptoms).
First asking respondents about a 7-day recall period did not affect the prevalence of acute gastroenteritis reported for a 1-month recall period. Recall period length did, however, have a major impact on estimates of acute gastroenteritis. Retrospective studies using different recall periods may not be comparable.
Using data collected from undergraduates at two large, public universities (N = 183), we examined features of student drawings (e.g., facial expressions) as reflections of dominant views of the ...elderly. Sketches depicted both negative (e.g., frailty) and positive stereotypes (e.g., kindness). They also illustrate gender inequality; for example, men are overrepresented in the drawings relative to their proportion in the elderly population. We discuss the use of student drawings as a tool to stimulate discussion on the social construction of "old age," the double standard of aging, and the nature, origin, and consequences of ageism.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in ...CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
Abstract
Summary
We report VCPA, our SNP/Indel Variant Calling Pipeline and data management tool used for the analysis of whole genome and exome sequencing (WGS/WES) for the Alzheimer’s Disease ...Sequencing Project. VCPA consists of two independent but linkable components: pipeline and tracking database. The pipeline, implemented using the Workflow Description Language and fully optimized for the Amazon elastic compute cloud environment, includes steps from aligning raw sequence reads to variant calling using GATK. The tracking database allows users to view job running status in real time and visualize >100 quality metrics per genome. VCPA is functionally equivalent to the CCDG/TOPMed pipeline. Users can use the pipeline and the dockerized database to process large WGS/WES datasets on Amazon cloud with minimal configuration.
Availability and implementation
VCPA is released under the MIT license and is available for academic and nonprofit use for free. The pipeline source code and step-by-step instructions are available from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (http://www.niagads.org/VCPA).
Supplementary information
Supplementary data are available at Bioinformatics online.
Abstract
Background
The Genome Center for Alzheimer’s Disease (GCAD) coordinates the integration of all available Alzheimer’s disease (AD) relevant whole genome sequencing (WGS) data with the goal of ...identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated through collaboration between investigators from the Alzheimer’s Disease Sequencing Project (ADSP) and GCAD. With the goal of minimizing data heterogeneity, introduced by different sequencing protocols and assays, GCAD processes all samples using standardized pipelines and performs quality control (QC)/quality assurance (QA) checks.
Methods
Raw sequencing data (FASTQs or BAMs) were aligned to GRCh38/hg38 by BWA, and variant calling and joint genotyping on single nucleotide variants (SNVs), insertions and deletions (indels), were done by GATK. Structural variants (SVs) were called per sample using the Smoove, Manta, and Strelka packages. Preliminary QA checks including sex check, contamination, and genotype concordance were performed followed by QC per ADSP protocol to evaluate the quality of samples and variants. To facilitate access and usage of massive joint‐genotype called VCF files, a compact version for storing variant info and sample genotypes only was released first.
Results
We dropped 275 (0.7%) samples of poor coverage (<20×), and we flagged 219 (0.6%) samples that were of borderline quality. As a result, the dataset (ADSP Release 4, 2022) includes 36,361 genomes from 40 diverse cohorts with 4 major ancestries: 16,573 Non‐Hispanic Whites, 11,358 Hispanics; 5,422 African Americans; and 2,802 Asians. Data are deeply sequenced (average genome coverage: 40x). All samples’ CRAMs and gVCFs from GATK were deposited into NIAGADS Data Sharing Service (DSS) (
https://dss.niagads.org/
) for public distribution. Joint‐genotyped called VCFs are undergoing a full QC/annotation process and will be made available. This joint‐genotyped called VCF contains >362M bi‐allelic variants, >58M multi‐allelic variants, with 95% of variants remaining after QC. SV calling is ongoing and data will be ready prior to the conference.
Conclusion
The ADSP and GCAD generate high quality SNVs, indels and SV calls. Currently GCAD is preparing the next release of ∼60,000 more ancestrally‐diverse WGS samples sequenced primarily through the ADSP Follow‐Up Study, which we anticipate will be released in 2023 to greatly benefit the AD genetics community.
Abstract
Background
Previous whole exome sequencing (WES) studies of Alzheimer’s disease (AD) have identified genome‐wide significant associations with rare variants in several novel genes and ...highlighted the need for investigations in larger samples. We combined WES and whole genome sequencing (WGS) data assembled by the Alzheimer Disease Sequencing Project (ADSP) to increase the power for detecting associations of AD with rare variants in gene coding regions.
Method
We developed an efficient computational pipeline to perform both pre‐merging and post‐merging genotype, variant and sample‐level quality control (QC) on WGS data containing 16,905 individuals and WES data for 20,504 individuals. The resultant sample included participants from European (EA, 11,279 AD cases, 8,924 controls), African American (AA, 2,757 AD cases, 4,336 controls), and Caribbean Hispanic (CH 1,438 AD cases, 3,256 controls) ancestries. We employed GENESIS to test association of AD with 250,465 bi‐allelic QC’d variants using a logistic model including covariates for age, sex, exome capture kit, read length, and ancestry principal components (PCs).
Result
In the total sample, variants from
APOE
and other known AD genes including
SORL1
(P = 5.30×10‐7),
NECTIN2
(P = 6.94×10‐7), and
TREM2
R47H (P = 2.34×10‐13) crossed or neared the study‐wide significance (SWS) threshold of P = 2.00×10‐7 (0.05/250,465). SWS or borderline significant associations were also found with variants in several novel loci including
TKTL2
(P = 2.35×10‐8),
D2HGDH
, (P = 1.09×10‐7)
, CECR1
(P = 4.02×10‐7),
PDHA2
(P = 2.76×10‐7),
GOLGA1
(P = 1.72×10‐7),
CYLD
(P = 1.84×10‐7), and
RP11‐243M5.4
(P = 1.37×10‐7). PSEN1 missense mutation G206A (rs63750082) previously associated with early onset AD in the CH group, was significantly associated with late onset AD in the same population (P = 1.58×10‐13). SWS association of AD with
APOE
was observed in all groups. Significant associations were also observed with variants in
SERPINB8
(P = 3.77×10‐9) and
FAM171A
(P = 7.20×10‐7) in EAs and
TLR4
(P = 4.58×10‐7) in CH. Associations with several top‐ranked variants were replicated in the Alzheimer’s Disease Genetics Consortium GWAS dataset that were imputed using the TOPMed reference panel and ADSP 5K WGS dataset.
Conclusion
We demonstrated that merging WGS and WES datasets can increase power to detect associations with rare coding variants in genes including ones previously implicated in AD (
CYLD
and TLR4) and early‐onset stroke (
CECR1
).
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