Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer's Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers

It was recently suggested that beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) functions as an amyloid beta (A beta)-degrading enzyme; in addition to its better understood role as an APP secretase. Due to this finding we sought to understand the possible genetic risk contributed by the BACE2 locus to the development of late-onset Alzheimer's disease (AD). In this study, we report that common single nucleotide polymorphism (SNP) variation in BACE2 is associated with altered AD risk in apolipoprotein E gene (APOE) epsilon 4 variant (e4) non-carriers. In addition, in e4 non-carriers diagnosed with AD or mild cognitive impairment (MCI), SNPs within the BACE2 locus are associated with cerebrospinal fluid (CSF) levels of A beta 1-42. Further, SNP variants in BACE2 are also associated with BACE2 RNA expression levels suggesting a potential mechanism for the CSF A beta 1-42 findings. Lastly, overexpression of BACE2 in vitro resulted in decreased A beta 1-40 and A beta 1-42 fragments in a cell line model of A beta production. These findings suggest that genetic variation at the BACE2 locus modifies AD risk for those individuals who don't carry the e4 variant of APOE. Further, our data indicate that the biological mechanism associated with this altered risk is linked to amyloid generation or clearance possibly through BACE2 expression changes.National Institute on Aging (NIA); National Alzheimer's Coordinating Center (NACC) [U01 AG016976]; National Institute on Aging: Ruth Seemann, John Hopkins Alzheimer's Disease Research Center (NIA) [AG05146, P50 AG16570, AG05128]; NINDS [NS39764]; Glaxo Smith Kline [P50-AG053760, AG05144, P50AG05681, P50 AG05136, P30-AG13846, 211002]; Arizona Biomedical Research Commission [4001, 0011, 05_ 901]; Michael J. Fox Foundation [AG10161, HHSN-271-2013-00030C]; McGowan Endowment; Medical Research Council, local NHS trusts and Newcastle University; Medical Research Council; Safa Al-Sarraj; Netherlands Brain Bank; Stichting MS Research, Brain Net Europe; Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds; Internationale Stiching Alzheimer Onderzoek; NIH-NIA [R01-AG041232]; State of Arizona DHS (Arizona Alzheimer's Consortium) - NIH EUREKA [R01-AG034504]; NIH intramural funds; UK Dementia Research Institute; DRI Ltd - UK Medical Research Council; Alzheimer's Society; Alzheimer's Research UK - Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Alzheimer'sAssociation; Alzheimer's Drug Discovery Foundation; Araclon Biotech; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd; Fujirebio; Johnson & Johnson Pharmaceutical Research & Development LLC.; Merck Co., Inc.; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Takeda Pharmaceutical Company; Canadian Institutes of Health Research isproviding funds; ADNI clinical sites in Canada; Foundation for the National Institutes of Health; Northern California Institute for Research and Education; Laboratory for Neuro Imaging at the University of Southern CaliforniaOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk

We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes

Congenital myasthenic syndrome caused by a frameshift insertion mutation in

Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families. Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed. Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology. Conclusions: These results expand on the spectrum of known loss-of-function GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD

Parent-reported child appetite moderates relationships between child genetic obesity risk and parental feeding practices

BackgroundFood parenting practices are associated with child weight. Such associations may reflect the effects of parents' practices on children's food intake and weight. However, longitudinal, qualitative, and behavioral genetic evidence suggests these associations could, in some cases, reflect parents' response to children's genetic risk for obesity, an instance of gene–environment correlation. We tested for gene–environment correlations across multiple domains of food parenting practices and explored the role of parent-reported child appetite in these relationships.Materials and methodsData on relevant variables were available for N = 197 parent–child dyads (7.54 ± 2.67 years; 44.4% girls) participating in RESONANCE, an ongoing pediatric cohort study. Children's body mass index (BMI) polygenic risk score (PRS) were derived based on adult GWAS data. Parents reported on their feeding practices (Comprehensive Feeding Practices Questionnaire) and their child's eating behavior (Child Eating Behavior Questionnaire). Moderation effects of child eating behaviors on associations between child BMI PRS and parental feeding practices were examined, adjusting for relevant covariates.ResultsOf the 12 parental feeding practices, 2 were associated with child BMI PRS, namely, restriction for weight control (β = 0.182, p = 0.011) and teaching about nutrition (β = −0.217, p = 0.003). Moderation analyses demonstrated that when children had high genetic obesity risk and showed moderate/high (vs. low) food responsiveness, parents were more likely to restrict food intake to control weight.ConclusionOur results indicate that parents may adjust their feeding practices in response to a child's genetic propensity toward higher or lower bodyweight, and the adoption of food restriction to control weight may depend on parental perceptions of the child's appetite. Research using prospective data on child weight and appetite and food parenting from infancy is needed to further investigate how gene–environment relationships evolve through development

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

nf-core/airrflow: nf-core/airrflow version 3.2.0 "Expecto patronum"

<h2>[3.2.0] - 2023-10-27 Expecto patronum</h2> <h3><code>Added</code></h3> <ul> <li><a href="https://github.com/nf-core/airrflow/pull/268">#268</a> Added parameters for FindThreshold in <code>modules.config</code>.</li> <li><a href="https://github.com/nf-core/airrflow/pull/268">#268</a> Validate samplesheet also for <code>assembled</code> samplesheet.</li> <li><a href="https://github.com/nf-core/airrflow/pull/259">#259</a> Update to <code>EnchantR v0.1.3</code>.</li> <li><a href="https://github.com/nf-core/airrflow/pull/266">#266</a> Added clonal reports tables to final report folder.</li> <li><a href="https://github.com/nf-core/airrflow/pull/266">#266</a> Added processes to include sampleID to filename in assembled workflow to keep it unique.</li> <li><a href="https://github.com/nf-core/airrflow/pull/276">#276</a> Parametrize FindThreshold Report and Presto Buildconsensus UMI.</li> <li><a href="https://github.com/nf-core/airrflow/pull/281">#281</a> Update to nf-core tools v2.10.</li> </ul> <h3><code>Fixed</code></h3> <ul> <li><a href="https://github.com/nf-core/airrflow/pull/268">#268</a> Allows for uppercase and lowercase locus in samplesheet <code>pcr_target_locus</code>.</li> <li><a href="https://github.com/nf-core/airrflow/pull/259">#259</a> Samplesheet only allows data from one species.</li> <li><a href="https://github.com/nf-core/airrflow/pull/259">#259</a> Introduced fix for a too long command with hundreds of datasets.</li> <li><a href="https://github.com/nf-core/airrflow/pull/266">#266</a> Convert samplesheet required columns to strings when needed.</li> <li><a href="https://github.com/nf-core/bcellmagic/pull/284">#284</a>: Use cached IMGT and IgBlast reference data by default.</li> </ul> <h3><code>Dependencies</code></h3> <p>| Dependency | Old version | New version | | ---------- | ----------- | ----------- | | r-enchantr | 0.1.2 | 0.1.9 | | r-alakazam | 1.2.1 | 1.3.0 | | r-shazam | 1.1.0 | 1.2.0 | | r-dowser | 1.2.0 | 2.0.0 | | fastqc | 0.11.9 | 0.12.1 |</p&gt

Memory performance is associated with education attainment: Greater influence of education in females

<p>November is national Alzheimer's Disease awareness month. Have you ever wondered how you can help the cause? We are using crowd-sourcing to study how the brain works with a simple ten minute memory game. Come and join our scientific research study at mindcrowd.org and be part of our fight against Alzheimer's and other brain diseases. Your healthy brain can help us understand what goes wrong during disease! After you complete the test you can see your results and compare yourself against other test takers.</p> <p>This figure shows several key findings from our study thus far. The data shown here is derived from approximately 20,000 test takers of all ages. We are showing three different education levels across both genders - High School degree or less, Undergraduate college degree, and Graduate degree. Note that for each gender more education is associated with higher memory performance (y-axis is test performance with higher numbers meaning better performance). In females, this effect is much more of a step-wise effect while in males the largest improvement is realized between undergraduate and graduate attainment. Secondly you can see from the figure that education attainment doesn't protect against the effect of age in memory performance (age is on the x-axis and increases from 25-85, left to right) - all education levels demonstrate an age-related decrease in performance. Lastly, you can see that males decline much more rapidly than females. This is indicated by the steeper slope of the lines in the males. So, a simple graph that demonstrates three very interesting aspects of memory performance.</p> <p>This is an actual scientific study. Please help us keep the integrity of our work high by only taking the test once and by not posting the word pairs here in the comments section. Thanks.</p> <p>NOTE FOR THE SCIENCE GEEKS - our memory task is a verbal paired associates learning paradigm. It tests a form of memory known as episodic memory. The significance of this effect in females is p < 2.2e-16 and in males it is p = 4.283e-15. The effect size for high school versus undergraduate is -7.12% in females and -3.41% in males, for undergraduate versus graduate it is -4.85% in females and -4.41% in males. The graph was made in R/ggplot2, the lines are linear fit with 95% shaded confidence intervals. The statistical analysis was performed using a multiple linear regression model that incorporated all of our other measured demographic and lifestyle variables (approximately 25 different other co-variates).</p

Between ages 18-85, men exhibit faster reaction times to a visual stimulus. Be a part of our research study into brain function at mindcrowd.org

<p>We are interested in better understanding how the brain works and we created a web-based game at mindcrowd.org with the hopes of generating the largest ever scientific study population. This plot illustrates our reaction time data analyzed by the participant’s gender. Each small “dot” represents one individual test taker (over 30,000 of them!) and they are colored with the stereotypical colors for gender. Age in years is denoted on the x-axis and on the y-axis is the median reaction time in milliseconds. The reaction time test has very simple rules – when a figure appears on the screen each test taker is asked to hit the enter key. It directly tests the connections between the test taker’s eyes-brain-finger. This is of general interest to neuroscientists because it is a question of basic connectivity, or neuronal “wiring”, in the body. We are interested in what influences this, and many other features of our brain and nervous system. Note from the data that the genders are separated in reaction time response by an average of approximately 20 milliseconds across the entire studied age spectrum from 18-85 (the lines are the mean response time with the bordering shaded areas reflecting the 95% confidence intervals for the measurement). This suggests that the male and female “wiring system” for this particular task is different. The reason why is a topic for another discussion… in the meantime please come and spend just 10 minutes at our research study site and join the MindCrowd! Visit us at mindcrowd.org and help us spread the word via your social network. Our goal is an ambitious one – to reach 1 million test takers! Help us please!</p

The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats

Enzastaurin is a Protein Kinase C-beta selective inhibitor that was developed to treat cancers. Protein Kinase C-beta is an important enzyme for a variety of neuronal functions; in particular, previous rodent studies have reported deficits in spatial and fear-conditioned learning and memory with lower levels of Protein Kinase C-beta. Due to Enzastaurin's mechanism of action, the present study investigated the consequences of Enzastaurin exposure on learning and memory in 12-month-old Fischer-344 male rats. Rats were treated daily with subcutaneous injections of either vehicle or Enzastaurin, and behaviorally tested using the spatial reference memory Morris Water Maze. Rats treated with Enzastaurin exhibited decreased overnight retention and poorer performance on the latter testing day, indicating a mild, but significant, memory impairment. There were no differences during the probe trial indicating that all animals were able to spatially localize the platform to the proper quadrant by the end of testing. RNA isolated from the hippocampus was analyzed using Next Generation Sequencing (lllumina). No statistically significant transcriptional differences were noted. Our findings suggest that acute Enzastaurin treatment can impair hippocampal-based learning and memory performance, with no effects on transcription in the hippocampus. We propose that care should be taken in future clinical trials that utilize Protein Kinase C-SS inhibitors, to monitor for possible cognitive effects, future research should examine if these effects are fully reversible.NIH-NINDS [R01-NS059873]; State of Arizona DHSOpen access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]