Human coronavirus NL63 nsp1 induces degradation of RNA polymerase II to inhibit host protein synthesis.

Coronavirus (CoV) nonstructural protein 1 (nsp1) is considered a pathogenic factor due to its ability to inhibit host antiviral responses by inducing general shutoff of host protein synthesis. Nsp1 is expressed by α- and ß-CoVs, but its functions and strategies to induce host shutoff are not fully elucidated. We compared the nsp1s from two ß-CoVs (SARS-CoV and SARS-CoV-2) and two α-CoVs (NL63 and 229E) and found that NL63 nsp1 has the strongest shutoff activity. Unlike SARS-CoV nsp1s, which bind to 40S ribosomes and block translation of cellular mRNA, NL63 nsp1 did not inhibit translation of mRNAs transfected into cells. Instead, NL63 nsp1 localized to the nucleus and specifically inhibited transcription of genes under an RNA polymerase II (RNAPII) promoter. Further analysis revealed that NL63 nsp1 induces degradation of the largest subunit of RNAPII, Rpb1. This degradation was detected regardless of the phosphorylation state of Rpb1 and was blocked by the proteasome inhibitor MG132. We also found that Rpb1 was ubiquitinated in NL63-infected cells, and inhibition of ubiquitination by a ubiquitin activating enzyme inhibitor (TAK243) prevented degradation of Rpb1 in virus-infected cells. These data reveal an unrecognized strategy of host shutoff by human α-CoV NL63: targeting host transcription by inducing Rpb1 degradation to prevent host protein expression. Our study indicates that viruses within the same family can use completely distinct mechanisms to regulate host antiviral responses.

A Ten Year Experience of Men's Health Events in a Socioeconomically Diverse City in the United States - Lessons Learned.

Community-based health events provide an opportunity to increase knowledge, awareness, and screening for acute and chronic diseases among individuals living in a socioeconomically diverse community. Because there are limited reports of such events, here we describe our ten-year experience of annual men's health fairs. This retrospective study of the Michigan Institute of Urology Foundation evaluated Men's Health Events held in Detroit, Michigan, from 2012 to 2021. Over 10 years, 11,129 men were screened and > 100,000 screenings were performed. The majority of the attendees were African-American men (61%), had a college degree (67%) or a high school diploma (26%), and had an annual income of <$35K (47%) or $35-60 K (30%). From 2012 to 2021, participants who saw a doctor in the past year rose from 62 to 70%; the median age of men rose from 52 to 58; their median testosterone levels increased from 353 ng/dL to 412 ng/dL, and men with concerning prostate-specific antigen values (≥ 4 ng/mL) doubled from 5% to 10%. Among participants, 59% had cholesterol levels of < 200 mg/dL, 28% of 200-240 mg/dL, and 13% of > 240 mg/dL; 7% had glucose levels of < 70 mg/dL, 68% of 70-105 mg/dL, and 25% of > 105 mg/dL ; 24% had ≥ 140 mmHg systolic and 18% had ≥ 90 mmHg diastolic blood pressure. Our findings suggest that community health events are successful at attracting and screening diverse community members. Such events should emphasize screening of high-risk individuals for acute and chronic diseases and promote other health-related behaviors.

Human parainfluenza virus type 1 regulates cholesterol biosynthesis and establishes quiescent infection in human airway cells.

Human parainfluenza virus type 1 (hPIV1) and 3 (hPIV3) cause seasonal epidemics, but little is known about their interaction with human airway cells. In this study, we determined cytopathology, replication, and progeny virion release from human airway cells during long-term infection in vitro. Both viruses readily established persistent infection without causing significant cytopathic effects. However, assembly and release of hPIV1 rapidly declined in sharp contrast to hPIV3 due to impaired viral ribonucleocapsid (vRNP) trafficking and virus assembly. Transcriptomic analysis revealed that both viruses induced similar levels of type I and III IFNs. However, hPIV1 induced specific ISGs stronger than hPIV3, such as MX2, which bound to hPIV1 vRNPs in infected cells. In addition, hPIV1 but not hPIV3 suppressed genes involved in lipid biogenesis and hPIV1 infection resulted in ubiquitination and degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate limiting enzyme in cholesterol biosynthesis. Consequently, formation of cholesterol-rich lipid rafts was impaired in hPIV1 infected cells. These results indicate that hPIV1 is capable of regulating cholesterol biogenesis, which likely together with ISGs contributes to establishment of a quiescent infection.

Suitability of Automated Writing Measures for Clinical Trial Outcome in Writer's Cramp.

BACKGROUND: Writer's cramp (WC) dystonia is a rare disease that causes abnormal postures during the writing task. Successful research studies for WC and other forms of dystonia are contingent on identifying sensitive and specific measures that relate to the clinical syndrome and achieve a realistic sample size to power research studies for a rare disease. Although prior studies have used writing kinematics, their diagnostic performance remains unclear. OBJECTIVE: This study aimed to evaluate the diagnostic performance of automated measures that distinguish subjects with WC from healthy volunteers. METHODS: A total of 21 subjects with WC and 22 healthy volunteers performed a sentence-copying assessment on a digital tablet using kinematic and hand recognition softwares. The sensitivity and specificity of automated measures were calculated using a logistic regression model. Power analysis was performed for two clinical research designs using these measures. The test and retest reliability of select automated measures was compared across repeat sentence-copying assessments. Lastly, a correlational analysis with subject- and clinician-rated outcomes was performed to understand the clinical meaning of automated measures. RESULTS: Of the 23 measures analyzed, the measures of word legibility and peak accelerations distinguished subjects with WC from healthy volunteers with high sensitivity and specificity and demonstrated smaller sample sizes suitable for rare disease studies, and the kinematic measures showed high reliability across repeat visits, while both word legibility and peak accelerations measures showed significant correlations with the subject- and clinician-rated outcomes. CONCLUSIONS: Novel automated measures that capture key aspects of the disease and are suitable for use in clinical research studies of WC dystonia were identified. © 2022 International Parkinson and Movement Disorder Society.

The Duke Myasthenia Gravis Clinic Registry: II. Analysis of outcomes.

INTRODUCTION/AIMS: The Duke Myasthenia Gravis (MG) Clinic Registry contains comprehensive physician-derived data on patients with MG seen in the Duke MG Clinic since 1980. The aim of this study was to report outcomes in patients seen in the clinic and treated according to the International Consensus Guidance statements. METHODS: This is a retrospective cohort study of patients initially seen after 2000 and followed for at least 2 years in the clinic. Treatment goal (TG) was defined as achieving MGFA post-intervention status of "minimal manifestations" or better; PIS was determined by the treating neurologist. Time-to-event analysis, including Cox proportional hazards modeling, was performed to assess the effect of sex, acetylcholine receptor antibody (AChR-Ab) status, age at disease onset, distribution (ocular vs generalized), thymectomy, and thymoma on the time to achieve TG. RESULTS: Among the 367 cohort patients, 72% achieved TG (median time less than 2 years). A greater proportion of patients with AChR-Abs and thymectomy achieved TG and they did so sooner than patients without these antibodies or thymectomy. Otherwise, there were no significant differences in these findings within the tested subgroups. The disease duration at the first Duke Clinic visit was shorter in patients who achieved TG than in those who did not. DISCUSSION: These results demonstrate outcomes that can be achieved in patients with MG treated according to the current Consensus Guidance statements. Among other things, they can be used to determine the added value and potential role of new treatment modalities developed since 2018.

Bioinformatics pipeline to guide post-GWAS studies in Alzheimer's: A new catalogue of disease candidate short structural variants.

BACKGROUND: Short structural variants (SSVs), including insertions/deletions (indels), are common in the human genome and impact disease risk. The role of SSVs in late-onset Alzheimer's disease (LOAD) has been understudied. In this study, we developed a bioinformatics pipeline of SSVs within LOAD-genome-wide association study (GWAS) regions to prioritize regulatory SSVs based on the strength of their predicted effect on transcription factor (TF) binding sites. METHODS: The pipeline utilized publicly available functional genomics data sources including candidate cis-regulatory elements (cCREs) from ENCODE and single-nucleus (sn)RNA-seq data from LOAD patient samples. RESULTS: We catalogued 1581 SSVs in candidate cCREs in LOAD GWAS regions that disrupted 737 TF sites. That included SSVs that disrupted the binding of RUNX3, SPI1, and SMAD3, within the APOE-TOMM40, SPI1, and MS4A6A LOAD regions. CONCLUSIONS: The pipeline developed here prioritized non-coding SSVs in cCREs and characterized their putative effects on TF binding. The approach integrates multiomics datasets for validation experiments using disease models.

A Bayesian perspective on Biogen's aducanumab trial.

This perspective is a companion to a recent editorial on the use of Bayesian analysis in clinical research. We aim to introduce and highlight the relevance and advantages that Bayesian inference offers to clinical trials using the data on the amyloid antibody aducanumab presented at a Food and Drug Administration hearing in November 2020 as an applied example. We apply Bayesian analysis of model plausibility and effect sizes based on simulated data of the two phase 3 trials of aducanumab in prodromal and mild dementia stages of Alzheimer's disease (AD). Bayesian analysis can quantify evidence in favor of, or against, the presence of an effect (i.e., provide evidence of absence), as well as assess the strength of the effect. This is in contrast to the binary conclusions provided by frequentist tests.

Clinical research in dementia: A perspective on implementing innovation.

The increasing global prevalence of dementia demands concrete actions that are aimed strategically at optimizing processes that drive clinical innovation. The first step in this direction requires outlining hurdles in the transition from research to practice. The different parties needed to support translational processes have communication mismatches; methodological gaps hamper evidence-based decision-making; and data are insufficient to provide reliable estimates of long-term health benefits and costs in decisional models. Pilot projects are tackling some of these gaps, but appropriate methods often still need to be devised or adapted to the dementia field. A consistent implementation perspective along the whole translational continuum, explicitly defined and shared among the relevant stakeholders, should overcome the "research-versus-adoption" dichotomy, and tackle the implementation cliff early on. Concrete next steps may consist of providing tools that support the effective participation of heterogeneous stakeholders and agreeing on a definition of clinical significance that facilitates the selection of proper outcome measures.

Microstructure and Properties of Atmospheric Plasma Sprayed (Al,Cr)2O3-TiO2 Coatings from Blends.

Coatings prepared from chromia-rich (Al,Cr)2O3 solid solution (ss) feedstock powders are intended to improve the properties of Cr2O3 coatings, but are rarely studied so far. In this work, the processability of a commercial (Al,Cr)2O3 solid solution (ss) powder containing 78 wt.% Cr2O3 by atmospheric plasma spraying (APS), the corresponding coating microstructures and properties were investigated. Possible further improvements were expected by blending with 2, 23 and 54 wt.% TiOx powder. For comparison, plain Cr2O3 and TiOx coatings were studied as well. The microstructures were analyzed using SEM, EDS and XRD measurements. Hardness (HV0.3) was measured, as well as the dry unidirectional sliding wear resistance and the abrasion wear resistance (ASTM G65). Moreover, the corrosion and electrical insulating properties were measured. The (Al,Cr)2O3 ss showed only a small change of the composition, and the formation of γ-Al2O3, as found for alumina-rich (Al,Cr)2O3 ss powders, was avoided. Compared to the plain chromia coating, some improvements of the processability and coating properties for the ss (Al,Cr)2O3 coating were found. The most balanced coating performance was achieved by blending the ss (Al,Cr)2O3 with 2 wt.% TiOx, as this coating showed both a high sliding and abrasion wear resistance, in combination with a high corrosion resistance.

Statistical inference for natural language processing algorithms with a demonstration using type 2 diabetes prediction from electronic health record notes.

The pointwise mutual information statistic (PMI), which measures how often two words occur together in a document corpus, is a cornerstone of recently proposed popular natural language processing algorithms such as word2vec. PMI and word2vec reveal semantic relationships between words and can be helpful in a range of applications such as document indexing, topic analysis, or document categorization. We use probability theory to demonstrate the relationship between PMI and word2vec. We use the theoretical results to demonstrate how the PMI can be modeled and estimated in a simple and straight forward manner. We further describe how one can obtain standard error estimates that account for within-patient clustering that arises from patterns of repeated words within a patient's health record due to a unique health history. We then demonstrate the usefulness of PMI on the problem of predictive identification of disease from free text notes of electronic health records. Specifically, we use our methods to distinguish those with and without type 2 diabetes mellitus in electronic health record free text data using over 400 000 clinical notes from an academic medical center.

TOMM40-APOE haplotypes are associated with cognitive decline in non-demented Blacks.

INTRODUCTION: The goal was to investigate effects of APOE-TOMM40-'523 haplotypes on cognitive decline in non-demented non-Hispanic Blacks (NHB), and determine whether effects differ from non-Hispanic Whites (NHW). METHODS: The impact of zero to two copies of the '523-Short variant (S; poly-T alleles < 20) within apolipoprotein E (APOE) genotype on a composite measure of global cognition and five domains was examined. RESULTS: In NHB with ε3/ε3 (N = 294), '523-S/S was associated with faster decline in global cognition (ß = -0.048, P = 0.017), episodic memory (ß = -0.05, P = 0.031), and visuospatial ability (ß = -0.037, P = 0.034) relative to those without '523-S. For NHB ε4+ (N = 182), '523-S/S had slower decline in global cognition (ß = 0.047, P = 0.042) and visuospatial ability (ß = 0.07, P = 0.0005) relative to '523-S non-carriers. NHB ε4+ with '523-S also had a slower rate of decline than NHWs ε4+ with '523-S. DISCUSSION: '523-S/S has a different effect on cognitive decline among NHB dependent on APOE allele. Differences in the effect of ε4-'523-S in NHB may explain prior mixed findings on ε4 and decline in this population.

Likelihood ratio statistics for gene set enrichment in Alzheimer's disease pathways.

INTRODUCTION: The study of Alzheimer's disease (AD) has revealed biological pathways with implications for disease neuropathology and pathophysiology. These pathway-level effects may also be mediated by individual characteristics or covariates such as age or sex. Evaluation of AD biological pathways in the context of interactions with these covariates is critical to the understanding of AD as well as the development of model systems used to study the disease. METHODS: Gene set enrichment methods are powerful tools used to interpret gene-level statistics at the level of biological pathways. We introduce a method for quantifying gene set enrichment using likelihood ratio-derived test statistics (gsLRT), which accounts for sample covariates like age and sex. We then use our method to test for age and sex interactions with protein expression levels in AD and to compare the pathway results between human and mouse species. RESULTS: Our method, based on nested logistic regressions is competitive with the existing standard for gene set testing in the context of linear models and complex experimental design. The gene sets we identify as having a significant association with AD-both with and without additional covariate interactions-are validated by previous studies. Differences between gsLRT results on mouse and human datasets are observed. DISCUSSION: Characterizing biological pathways involved in AD builds on the important work involving single gene drivers. Our gene set enrichment method finds pathways that are significantly related to AD while accounting for covariates that may be relevant to disease development. The method highlights commonalities and differences between human AD and mouse models, which may inform the development of higher fidelity models for the study of AD.

A Triage Model for Interhospital Transfers of Low Risk Intracerebral Hemorrhage Patients.

OBJECTIVES: Intracerebral hemorrhage comprises a large proportion of inter-hospital transfers to comprehensive stroke centers from centers without comprehensive stroke center resources despite lack of mortality benefit and low comprehensive stroke center resource utilization. The subset of patients who derive the most benefit from inter-hospital transfers is unclear. Here, we create a triage model to identify patients who can safely avoid transfer to a comprehensive stroke center. MATERIALS AND METHODS: A retrospective cohort of spontaneous intracerebral hemorrhage patients transferred to our comprehensive stroke center from surrounding centers was used. Patients with early discharge from the Neuroscience Intensive Care Unit without use of comprehensive stroke center resources were identified as low risk, non-utilizers. Variables associated with this designation were used to develop and validate a triage model. RESULTS: The development and replication cohorts comprised 358 and 99 patients respectively, of whom 78 (22%) and 26 (26%) were low risk, non-utilizers. Initial Glasgow Coma Scale and baseline hemorrhage volume were associated with low risk, non-utilizers in multivariate analysis. Initial Glasgow Coma Scale >13, intracerebral hemorrhage volume <15ml, absence of intraventricular hemorrhage, and supratentorial location had an area under curve, specificity, and sensitivity of 0.72, 91.4%, 52.6%, respectively, for identifying low risk, non-utilizers, and 0.75, 84.9%, 65.4%, respectively, in the replication cohort. CONCLUSIONS: Spontaneous intracerebral hemorrhage patients with Glasgow Coma Scale >13, intracerebral hemorrhage volume <15 ml, absence of intraventricular hemorrhage, and supratentorial location might safely avoid inter-hospital transfer to a comprehensive stroke center. Validation in a prospective, multicenter cohort is warranted.

Changes in the Coating Composition Due to APS Process Conditions for Al2O3-Cr2O3-TiO2 Ternary Powder Blends.

Thermally sprayed coatings from the single oxides and binary compositions of the Al2O3-Cr2O3-TiO2 system show multifunctional properties. Ternary compositions are promising for further improvement in their performance. The stability of the composition during coating formation is an important issue for blended feedstock powders in order to obtain the desired properties. This work focuses on the compositional changes of a ternary blend of Al2O3, Cr2O3 and TiOx powders of equal content by mass in a conventional atmospheric plasma spraying (APS) process using an Ar/H2 plasma gas mixture. By increasing the argon flow rate at constant hydrogen flow rate, the total plasma gas flow rate and the Ar/H2 ratio were varied. For the highest argon flow rate, this resulted in an average particle velocity of 140% and an average particle temperature of 90% of the initial values, respectively. Coating composition and microstructure were studied by optical microscopy, SEM, including EDS analyses, and XRD. In addition, the coating hardness and electrical impedance were also measured. Differences in the "difficulty of melting factor" (DMF) and the thermal diffusivity of the three oxides appear to be responsible for the dramatic change of the coating composition with an increasing argon flow rate. For the highest argon flow rate applied, besides TiO2, the coating contains only 8 wt.% Al2O3, while the Cr2O3 content remained almost constant. At the same time, the change of the Ar/H2 ratio resulted in the formation of stoichiometric TiO2 in the coating by oxidation of TiOx in the feedstock powder. Moreover, a small content of titanium was found in the Cr2O3 splats, showing that there are only limited interactions between the large oxide powder particles. Thus, the study has shown that stability of the chemical composition during spraying of ternary powder blends is strongly influenced by the process conditions.

The association between neighborhood socioeconomic status, cardiovascular and cerebrovascular risk factors, and cognitive decline in the Health and Retirement Study (HRS).

Background: A small but growing body of evidence supports a relationship between neighborhood socioeconomic status (NSES) and cognitive decline. Additional work is needed to characterize this relationship controlling for risk factors such as cardiovascular, cerebrovascular, and genetic risk factors.Methods: Cognitive decline was assessed in association with NSES, and cardiovascular and cerebrovascular risk factors (heart disease, diabetes, hypertension, and stroke) in 8,198 individuals from the 1992-2010 waves of the Health and Retirement Study (HRS). Latent class trajectory analysis determined the number of cognitive trajectory classes that best fit the data, and a multinomial logistic regression model in the latent class framework assessed the risk for cognitive classes conferred by NSES index score and heart disease, diabetes, hypertension, and stroke across three trajectory classes of cognitive function. The analyses controlled for genetic risk for cognitive decline (including APOE genotype) and demographic variables, including education.Results: The HRS sample was 57.6% female and 85.5% White, with a mean age of 67.5(3.5) years at baseline. The three-quadratic-class model best fit the data, where higher classes represented better cognitive function. Those with better cognitive function were mainly younger white females. Those in the highest quartile of NSES had 57% higher odds of being in the high cognitive function class. Heart disease, diabetes, hypertension, and stroke each increased the odds having of lower cognitive function.Conclusions: In examining the relationship of cognitive status with various variables, neighborhood socioeconomic status, cardiovascular risk, and cerebrovascular risk persisted across the cognitive trajectory classes.

Delayed stabilisation of dynamically unstable syndesmotic injuries results in worse functional outcomes.

PURPOSE: Patients with primarily ligamentous injuries of the distal tibiofibular joint comprise up to 12% of all ankle sprains. Patients frequently present late after a syndesmosis injury and delayed treatment potentially leads to pain, prolonged disability and arthritis in the long term. This study aimed to assess clinical outcomes in patients who required syndesmosis fixation in the presence of arthroscopically proven instability, the hypothesis being that a delay to treatment would be associated with worse function. METHOD: A retrospective cohort study was performed of patients with dynamic instability requiring fixation between the years of 2010-2016. The procedures were performed by two foot and ankle fellowship trained orthopaedic surgeons, over three hospital sites. Patients were classified into three groups based on the time since injury to surgery, acute syndesmotic injury (< 6 weeks), sub-acute (6 weeks-6 months) and chronic syndesmotic injury (> 6 months). Functional scores were retrospectively collected using the Foot and Ankle Outcome Score (FAOS). RESULTS: Compared to patients with acute injuries, those with chronic injuries had significantly lower FAOS subscales (p < 0.001), with the greatest difference in quality of life (- 20.7, 95% CI - 31.6 to - 9.8, p = 0.012). There was a mean follow-up of 4.3 years. Although the average FAOS subscales in those with sub-acute injuries were lower than in those with acute injuries, the difference was not statistically significant. CONCLUSION: The results of this study suggest that delayed surgical stabilisation (> 6 months) is associated with significantly worse clinical function, and thus timely identification and early referral of those patients with potentially unstable syndesmotic injuries is recommended. LEVEL OF EVIDENCE: Level III.

Shared genetic etiology underlying late-onset Alzheimer's disease and posttraumatic stress syndrome.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies. METHODS: We performed genetic pleiotropy analysis using LOAD and PTSD genome-wide association study (GWAS) datasets from white and African-American populations, followed by functional-genomic analyses. RESULTS: We found an enrichment for LOAD across increasingly stringent levels of significance with the PTSD GWAS association (LOAD|PTSD) in the discovery and replication cohorts and a modest enrichment for the reverse conditional association (PTSD|LOAD). LOAD|PTSD association analysis identified and replicated the MS4A genes region. These genes showed similar expression pattern in brain regions affected in LOAD, and across-brain-tissue analysis identified a significant association for MS4A6A. The African-American samples showed moderate enrichment; however, no false discovery rate-significant associations. DISCUSSION: We demonstrated common genetic signatures for LOAD and PTSD and suggested immune response as a common pathway for these diseases.

MRI for high ankle sprains with an unstable syndesmosis: posterior malleolus bone oedema is common and time to scan matters.

PURPOSE: Early clinical examination combined with MRI allows accurate diagnosis of syndesmosis instability after a high ankle sprain. However, patients often present late. The aims of the current study were to describe MRI characteristics associated with syndesmosis instability and to test the hypothesis that MRI patterns would differ according to time from injury. METHODS: Over a 5-year period, 164 consecutive patients who had arthroscopically proven syndesmosis instability requiring fixation were retrospectively studied. Patients with distal fibula fractures were not included. Injuries were classified as acute in 108 patients (< 6 weeks), intermediate in 32 (6-12 weeks) and chronic in 24 patients (> 12 weeks). RESULTS: Posterior malleolus bone oedema was noted in 65 (60.2%), and posterior malleolus fracture in 17 (15.7%) of acute patients, respectively, which did not significantly differ over time. According to MRI, reported rates of posterior syndesmosis disruption significantly differed over time, observed in 101 (93.5%), 28 (87.5%) and 13 (54.2%) of acute, intermediate and chronic patients, respectively (p < 0.001). Apparent rates of PITFL injury significantly reduced with time (p < 0.001). CONCLUSIONS: MRI detected a posterior syndesmosis injury in 93.5% of patients acutely but became less reliable with time. The clinical relevance of this study is that posterior malleolus bone oedema may be the only marker of a complete syndesmosis injury and can help clinically identify those injuries which require arthroscopic assessment for instability. If suspicious of a high ankle sprain, we advocate early MRI assessment to help determine stable versus unstable injuries as MRI becomes less reliable after 12 weeks. LEVEL OF EVIDENCE: III.

A systems-based model of Alzheimer's disease.

The new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease has been developed to accelerate drug discovery and offer a common structure and language to construct new Alzheimer's disease conceptual models. However, as a "complex" disease, a model based on systems-level understanding is needed to accommodate the complex, interacting etiologic pathways and the system-level changes associated with Alzheimer's disease pathogenesis and interventions that are currently known and which will be identified in the future. To accomplish this, the evolution of the structure of the research framework itself should be encouraged.

Bioinformatics strategy to advance the interpretation of Alzheimer's disease GWAS discoveries: The roads from association to causation.

INTRODUCTION: Genome-wide association studies (GWAS) discovered multiple late-onset Alzheimer's disease (LOAD)-associated SNPs and inferred the genes based on proximity; however, the actual causal genes are yet to be identified. METHODS: We defined LOAD-GWAS regions by the most significantly associated SNP ±0.5 Mb and developed a bioinformatics pipeline that uses and integrates chromatin state segmentation track to map active enhancers and virtual 4C software to visualize interactions between active enhancers and gene promoters. We augmented our pipeline with biomedical and functional information. RESULTS: We applied the bioinformatics pipeline using three ∼1 Mb LOAD-GWAS loci: BIN1, PICALM, CELF1. These loci contain 10-24 genes, an average of 106 active enhancers and 80 CTCF sites. Our strategy identified all genes corresponding to the promoters that interact with the active enhancer that is closest to the LOAD-GWAS-SNP and generated a shorter list of prioritized candidate LOAD genes (5-14/loci), feasible for post-GWAS investigations of causality. DISCUSSION: Interpretation of LOAD-GWAS discoveries requires the integration of brain-specific functional genomic data sets and information related to regulatory activity.