Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD ...are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of β cell CFTR deletion and normal and CF human pancreas and islets. Specific deletion of CFTR from murine β cells did not affect β cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein and electrical activity were not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion, with few changes in key islet-regulatory transcripts. Furthermore, approximately 65% of β cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is caused by β cell loss and intraislet inflammation in the setting of a complex pleiotropic disease and not by intrinsic islet dysfunction from CFTR mutation.
The clinical course of multiple sclerosis (MS) is highly variable, and research data collection is costly and time consuming. We evaluated natural language processing techniques applied to electronic ...medical records (EMR) to identify MS patients and the key clinical traits of their disease course.
We used four algorithms based on ICD-9 codes, text keywords, and medications to identify individuals with MS from a de-identified, research version of the EMR at Vanderbilt University. Using a training dataset of the records of 899 individuals, algorithms were constructed to identify and extract detailed information regarding the clinical course of MS from the text of the medical records, including clinical subtype, presence of oligoclonal bands, year of diagnosis, year and origin of first symptom, Expanded Disability Status Scale (EDSS) scores, timed 25-foot walk scores, and MS medications. Algorithms were evaluated on a test set validated by two independent reviewers.
We identified 5789 individuals with MS. For all clinical traits extracted, precision was at least 87% and specificity was greater than 80%. Recall values for clinical subtype, EDSS scores, and timed 25-foot walk scores were greater than 80%.
This collection of clinical data represents one of the largest databases of detailed, clinical traits available for research on MS. This work demonstrates that detailed clinical information is recorded in the EMR and can be extracted for research purposes with high reliability.
The experimental and computational techniques for capturing information about protein structures and genetic variation within the human genome have advanced dramatically in the past 20 years, ...generating extensive new data resources. In this review, we discuss these advances, along with new approaches for determining the impact a genetic variant has on protein function. We focus on the potential of new methods that integrate human genetic variation into protein structures to discover relationships to disease, including the discovery of mutational hotspots in cancer-related proteins, the localization of protein-altering variants within protein regions for common complex diseases, and the assessment of variants of unknown significance for Mendelian traits. We expect that approaches that integratethese data sources will play increasingly important roles in disease gene discovery and variant interpretation.
Summary
Objective
Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage‐gated sodium (NaV) channels as a contributor to the ...pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability, mainly by a use‐dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity.
Methods
We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, a U.S. Food and Drug Administration (FDA)–approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2aQ54 mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting, and survival of Scn2aQ54 mice.
Results
We found that ranolazine was capable of reducing seizure frequency by approximately 50% in Scn2aQ54 mice. The more potent persistent current blocker GS967 reduced seizure frequency by >90% in Scn2aQ54 mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2aQ54 mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2aQ54 mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting.
Significance
Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and that this compound could inform development of new agents.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Background
Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is ...typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood. Prior clinical observations suggest that abnormal T-cell function may play a central role in MCD pathogenesis. Based on these observations, we hypothesized that T-cell responses to specific exposures or antigens lead to a clonal expansion of T-cell subsets, a restriction in the T-cell repertoire, and an elaboration of specific circulating factors that trigger disease onset and relapses.
Methods
To test these hypotheses, we sequenced T-cell receptors in fourteen MCD, four focal segmental glomerulosclerosis (FSGS), and four membranous nephropathy (MN) patients with clinical data and blood samples drawn during active disease and during remission collected by the Nephrotic Syndrome Study Network (NEPTUNE). We calculated several T-cell receptor diversity metrics to assess possible differences between active disease and remission states in paired samples.
Results
Median productive clonality did not differ between MCD active disease (0.0083; range: 0.0042, 0.0397) and remission (0.0088; range: 0.0038, 0.0369). We did not identify dominant clonotypes in MCD active disease, and few clonotypes were shared with FSGS and MN patients.
Conclusions
While these data do not support an obvious role of the adaptive immune system T-cells in MCD pathogenesis, further study is warranted given the limited sample size.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
.
INTRODUCTION
Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer's disease (AD) risk by independent lines of evidence. We explored this ...association by comparing the frequencies of viral species identified in a large sample of AD cases and controls.
METHODS
DNA sequence reads that did not align to the human genome in sequences were mapped to viral reference sequences, quantified, and then were tested for association with AD in whole exome sequences (WES) and whole genome sequences (WGS) datasets.
RESULTS
Several viruses were significant predictors of AD according to the machine learning classifiers. Subsequent regression analyses showed that herpes simplex type 1 (HSV‐1) (odds ratio OR = 3.71, p = 8.03 × 10−4) and human papillomavirus 71 (HPV‐71; OR = 3.56, p = 0.02), were significantly associated with AD after Bonferroni correction. The phylogenetic‐related cluster of Herpesviridae was significantly associated with AD in several strata of the data (p < 0.01).
DISCUSSION
Our results support the hypothesis that viral infection, especially HSV‐1, is associated with AD risk.
Since publication of the human genome in 2003, geneticists have been interested in risk variant associations to resolve the etiology of traits and complex diseases. The International HapMap ...Consortium undertook an effort to catalog all common variation across the genome (variants with a minor allele frequency (MAF) of at least 5% in one or more ethnic groups). HapMap along with advances in genotyping technology led to genome-wide association studies which have identified common variants associated with many traits and diseases. In 2008 the 1000 Genomes Project aimed to sequence 2500 individuals and identify rare variants and 99% of variants with a MAF of <1%.
To determine whether the 1000 Genomes Project includes all the variants in HapMap, we examined the overlap between single nucleotide polymorphisms (SNPs) genotyped in the two resources using merged phase II/III HapMap data and low coverage pilot data from 1000 Genomes.
Comparison of the two data sets showed that approximately 72% of HapMap SNPs were also found in 1000 Genomes Project pilot data. After filtering out HapMap variants with a MAF of <5% (separately for each population), 99% of HapMap SNPs were found in 1000 Genomes data.
Not all variants cataloged in HapMap are also cataloged in 1000 Genomes. This could affect decisions about which resource to use for SNP queries, rare variant validation, or imputation. Both the HapMap and 1000 Genomes Project databases are useful resources for human genetics, but it is important to understand the assumptions made and filtering strategies employed by these projects.
More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare ...variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure-based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (
,
, and
) and another suggestive gene from the ADSP WES data. For
and
, two known Alzheimer's disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes.
is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.
INTRODUCTION
Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA).
METHODS
We applied principal component analysis using Gaussian mixture models and an ...Ashkenazi Jewish (AJ) reference genome‐wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene‐based analyses were performed using aggregated rare variants.
RESULTS
In addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10−9), rs541586606 near RAB3B (p = 5.01 × 10−8), and rs760573036 between SPOCK3 and ANXA10 (p = 6.32 × 10−8). In EW analyses (1504 cases and 2047 controls), study‐wide significant association was observed with rs1003710 near SMAP2 (p = 1.91 × 10−7). A significant gene‐based association was identified with GIPR (p = 7.34 × 10−7).
DISCUSSION
Our results highlight the efficacy of founder populations for AD genetic studies.
Abstract
Most Alzheimer’s disease (AD)-associated genetic variants do not change protein coding sequence and thus likely exert their effects through regulatory mechanisms. RNA editing, the ...post-transcriptional modification of RNA bases, is a regulatory feature that is altered in AD patients that differs across ancestral backgrounds. Editing QTLs (edQTLs) are DNA variants that influence the level of RNA editing at a specific site. To study the relationship of DNA variants genome-wide, and particularly in AD-associated loci, with RNA editing, we performed edQTL analyses in self-reported individuals of African American (AF) or White (EU) race with corresponding global genetic ancestry averaging 82.2% African ancestry (AF) and 96.8% European global ancestry (EU) in the two groups, respectively. We used whole-genome genotyping array and RNA sequencing data from peripheral blood of 216 AD cases and 212 age-matched, cognitively intact controls. We identified 2144 edQTLs in AF and 3579 in EU, of which 1236 were found in both groups. Among these, edQTLs in linkage disequilibrium (r2 > 0.5) with AD-associated genetic variants in the SORL1, SPI1 and HLA-DRB1 loci were associated with sites that were differentially edited between AD cases and controls. While there is some shared RNA editing regulatory architecture, most edQTLs had distinct effects on the rate of RNA editing in different ancestral populations suggesting a complex architecture of RNA editing regulation. Altered RNA editing may be one possible mechanism for the functional effect of AD-associated variants and may contribute to observed differences in the genetic etiology of AD between ancestries.
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