30 research outputs found

    Monocyte metabolic transcriptional programs associate with resistance to tuberculin skin test/interferon-γ release assay conversion.

    Get PDF
    After extensive exposure to Mycobacterium tuberculosis (Mtb), most individuals acquire latent Mtb infection (LTBI) defined by a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA). To identify mechanisms of resistance to Mtb infection, we compared transcriptional profiles from highly exposed contacts who resist TST/IGRA conversion (resisters, RSTRs) and controls with LTBI using RNAseq. Gene sets related to carbon metabolism and free fatty acid (FFA) transcriptional responses enriched across 2 independent cohorts suggesting RSTR and LTBI monocytes have distinct activation states. We compared intracellular Mtb replication in macrophages treated with FFAs and found that palmitic acid (PA), but not oleic acid (OA), enhanced Mtb intracellular growth. This PA activity correlated with its inhibition of proinflammatory cytokines in Mtb-infected cells. Mtb growth restriction in PA-treated macrophages was restored by activation of AMP kinase (AMPK), a central host metabolic regulator known to be inhibited by PA. Finally, we genotyped AMPK variants and found 7 SNPs in PRKAG2, which encodes the AMPK-γ subunit, that strongly associated with RSTR status. Taken together, RSTR and LTBI phenotypes are distinguished by FFA transcriptional programs and by genetic variation in a central metabolic regulator, which suggests immunometabolic pathways regulate TST/IGRA conversion

    New insights into the genetic etiology of Alzheimer's disease and related dementias

    Get PDF
    Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

    Masked speech recognition and reading in children (Miller et al., 2018)

    No full text
    <div><b>Purpose: </b>The relationship between reading (decoding) skills, phonological processing abilities, and masked speech recognition in typically developing children was explored. This experiment was designed to evaluate the relationship between phonological processing and decoding abilities and 2 aspects of masked speech recognition in typically developing children: (a) the ability to benefit from temporal and spectral modulations within a noise masker and (b) the masking exerted by a speech masker.</div><div><b>Method:</b> Forty-two typically developing 3rd- and 4th-grade children with normal hearing, ranging in age from 8;10 to 10;6 years (mean age = 9;2 years, <i>SD</i> = 0.5 months), completed sentence recognition testing in 4 different maskers: steady-state noise, temporally modulated noise, spectrally modulated noise, and two-talker speech. Children also underwent assessment of phonological processing abilities and assessments of single-word decoding. As a comparison group, 15 adults with normal hearing also completed speech-in-noise testing.</div><div><b>Results: </b>Speech recognition thresholds varied between approximately 3 and 7 dB across children, depending on the masker condition. Compared to adults, performance in the 2-talker masker was relatively consistent across children. Furthermore, decreasing the signal-to-noise ratio had a more precipitously deleterious effect on children’s speech recognition in the 2-talker masker than was observed for adults. For children, individual differences in speech recognition threshold were not predicted by phonological awareness or decoding ability in any masker condition.</div><div><b>Conclusions: </b>No relationship was found between phonological awareness and/or decoding ability and a child’s ability to benefit from spectral or temporal modulations. In addition, phonological awareness and/or decoding ability was not related to speech recognition in a 2-talker masker. Last, these data suggest that the between-listeners variability often observed in 2-talker maskers for adults may be smaller for children. The reasons for this child–adult difference need to be further explored.</div><div><br></div><div><b>Supplemental Material S1. </b>Phonological processing/reading measures: children (ordering of data is consistent across Supplemental Materials S2 and S4). </div><div><br></div><div><b>Supplemental Material S2.</b> Masker condition signal recognition thresholds (SRTs, dB SNR) in children (ordering of data is consistent across Supplemental Materials S1 and S4). </div><div><br></div><div><b>Supplemental Material S3.</b> Masker condition signal recognition thresholds (SRTs, dB SNR) in adults (ordering of data is consistent with Supplemental Material S5). </div><div><br></div><div><b>Supplemental Material S4.</b> Masker condition signal recognition slopes in children (ordering of data is consistent across Supplemental Materials S1 and S2). </div><div><br></div><div><b>Supplemental Material S5.</b> Masker condition signal recognition slopes in adults (ordering of data is consistent with Supplemental Material S3). </div><div><br></div><div><b>Supplemental Material S6.</b> Least-squares (LS) means estimates of masker condition signal recognition thresholds (SRTs) in adults and children. </div><div><br></div><div><b>Supplemental Material S7.</b> Least-squares (LS) means estimates of masker condition signal recognition slopes in adults and children. </div><div><br></div><div><b>Supplemental Material S8.</b> Two-talker masker speech recognition threshold (SRT) regression results: children. </div><div><b><br></b></div><div><b>Supplemental Material S9.</b> Spectral modulation benefit regression results: children.</div><div><br></div><div><b>Supplemental Material S10. </b>Amplitude modulation benefit regression results: children.</div><div><br></div><div><b>Supplemental Material S11.</b> Steady-state noise slope regression results: children. </div><div><br></div><div>Miller, G., Lewis, B., Benchek, P., Buss, E., & Calandruccio, L. (2018). Masked speech recognition and reading ability in school-age children: Is there a relationship? <i>Journal of Speech, Language, and Hearing Research, 61, </i>776–788<i>.</i> https://doi.org/10.1044/2017_JSLHR-H-17-0279</div

    Hadoop and PySpark for reproducibility and scalability of genomic sequencing studies

    No full text
    Modern genomic studies are rapidly growing in scale, and the analytical approaches used to analyze genomic data are increasing in complexity. Genomic data management poses logistic and computational challenges, and analyses are increasingly reliant on genomic annotation resources that create their own data management and versioning issues. As a result, genomic datasets are increasingly handled in ways that limit the rigor and reproducibility of many analyses. In this work, we examine the use of the Spark infrastructure for the management, access, and analysis of genomic data in comparison to traditional genomic workflows on typical cluster environments. We validate the framework by reproducing previously published results from the Alzheimer's Disease Sequencing Project. Using the framework and analyses designed using Jupyter notebooks, Spark provides improved workflows, reduces user-driven data partitioning, and enhances the portability and reproducibility of distributed analyses required for large-scale genomic studies

    Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection

    No full text
    Tuberculosis and sarcoidosis are inflammatory diseases characterized by granulomas that may occur in any organ but are often found in the lung. The panoply of classical human leukocyte antigen (HLA) alleles associated with occurrence and/or severity of both diseases varies considerably across studies. This heterogeneity of results, due to variation in factors like ancestry and disease subphenotype, as well as the use of simple modeling strategies to elucidate likely complex relationships, has made conclusions about underlying commonalities difficult. Here we perform HLA association analyses in individuals of African ancestry, using a greater resolution to include subphenotypes of disease and employing more comprehensive analytical techniques. Using a novel application of nearest-neighbor feature selection to score allelic importance, we investigated HLA allele association with Mycobacterium tuberculosis exposure outcomes in the first analysis of both latent Mycobacterium tuberculosis infection and active disease compared with those who, despite long-term exposure to active index cases, have neither positive diagnostic tests nor display clinical symptoms. We also compared persistent to resolved sarcoidosis. This led to the identification of novel HLA associations and evidence of main effects and interaction effects. We found strikingly similar main effects and interaction effects at HLA-DRB1, -DQB1, and -DPB1 in those resistant to tuberculosis (either latent or active) and persistent sarcoidosis

    Association between genes regulating neural pathways for quantitative traits of speech and language disorders

    No full text
    Abstract Speech sound disorders (SSD) manifest as difficulties in phonological memory and awareness, oral motor function, language, vocabulary, reading, and spelling. Families enriched for SSD are rare, and typically display a cluster of deficits. We conducted a genome-wide association study (GWAS) in 435 children from 148 families in the Cleveland Family Speech and Reading study (CFSRS), examining 16 variables representing 6 domains. Replication was conducted using the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 18 significant loci (combined p < 10−8) that we pursued bioinformatically. We prioritized 5 novel gene regions with likely functional repercussions on neural pathways, including those which colocalized with differentially methylated regions in our sample. Polygenic risk scores for receptive language, expressive vocabulary, phonological awareness, phonological memory, spelling, and reading decoding associated with increasing clinical severity. In summary, neural-genetic influence on SSD is primarily multigenic and acts on genomic regulatory elements, similar to other neurodevelopmental disorders

    Methylome-wide Analysis Reveals Epigenetic Marks Associated With Resistance to Tuberculosis in Human Immunodeficiency Virus–Infected Individuals From East Africa

    No full text
    Abstract Background Tuberculosis (TB) is the most deadly infectious disease globally and is highly prevalent in the developing world. For individuals infected with both Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV), the risk of active TB is 10% or more annually. Previously, we identified in a genome-wide association study (GWAS) a region on chromosome 5 associated with resistance to TB, which included epigenetic marks that could influence gene regulation. We hypothesized that HIV-infected individuals exposed to Mtb who remain disease free carry epigenetic changes that strongly protect them from active TB. Methods We conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania and integrated data from our GWAS. Results We identified 3 regions of interest that included markers that were differentially methylated between TB cases and controls with latent TB infection: chromosome 1 (RNF220, P = 4 × 10–5), chromosome 2 (between COPS8 and COL6A3, P = 2.7 × 10–5), and chromosome 5 (CEP72, P = 1.3 × 10–5). These methylation results co-localized with associated single-nucleotide polymorphisms (SNPs), methylation QTLs, and methylation × SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung. Conclusions Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants

    Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: evidence for coevolution?

    No full text
    Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB

    Structural characterization of rare missense variants within known neurodegenerative disease proteins

    No full text
    Background Recent work suggests unexplained heritability of Alzheimer’s Disease (AD) may involve rare variants in genes implicated in other neurodegenerative disorders. However, existing gene‐based tests have insufficient power to detect true associations when neutral variants are included. Therefore, identifying variants with potentially high impact on protein function before computing gene‐based statistical associations is critical. Method We employed the Phenotype Consensus ANalysis (PCAN) approach to identify genes with Mendelian associations to neurodegenerative disorders using semantic similarity, resulting in a candidate gene list of 24 genes not associated with AD and two previously associated genes (PSEN1 and TREM2). We applied the PathProx algorithm to identify Alzheimer’s Disease Sequencing Project (ADSP) Discovery Phase variants significantly clustered with known pathogenic variants compared to benign variants within 3D protein structures. Pathogenic variants for Mendelian neurodegenerative disorders were curated from ClinVar and benign variants from ExAC. Additionally, we predicted the impact of each ADSP variant on protein stability (vs. canonical wildtype amino acid) via change in free energy of folding (∆∆G) estimated by Rosetta software. Result Out of 1,365 ADSP missense variants in 26 genes, we identified 230 that were proximal (using PathProx) to known pathogenic variants. A total of 230 variants had ∆∆G values indicating their potential to thermodynamically destabilize a protein’s structure (91 variants were also proximal to known clinical variants). Gene‐based testing using these predicted functional variants identified two novel genes (CSF1R, and SERPINI1) associated with AD risk. Finally, models for PSEN1 and TREM2 using the PathProx or ∆∆G‐identified variants remained statistically significant with similar p‐values to models using all missense variants. Conclusion We have identified subsets of missense variants likely to impact the function of proteins associated with neurodegenerative diseases in the ADSP. These annotations can be used in multiple ways, such as highlighting variant sets for use in gene‐based testing and prioritizing variants for in vitro testing. Additionally, functional characterization of rare variants using PathProx and ∆∆G could aide in in heterogeneity testing of multifactorial diseases like AD. Finally, our methodology is phenotype‐centric and applicable to other diseases with overlapping phenotypes to identify candidate genes in a variety of neurological disorders
    corecore