Dataset Information

Delineating the Common Biological Pathways Perturbed by ASD's Genetic Etiology: Lessons from Network-Based Studies.

ABSTRACT: In recent decades it has become clear that Autism Spectrum Disorder (ASD) possesses a diverse and heterogeneous genetic etiology. Aberrations in hundreds of genes have been associated with ASD so far, which include both rare and common variations. While one may expect that these genes converge on specific common molecular pathways, which drive the development of the core ASD characteristics, the task of elucidating these common molecular pathways has been proven to be challenging. Several studies have combined genetic analysis with bioinformatical techniques to uncover molecular mechanisms that are specifically targeted by autism-associated genetic aberrations. Recently, several analysis have suggested that particular signaling mechanisms, including the Wnt and Ca²⁺/Calmodulin-signaling pathways are often targeted by autism-associated mutations. In this review, we discuss several studies that determine specific molecular pathways affected by autism-associated mutations, and then discuss more in-depth into the biological roles of a few of these pathways, and how they may be involved in the development of ASD. Considering that these pathways may be targeted by specific pharmacological intervention, they may prove to be important therapeutic targets for the treatment of ASD.

SUBMITTER: Oron O

PROVIDER: S-EPMC5412412 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Delineating the Common Biological Pathways Perturbed by ASD's Genetic Etiology: Lessons from Network-Based Studies.

Oron Oded O Elliott Evan E

International journal of molecular sciences 20170414 4

In recent decades it has become clear that Autism Spectrum Disorder (ASD) possesses a diverse and heterogeneous genetic etiology. Aberrations in hundreds of genes have been associated with ASD so far, which include both rare and common variations. While one may expect that these genes converge on specific common molecular pathways, which drive the development of the core ASD characteristics, the task of elucidating these common molecular pathways has been proven to be challenging. Several studie ...[more]

PMID: 28420080

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Project description:BackgroundSubstantial research has investigated the adverse effects of traffic-related air pollutants (TRAP) on human health. Convincing associations between TRAP and respiratory and cardiovascular diseases are known, but the underlying biological mechanisms are not well established. High-resolution metabolomics (HRM) is a promising platform for untargeted characterization of molecular mechanisms between TRAP and health indexes.ObjectivesWe examined metabolic perturbations associated with short-term exposures to TRAP, including carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), fine particulate matter (PM2.5), organic carbon (OC), and elemental carbon (EC) among 180 participants of the Center for Health Discovery and Well-Being (CHDWB), a cohort of Emory University-affiliated employees.MethodsA cross-sectional study was conducted on baseline visits of 180 CHDWB participants enrolled during 2008-2012, in whom HRM profiling was determined in plasma samples using liquid chromatography-high-resolution mass spectrometry with positive and negative electrospray ionization (ESI) modes. Ambient pollution concentrations were measured at an ambient monitor near downtown Atlanta. Metabolic perturbations associated with TRAP exposures were assessed following an untargeted metabolome-wide association study (MWAS) framework using feature-specific Tobit regression models, followed by enriched pathway analysis and chemical annotation.ResultsSubjects were predominantly white (76.1%) and non-smokers (95.6%), and all had at least a high school education. In total, 7821 and 4123 metabolic features were extracted from the plasma samples by the negative and positive ESI runs, respectively. There are 3421 features significantly associated with at least one air pollutant by negative ion mode, and 1691 features by positive ion mode. Biological pathways enriched by features associated with the pollutants are primarily involved in nucleic acids damage/repair (e.g., pyrimidine metabolism), nutrient metabolism (e.g., fatty acid metabolism), and acute inflammation (e.g., histidine metabolism and tyrosine metabolism). NO2 and EC were associated most consistently with these pathways. We confirmed the chemical identity of 8 metabolic features in negative ESI and 2 features in positive ESI, including metabolites closely linked to oxidative stress and inflammation, such as histamine, tyrosine, tryptophan, and proline.ConclusionsWe identified a range of ambient pollutants, including components of TRAP, associated with differences in the metabolic phenotype among the cohort of 180 subjects. We found Tobit models to be a robust approach to handle missing data among the metabolic features. The results were encouraging of further use of HRM and MWAS approaches for characterizing molecular mechanisms underlying exposure to TRAP.

Dataset Information

Delineating the Common Biological Pathways Perturbed by ASD's Genetic Etiology: Lessons from Network-Based Studies.

Publications

Delineating the Common Biological Pathways Perturbed by ASD's Genetic Etiology: Lessons from Network-Based Studies.

Similar Datasets

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