Circulating Non-Coding RNAs as a Signature of Autism Spectrum Disorder Symptomatology.
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ABSTRACT:
SUBMITTER: Salloum-Asfar S
PROVIDER: S-EPMC8235321 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:More than 98% of the human genome is made up of non-coding DNA, but techniques to ascertain its contribution to human disease have lagged far behind our understanding of protein coding variations. Autism spectrum disorder (ASD) has been mostly associated with coding variations via de novo single nucleotide variants (SNVs), recessive/homozygous SNVs, or de novo copy number variants (CNVs); however, most ASD cases continue to lack a genetic diagnosis. We analyzed 187 consanguineous ASD families for biallelic CNVs. Recessive deletions were significantly enriched in affected individuals relative to their unaffected siblings (17% versus 4%, p < 0.001). Only a small subset of biallelic deletions were predicted to result in coding exon disruption. In contrast, biallelic deletions in individuals with ASD were enriched for overlap with regulatory regions, with 23/28 CNVs disrupting histone peaks in ENCODE (p < 0.009). Overlap with regulatory regions was further demonstrated by comparisons to the 127-epigenome dataset released by the Roadmap Epigenomics project, with enrichment for enhancers found in primary brain tissue and neuronal progenitor cells. Our results suggest a novel noncoding mechanism of ASD, describe a powerful method to identify important noncoding regions in the human genome, and emphasize the potential significance of gene activation and regulation in cognitive and social function.
| S-EPMC7441318 | biostudies-literature
Project description:Genetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, we first identified ASD-related lncRNAs based on genomic variant data of individuals with ASD from a twin study. In total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by an independent copy number variant (CNV) dataset. Then, the functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of their three different types of functional neighbor genes (i.e., genomic neighbors, competing endogenous RNA (ceRNA) neighbors, and gene co-expression neighbors in the cortex). The results have shown that most of the functional neighbor genes of ASD-related lncRNAs were enriched in nervous system development, inflammatory responses, and transcriptional regulation. Moreover, we explored the differential functions of ASD-related lncRNAs in distinct brain regions by using gene co-expression network analysis based on tissue-specific gene expression profiles. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. In addition, a functional network analysis was conducted for the highly reliable functional neighbor genes of ASD-related lncRNAs. We found that all the highly reliable functional neighbor genes were connected in a single functional network, which provided additional clues for the action mechanisms of ASD-related lncRNAs. Finally, we predicted several potential drugs based on the enrichment of drug-induced pathway sets in the ASD-altered biological pathway list. Among these drugs, several (e.g., amoxapine, piperine, and diflunisal) were partly supported by the previous reports. In conclusion, ASD-related lncRNAs participated in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. Detailed investigation into ASD-related lncRNAs can provide clues for developing potential ASD diagnosis biomarkers and therapy.
| S-EPMC7525012 | biostudies-literature
Project description:22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cortical thickness between 1) individuals with 22q11.2DS (n = 62) and neurotypical controls (n = 57) and 2) 22q11.2DS individuals with ASD symptomatology (n = 30) and those without (n = 25). We firstly observed significant differences in surface anatomy between 22q11.2DS individuals and controls for all 3 neuroanatomical features, predominantly in parietotemporal regions, cingulate and dorsolateral prefrontal cortices. We also established that 22q11.2DS individuals with ASD symptomatology were neuroanatomically distinct from 22q11.2DS individuals without ASD symptoms, particularly in brain regions that have previously been linked to ASD (e.g., dorsolateral prefrontal cortices and the entorhinal cortex). Our findings indicate that different clinical 22q11.2DS phenotypes, including those with ASD symptomatology, may represent different neurobiological subgroups. The spatially distributed patterns of neuroanatomical differences associated with ASD symptomatology in 22q11.2DS may thus provide useful information for patient stratification and the prediction of clinical outcomes.
| S-EPMC6644859 | biostudies-literature
Project description:BackgroundAutism spectrum disorders (ASD) manifest with neurodevelopmental phenotypes including communicative, social and behavioral impairments that affect as many as 1 in 88 children. The majority of autism cases have no known genetic cause, suggesting complex genetics of the disorder, but a few genes of large effect have been identified.MethodsIn order to identify novel ASD genetic correlates, we investigated non-protein coding RNAs (ncRNAs) which are abundantly transcribed from the human genome, enriched in the brain, and have been implicated in neurodevelopmental disorders. Using an algorithm that we developed, we examined a publicly available transcriptomics database, AceView, to identify the natural antisense transcripts (NATs) that overlap with known autism-related genes. We validated the presence and differential expression of NATs in different brain regions of ASD and control brains using qRT-PCR. Additionally, we investigated the subcellular localization of these transcripts in a neuronal cell line using RNA-sequencing (RNA-seq).ResultsWe found noncoding antisense RNA transcripts at approximately 40% of loci previously implicated in ASD. We confirmed the expression of 10 antisense RNAs in different postmortem human brain tissues. The expression of five antisense transcripts was found to be region-specific, suggesting a role for these ncRNAs in the development and function of specific brain regions. Some antisense RNAs overlapping suspected ASD genes exhibited concordant expression relative to their sense protein-coding genes, while other sense-antisense pairs demonstrate a discordant relationship. Interestingly, the antisense RNA corresponding to the SYNGAP1 locus (SYNGAP1-AS) was found to be differentially expressed in brain regions of patients with ASD compared to control individuals. RNA-seq analysis of subcellular compartments from SH-SY5Y human neuroblastoma cells demonstrated that antisense RNAs to ASD candidate genes are predominantly expressed in the nucleoplasmic or chromatin compartments, implying their involvement in nuclear-associated processes.ConclusionsOur data suggests that NATs are abundantly expressed from ASD-related loci and provide evidence for their roles in target gene regulation, neurodevelopment and autism pathogenesis. This class of RNA should therefore be considered in functional studies aimed at understanding genetic risk factors for ASD.
| S-EPMC3851999 | biostudies-literature
Project description:Novel molecular signatures are needed to improve the early and accurate diagnosis of autism spectrum disorder (ASD), and indicate physicians to provide timely intervention. This study aimed to identify a robust blood non-coding RNA (ncRNA) signature in diagnosing ASD. One hundred eighty six blood samples in the microarray dataset were randomly divided into the training set (n = 112) and validation set (n = 72). Then, the microarray probe expression profile was re-annotated into the expression profile of 4143 ncRNAs though probe sequence mapping. In the training set, least absolute shrinkage and selection operator (LASSO) penalized generalized linear model was adopted to identify the 20-ncRNA signature, and a diagnostic score was calculated for each sample according to the ncRNA expression levels and the model coefficients. The score demonstrated an excellent diagnostic ability for ASD in the training set (area under receiver operating characteristic curve [AUC] = 0.96), validation set (AUC = 0.97) and the overall (AUC = 0.96). Moreover, the blood samples of 23 ASD patients and 23 age- and gender-matched controls were collected as the external validation set, in which the signature also showed a good diagnostic ability for ASD (AUC = 0.96). In subgroup analysis, the signature was also robust when considering the potential confounders of sex, age, and disease subtypes. In comparison with a 55-gene signature deriving from the same dataset, the ncRNA signature showed an obviously better diagnostic ability (AUC: 0.96 vs 0.68, P < .001). In conclusion, this study identified a robust blood ncRNA signature in diagnosing ASD, which might help improve the diagnostic accuracy for ASD in clinical practice.
| S-EPMC7220435 | biostudies-literature
Project description:To date, the main criterion by which long ncRNAs (lncRNAs) are discriminated from mRNAs is based on the capacity of the transcripts to encode a protein. However, it becomes important to identify non-ORF-based sequence characteristics that can be used to parse between ncRNAs and mRNAs. In this study, we first established an extremely selective workflow to define a highly refined database of lncRNAs which was used for comparison with mRNAs. Then using this highly selective collection of lncRNAs, we found the CG dinucleotide frequencies were clearly distinct. In addition, we showed that the bias in CG dinucleotide frequency was conserved in human and mouse genomes. We propose that this sequence feature will serve as a useful classifier in transcript classification pipelines. We also suggest that our refined database of "bona fide" lncRNAs will be valuable for the discovery of other sequence characteristics distinct to lncRNAs.
| S-EPMC4158813 | biostudies-other
Project description:Autism spectrum disorder (ASD) refers to a heterogeneous group of complex neurodevelopmental disorders characterized by social skill and communication deficits, along with stereotyped repetitive behavior. miRNAs, small non-coding RNAs that have been recognized as critical regulators of gene expression, play a key role in the neurodevelopmental transcriptional networks of the human brain. Previous investigations have proven that circulating miRNAs open up new possibilities for the emerging roles of diagnostic and prognostic biomarkers in human disorders and diseases. Biomarker development has been progressively becoming more recognized as a cornerstone in medical diagnosis, paving the way to drug discoveries and limiting the progression of various diseases. Due to the complexity of ASD, considerable endeavors have either unsuccessfully identified biomarkers for the disorder or have not yet been established. Cell-free circulating miRNAs in biofluids are extraordinarily stable and considered to represent the next-generation of clinical, non-invasive, biomarkers for many pathologies including neurological and neurodevelopmental disorders. Here, we conducted a review of all peer-reviewed articles addressing the circulating profiles of miRNAs, mostly performed in serum and saliva samples in individuals with ASD.
| S-EPMC6808050 | biostudies-literature
Project description:Background:The endocannabinoid system (ECS) is a major regulator of synaptic plasticity and neuromodulation. Alterations of the ECS have been demonstrated in several animal models of autism spectrum disorder (ASD). In some of these models, activating the ECS rescued the social deficits. Evidence for dysregulations of the ECS in human ASD are emerging, but comprehensive assessments and correlations with disease characteristics have not been reported yet. Methods:Serum levels of the main endocannabinoids, N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), and their related endogenous compounds, arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA), were analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD (age = 13.1 ± 4.1, range 6-21; 79% boys) and 93 age- and gender-matched neurotypical children (age = 11.8 ± 4.3, range 5.5-21; 79% boys). Results were associated with gender and use of medications, and were correlated with age, BMI, and adaptive functioning of ASD participants as reflected by scores of Autism Diagnostic Observation Schedule (ADOS-2), Vineland Adaptive Behavior Scale-II (VABS-II), and Social Responsiveness Scale-II (SRS-2). Results:Children with ASD had lower levels (pmol/mL, mean ± SEM) of AEA (0.722 ± 0.045 vs. 1.252 ± 0.072, P < 0.0001, effect size 0.91), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P < 0.0001, effect size 0.94), and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P < 0.0001, effect size 0.65), but not AA and 2-AG. Serum levels of AEA, OEA, and PEA were not significantly associated or correlated with age, gender, BMI, medications, and adaptive functioning of ASD participants. In children with ASD, but not in the control group, younger age and lower BMI tended to correlate with lower AEA levels. However, these correlations were not statistically significant after a correction for multiple comparisons. Conclusions:We found lower serum levels of AEA, PEA, and OEA in children with ASD. Further studies are needed to determine whether circulating endocannabinoid levels can be used as stratification biomarkers that identify clinically significant subgroups within the autism spectrum and if they reflect lower endocannabinoid "tone" in the brain, as found in animal models of ASD.
| S-EPMC6354384 | biostudies-literature
Project description:ObjectivesWe used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome.MethodsThe study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls.ResultsAmong 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity.ConclusionsmiR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk.
| S-EPMC4277726 | biostudies-literature
Project description:This study aimed to analyse and compare the storytelling of 25 children with Autism Spectrum Disorder (ASD) with a comparison group of 25 children with typical development. Children's narratives were transcribed verbatim, and their forms and contents were analysed. The two groups were matched according to the narrative cohesion of the story using the Bears Family Projective Test, equivalent verbal age, sex, and socioeconomic level. No differences in the forms of the stories emerged, but compared with the narratives of the typical development group, the narrative contents of the ASD group showed more adaptive and maladaptive behaviours of the characters, more problems, and less use of the atmosphere outside the home. These contents are related to the intensity of the anxious symptomatology indicated by the ASD group, their family members and teachers.
| S-EPMC7153759 | biostudies-literature