Genome-wide, Integrative Analysis Implicates MicroRNA Dysregulation in Autism Spectrum Disorder

Overview

Journal Nat Neurosci

Date 2016 Aug 30

PMID 27571009

Citations 108

Authors

Ye E Wu

Neelroop N Parikshak

T Grant Belgard

Daniel H Geschwind

Affiliations

Soon will be listed here.

Abstract

Genetic variants conferring risk for autism spectrum disorder (ASD) have been identified, but the role of post-transcriptional mechanisms in ASD is not well understood. We performed genome-wide microRNA (miRNA) expression profiling in post-mortem brains from individuals with ASD and controls and identified miRNAs and co-regulated modules that were perturbed in ASD. Putative targets of these ASD-affected miRNAs were enriched for genes that have been implicated in ASD risk. We confirmed regulatory relationships between several miRNAs and their putative target mRNAs in primary human neural progenitors. These include hsa-miR-21-3p, a miRNA of unknown CNS function that is upregulated in ASD and that targets neuronal genes downregulated in ASD, and hsa_can_1002-m, a previously unknown, primate-specific miRNA that is downregulated in ASD and that regulates the epidermal growth factor receptor and fibroblast growth factor receptor signaling pathways involved in neural development and immune function. Our findings support a role for miRNA dysregulation in ASD pathophysiology and provide a rich data set and framework for future analyses of miRNAs in neuropsychiatric diseases.

Citing Articles

MicroRNA Profiling Identifies Age-Associated MicroRNAs and Potential Biomarkers for Early Diagnosis of Autism.

Salloum-Asfar S, Ltaief S, Taha R, Nour-Eldine W, Abdulla S, Al-Shammari A Int J Mol Sci. 2025; 26(5).

PMID: 40076668 PMC: 11900285. DOI: 10.3390/ijms26052044.

Glycosylation Pathways Targeted by Deregulated miRNAs in Autism Spectrum Disorder.

Mirabella F, Randazzo M, Rinaldi A, Pettinato F, Rizzo R, Sturiale L Int J Mol Sci. 2025; 26(2).

PMID: 39859496 PMC: 11766332. DOI: 10.3390/ijms26020783.

Transcriptomic Evidence Reveals the Dysfunctional Mechanism of Synaptic Plasticity Control in ASD.

Kong C, Bing Z, Yang L, Huang Z, Wang W, Grebogi C Genes (Basel). 2025; 16(1).

PMID: 39858558 PMC: 11764921. DOI: 10.3390/genes16010011.

MicroRNAs as Regulators, Biomarkers, and Therapeutic Targets in Autism Spectrum Disorder.

Yao T, Chen L, Du Y, Jiang Z, Cheng Y Mol Neurobiol. 2024; 62(4):5039-5056.

PMID: 39503812 DOI: 10.1007/s12035-024-04582-x.

Autism spectrum disorder: difficulties in diagnosis and microRNA biomarkers.

Martinez B, Peplow P Neural Regen Res. 2024; 20(10):2776-2786.

PMID: 39314171 PMC: 11826456. DOI: 10.4103/NRR.NRR-D-24-00712.

References

Arbiza L, Gronau I, Aksoy B, Hubisz M, Gulko B, Keinan A . Genome-wide inference of natural selection on human transcription factor binding sites. Nat Genet. 2013; 45(7):723-9. PMC: 3932982. DOI: 10.1038/ng.2658. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Mor M, Nardone S, Sams D, Elliott E . Hypomethylation of miR-142 promoter and upregulation of microRNAs that target the oxytocin receptor gene in the autism prefrontal cortex. Mol Autism. 2015; 6:46. PMC: 4535255. DOI: 10.1186/s13229-015-0040-1. View

Kang H, Kawasawa Y, Cheng F, Zhu Y, Xu X, Li M . Spatio-temporal transcriptome of the human brain. Nature. 2011; 478(7370):483-9. PMC: 3566780. DOI: 10.1038/nature10523. View

Geschwind D, State M . Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol. 2015; 14(11):1109-20. PMC: 4694565. DOI: 10.1016/S1474-4422(15)00044-7. View

. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511(7510):421-7. PMC: 4112379. DOI: 10.1038/nature13595. View

Garcia D, Baek D, Shin C, Bell G, Grimson A, Bartel D . Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nat Struct Mol Biol. 2011; 18(10):1139-46. PMC: 3190056. DOI: 10.1038/nsmb.2115. View

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S . TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013; 14(4):R36. PMC: 4053844. DOI: 10.1186/gb-2013-14-4-r36. View

Hirokawa N, Niwa S, Tanaka Y . Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron. 2010; 68(4):610-38. DOI: 10.1016/j.neuron.2010.09.039. View

10.

Lewis B, Burge C, Bartel D . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005; 120(1):15-20. DOI: 10.1016/j.cell.2004.12.035. View

11.

Sanders S, He X, Willsey A, Ercan-Sencicek A, Samocha K, Cicek A . Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron. 2015; 87(6):1215-1233. PMC: 4624267. DOI: 10.1016/j.neuron.2015.09.016. View

12.

Hansen K, Irizarry R, Wu Z . Removing technical variability in RNA-seq data using conditional quantile normalization. Biostatistics. 2012; 13(2):204-16. PMC: 3297825. DOI: 10.1093/biostatistics/kxr054. View

13.

Anders S, Huber W . Differential expression analysis for sequence count data. Genome Biol. 2010; 11(10):R106. PMC: 3218662. DOI: 10.1186/gb-2010-11-10-r106. View

14.

Langfelder P, Luo R, Oldham M, Horvath S . Is my network module preserved and reproducible?. PLoS Comput Biol. 2011; 7(1):e1001057. PMC: 3024255. DOI: 10.1371/journal.pcbi.1001057. View

15.

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

16.

Miller J, Horvath S, Geschwind D . Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proc Natl Acad Sci U S A. 2010; 107(28):12698-703. PMC: 2906579. DOI: 10.1073/pnas.0914257107. View

17.

Wong R, Guillaud L . The role of epidermal growth factor and its receptors in mammalian CNS. Cytokine Growth Factor Rev. 2004; 15(2-3):147-56. DOI: 10.1016/j.cytogfr.2004.01.004. View

18.

Rossin E, Lage K, Raychaudhuri S, Xavier R, Tatar D, Benita Y . Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet. 2011; 7(1):e1001273. PMC: 3020935. DOI: 10.1371/journal.pgen.1001273. View

19.

Geschwind D, Flint J . Genetics and genomics of psychiatric disease. Science. 2015; 349(6255):1489-94. PMC: 4694563. DOI: 10.1126/science.aaa8954. View

20.

Parikshak N, Luo R, Zhang A, Won H, Lowe J, Chandran V . Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell. 2013; 155(5):1008-21. PMC: 3934107. DOI: 10.1016/j.cell.2013.10.031. View