Autism-Associated Gene Expression in Peripheral Leucocytes Commonly Observed between Subjects with Autism and Healthy Women Having Autistic Children

Yuki Kuwano,Kazuhito Rokutan,Tomoko Kawai,Yoko Kamio,Akiko Takaki,Sakurako Katsuura,Naoko Inada,Monica Uddin

doi:10.1371/journal.pone.0024723

Abstract

Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication, and restricted and repetitive behaviors and interests
Unpaired t test with Benjamini-Hochberg correction for multiple comparisons at the 0.05 false discovery rate (FDR) selected 9,784 probes that were differentially expressed between the ASD and Control groups
Interaction (p-value: 5.86E-06), 2) Reproductive System Development and Function (5.86E-06), 3) Tissue Development (5.86E-06). These results indicated that some genetic predisposition of ASD found in the ASD group was shared by only healthy women having ASD children, but not healthy women having non-ASD children or healthy adults, which could be detectable as an ASD-associated gene expression signature in peripheral leukocytes

Summary

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication, and restricted and repetitive behaviors and interests. Studies have shown a marked increase in the occurrence rate of autism and milder phenotypes with subtle communication/social impairments or stereotypic behaviors among the relatives of autistic individuals compared with those of controls [5], [6] Considering such evidence for familial aggregation of autism phenotypes with various degrees, multiple susceptibility factors, including genetic factors, are considered to be involved in the clinical manifestation of autism spectrum, interacting in complex ways with experiential factors during developmental courses [7]. Analysis in human postmortem cortical tissues from ASD cases has shown the association between a SNP in the promoter of the met proto-oncogene (MET) gene and a risk for ASD [17], [18] This gene encodes the MET receptor tyrosine kinase and contributes to development of the cerebral cortex and cerebellum, which process may be disrupted in autism. Voineagu et al have reported that analysis of postmortem brain tissue samples from autism cases showed the splicing dysregulation and altered gene expression involved in neuronal and synaptic signaling dysfunction in the ASD brain [19]

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Conclusion