Integration of Transcriptome and Exome Genotyping Identifies Significant Variants with Autism Spectrum Disorder

Autism is a complex disease with genetic predisposition factors. Real factors for treatment and early diagnosis are yet to be defined. This study integrated transcriptome and exome genotyping for identifying functional variants associated with autism spectrum disorder and their impact on gene expression to find significant variations. More than 1800 patients were screened, and 70 (47 male/23 female) with an average age of 7.56 +/- 3.68 years fulfilled the DSM-5 criteria for autism. Analysis revealed 682 SNPs of 589 genes significantly (p < 0.001) associated with autism among the putative functional exonic variants (n = 243,345) studied. Olfactory receptor genes on chromosome 6 were significant after Bonferroni correction (alpha = 0.05/243345 = 2.05 x 10(-7)) with a high degree of linkage disequilibrium on 6p22.1 (p = 6.71 x 10(-9)). The differentially expressed gene analysis of autistic patients compared to controls in whole RNA sequencing identified significantly upregulated (foldchange >= 0.8 and p-value <= 0.05; n = 125) and downregulated (foldchange <=-0.8 and p-value <= 0.05; n = 117) genes. The integration of significantly up- and downregulated genes and genes of significant SNPs identified regulatory variants (rs6657480, rs3130780, and rs1940475) associated with the up- (ITGB3BP) and downregulation (DDR1 and MMP8) of genes in autism spectrum disorder in people of Arab ancestries. The significant variants could be a biomarker of interest for identifying early autism among Arabs and helping to characterize the genes involved in the susceptibility mechanisms for autistic subjects.

Automated summary

This study integrated transcriptome and exome genotyping data to identify functional variants associated with autism spectrum disorder and their impact on gene expression. Significant differences were found in gene expression between autistic patients and controls. In addition, the study identified important genetic variants associated with autism spectrum disorder in Arab populations.