Abstract
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 (α = 0.05/243345 = 2.05 × 10−7) with a high degree of linkage disequilibrium on 6p22.1 (p = 6.71 × 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.
Highlights
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that exhibits a wide range of symptoms of varying severity and has a high prevalence in theGulf region [1]
The top 10 most significantly (p < 2.05 × 10−7 ) associated SNPs were in the region of the olfactory receptor genes OR12D2 and OR5V1 on chromosome 6p22.1 (Figure 2)
The significant genes in this study included integrin subunit alpha 11 (ITGA11), which is associated with attention deficit hyperactivity disorder and attention deficit disorder with hyperactivity; MHC class I polypeptide-related sequence A (MICA), associated with symptoms of inflammatory bowel disease, chronic ulcerative colitis, and Crohn’s disease; bromodomain-containing 2 (BRD2), which has been linked to Alzheimer’s disease and myoclonic epilepsy; cell division cycle 14C pseudogene (CDC14C), which is associated with Parkinson’s disease and sleep; methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L), which is associated with stroke and Alzheimer’s disease; myosin IXB (MYO9B), associated with symptoms of celiac disease, inflammatory bowel disease, chronic ulcerative colitis, multiple sclerosis, and schizophrenia; and ring finger protein 144A (RNF144A), which has been associated with depressive disorder, schizophrenia, and stroke (Table S2) [23,24,25,26,27,28,29,30,31,32,33,34,35]
Summary
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that exhibits a wide range of symptoms of varying severity and has a high prevalence in theGulf region [1]. Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that exhibits a wide range of symptoms of varying severity and has a high prevalence in the. Recent research suggests that gene variants, altered biological mechanisms, and the environment together influence the development of autism [2]. The most common symptoms of autism are impaired social skills, difficulty with communication, Pharmaceuticals 2022, 15, 158. Pharmaceuticals 2022, 15, 158 and repetitive movements. ASD heritability has been estimated to be 40–90%, and a number of common variants contribute to the significant variability in the condition, in addition to epigenetic, environmental, and hormonal factors [4,5,6]. The Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition includes atypical sensory processing, which has been reported in more than 70% of patients with ASD as a diagnostic criterion (DSM-5; American Psychiatric Association, 2013) [7,8,9]
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