Methylenetetrahydrofolate Reductase Gene Variants Confer Potential Vulnerability to Autism Spectrum Disorder in a Saudi Community

PURPOSE: Several interacting genes or single nucleotide polymorphisms (SNPs) are vulnerable to the risk of autism spectrum disorder (ASD). Here we explored associations between SNPs in the methylenetetrahydrofolate reductase (MTHFR) gene or combined genotypes and the risk of ASD in a Saudi community. SUBJECTS AND METHODS: ASD severity symptoms were assessed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria and scores on the childhood autism rating scale (CARS). Genomic DNA from buccal cells was analyzed for 112 cases and 104 healthy controls using TaqMan genotyping assays of 677C>T rs1801133 and 1298A>C rs1801131 SNPs in the MTHFR gene. SNPStats software was utilized to determine the best interactive model of inheritance of genotypic data. RESULTS: Controls were consistent with Hardy-Weinberg equilibrium in the examined SNPs. Our data showed associations between the 677C>T and 1298A>C SNPs and ASD risk (odds ratio [OR]= 5.2; 95% confidence interval [CI], 3.1–9.8 and OR= 22.2; 95% CI, 7.9–62.3, respectively). Genotype associations of 677C>T and 1298A>C were identified in cases compared with controls (P= 0.0012 and P= 0.0008, respectively). The examined SNPs were significantly associated with ASD cases having ≥37 scores (codominant and recessive models; P= 0.001 and P= 0.0005, respectively). Six combined genotypes—C/C-A/A (42.9%), C/T-A/A (17.9%), C/T-C/C (14.5%), C/T-A/C (10.9%), T/T-C/C (10.9%), and T/T-A/A (3.6%)—were found in ASD cases. Global haplotype analysis showed a significant difference in haplotype distribution between cases and controls (P= 0.00057). The two SNPs were found to be in relatively strong linkage disequilibrium (D`= 0.63, r(2)= 0.260). CONCLUSION: Our findings suggest that the 677C>T and 1298A>C SNPs add to each other for potential vulnerability to increase the risk of ASD, particularly if they can be confirmed in larger cohorts along with other genetic/environmental factors. Our study could create reference data for future genetic association studies in the Saudi population and for use by government and health experts to develop regional health management programs.