Methylenetetrahydrofolate Reductase Gene and Potential Risk to Autism Spectrum Disorder

Purpose: We explored whether the methylenetetrahydrofolate reductase (MTHFR) variants affected susceptibility to the risk of autism spectrum disorder (ASD) in the Saudi community. Subjects and Methods: Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria and scores on the childhood autism rating scale (CARS) were used to assess the ASD severity symptoms. Samples of genomic DNA from buccal cells of 112 patients with ASD and 104 healthy controls were analyzed using TaqMan™ genotyping assays for the 677C>T rs1801133 and 1298A>C rs1801131 SNPs in the MTHFR gene. SNPStats software (https://www.snpstats.net) was utilized to choose the best interactive inheritance mode for selected SNPs. We have used the Search Tool of the Retrieval of Interacting Genes (STRING) database (https://string-db.org) to predict the protein-protein interaction network of the MTFR gene. Results: Controls were consistent with Hardy-Weinberg equilibrium in the examined SNPs. Our data showed associations between the MTHFR rs1801133 C>T and MTHFR rs1801131 A>C SNPs and ASD risk (odds ratio [OR]= 5.2 and 22.2, respectively). Genotype associations of these SNPs were statistically significant 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). Among six combined genotypes, the C/C-A/A was the most common in ASD cases (42.9%). 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, r2 = 0.260). Conclusion: Our data show that the MTHFR rs1801133 and rs1801131 SNPs interact to enhance the risk of ASD, especially if confirmed in larger cohorts with other genetic/environmental variables. Our findings could serve as a foundation for future genetic association studies in the Saudi population, as well as for government and health-care professionals developing regional health-management initiatives.