The Contribution of Ethnicity to the Association of MTHFR Variants C677T and A1298C with Autism Spectrum Disorder: A Meta-Analysis

<b>Background:</b> Common polymorphisms in the <i>MTHFR</i> gene, <i>C677T</i> and <i>A1298C</i>, have been associated with increased risk for psychiatric neurodevelopmental disorders, including autism spectrum disorder (ASD). However, studies provide conflicting evidence for the strength of the association with ASD based on both the allelic variant and population structure of the cohorts studied. <b>Methods:</b> Using systematic literature search and selection criteria, we calculated ASD-associated odds ratios for the two most-reported MTHFR variants. Twenty-two articles reported the association between <i>MTHFR C677T</i> and ASD, including 13913 subjects (4391 cases, 9522 controls). Nine articles, including 3009 subjects (1462 cases, 1547 controls), evaluated the link between <i>MTHFR A1298C</i> and ASD susceptibility. <b>Results:</b> We identified a statistical association between ASD and the <i>MTHFR C677T</i> variant, regardless of race or ethnicity. However, there was no statistical support for an association between ASD and the <i>MTHFR A1298C</i> variant. In both cases, substantial-to-considerable residual heterogeneity remained (I² ~67% and 73%, respectively). Exploring the heterogeneity by meta-regression on race/ethnicity, the African (Egyptian) cohort with <i>MTHFR C677T</i> variants had a higher ASD susceptibility than Asian or European cohorts in most models, though this susceptibility difference was not observed between Africans and Europeans for the homozygous case (TT vs. CC). Similarly, the African (Egyptian) cohort with <i>MTHFR A1298C</i> variants also had a higher ASD susceptibility than Asian or European cohorts in most models, though this susceptibility difference was not observed between Africans and Asians for the homozygous case (CC vs. AA). <b>Conclusions:</b> Our findings support previous analyses that identified a statistical association between ASD and the <i>MTHFR C677T</i> variant but none between ASD and the <i>MTHFR A1298C</i> variant. We also reveal a greater potential for these variants to exacerbate ASD phenotypes in an African (Egyptian) cohort. Future studies should assess the mechanistic contribution of these variants to MTHFR function, especially potential hypomorphic sensitivity in individuals with African (Egyptian) ancestry.