MTHFR Gene Variants and Major Depressive Disorder in Mexican-Mestizos

Background: Major depressive disorder (MDD) arises from genetic and environmental factors. We evaluated functional variation in methylenetetrahydrofolate reductase (MTHFR), circulating MTHFR protein, and homocysteine (HCY) in Mexican-Mestizo participants. Methods: We analyzed 1507 individuals across four cohorts: a primary case–control sample (358 DSM-IV-TR MDD cases, 170 psychiatrically screened controls), a community cohort (n = 204), and a general population cohort (n = 775) for allele-frequency context. We genotyped rs1801133 (C677T) and rs13306560 using TaqMan assays. Serum MTHFR and HCY were measured by ELISA in available subsamples (n reported where applicable). Primary analyses tested association of genotypes with MDD under codominant, allelic, and recessive models; false discovery rate (FDR) correction accounted for multiple genetic models. Exploratory multivariable logistic regression adjusted for sex, age, and adverse childhood experiences. Results: The rs13306560 A allele was rare (~2.6%) and showed no association with MDD. Under a recessive model, the rs1801133 TT genotype was more frequent among cases (33.3%) than controls (23.5%) (χ2 p = 0.036); this association did not survive FDR correction (q = 0.117) and is reported as hypothesis-generating. In an exploratory adjusted logistic regression (N = 446) using the post hoc recessive coding, TT homozygotes had higher odds of MDD versus CC/CT (OR = 1.98, 95% CI 1.23–3.17, p = 0.005). Serum MTHFR concentrations were higher in cases than controls (median 1834.8 vs. 1241.9 pg/mL; Mann–Whitney U = 343, p = 0.017). Serum MTHFR displayed a borderline positive correlation with HAM-D scores (Spearman r = 0.24, p = 0.050). Conclusions: In this Mexican-Mestizo sample, MTHFR C677T (rs1801133) homozygosity and elevated circulating MTHFR emerged as preliminary, hypothesis-generating candidates for MDD risk. The genetic association did not meet multiple-testing correction (q = 0.117) and requires independent replication; the serum MTHFR case–control difference survived correction (q = 0.034) but warrants confirmation given the small biomarker subsample. A mechanistic study is needed to clarify causality and clinical relevance.