{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:59:06Z","timestamp":1792789146114,"version":"4.5.0"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado","award":["E-015 (project 382.2014)"],"award-info":[{"award-number":["E-015 (project 382.2014)"]}],"id":[{"id":"https:\/\/ror.org\/02d93ae38","id-type":"ROR","asserted-by":"crossref"}]},{"award":["E-015 (project 382.2014)"],"award-info":[{"award-number":["E-015 (project 382.2014)"]}],"id":[{"id":"https:\/\/ror.org\/02d93ae38","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Universidad Aut\u00f3noma de Guadalajara","award":["CS-FS-2026-026"],"award-info":[{"award-number":["CS-FS-2026-026"]}],"id":[{"id":"https:\/\/ror.org\/05ppk0267","id-type":"ROR","asserted-by":"crossref"}]},{"award":["CS-FS-2026-026"],"award-info":[{"award-number":["CS-FS-2026-026"]}],"id":[{"id":"https:\/\/ror.org\/05ppk0267","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Behav. Sci.","Behavioral Sciences"],"abstract":"<jats:p>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\u2013control 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%) (\u03c72\u00a0p = 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\u20133.17, p = 0.005). Serum MTHFR concentrations were higher in cases than controls (median 1834.8 vs. 1241.9 pg\/mL; Mann\u2013Whitney 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\u2013control 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.<\/jats:p>","DOI":"10.3390\/bs16091639","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:10:23Z","timestamp":1789373423000},"page":"1639","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MTHFR Gene Variants and Major Depressive Disorder in Mexican-Mestizos"],"prefix":"10.3390","volume":"16","author":[{"given":"Miriam Pavelth","family":"Casillas-\u00c1vila","sequence":"first","affiliation":[{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Universidad de Guadalajara, Guadalajara 44100, Mexico"},{"name":"Hospital Civil \u201cDr. Antonio Gonz\u00e1lez Guevara\u201d, Tepic 63169, 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