Methylenetetrahydrofolate reductase (<i>MTHFR</i>) C677T and A1298C polymorphisms are associated with major depressive disorder in the Saudi patients attending Erada complex for mental health and Erada services - Jeddah, Saudi Arabia.

<i>Background</i>: Major Depressive Disorder (MDD) is a prevalent and debilitating mental disorder that has been linked to hyperhomocysteinemia and folate deficiency. These conditions are influenced by the methylenetetrahydrofolate reductase (<i>MTHFR</i>) gene, which plays a crucial role in converting homocysteine to methionine and is essential for folate metabolism and neurotransmitter synthesis, including serotonin. <i>Study aim</i>: This study explored the association between <i>MTHFR C677T</i> and <i>A1298C</i> polymorphisms among Saudi MDD patients attending the Erada Complex for Mental Health and Erada Services outpatient clinic in Jeddah, Saudi Arabia. <i>Methods</i>: The study involved 87 MDD patients and 87 control subjects. Saliva samples were collected, and genomic DNA was extracted. Polymerase chain reaction-restriction fragment length polymorphism was used to detect <i>MTHFR</i> gene polymorphisms. <i>Results</i>: A significant difference was observed in the distribution of genotype frequencies for <i>MTHFR C677T</i> and <i>A1298C</i> polymorphisms between MDD patients and controls in the Saudi cohort (<i>C677T</i>: <i>P</i> = 0.001; <i>A1298C</i>: <i>P</i> = 0.01) Risk analysis indicated that individuals with the mutant TT genotype of the <i>C677T</i> polymorphism (Odd Ratio (OR) = 6.80, CI 95% = 1.47-31.36, <i>P</i> = 0.01) and the mutant CC genotype of the <i>A1298C</i> polymorphism (OR = 2.64, CI 95% = 1.36-5.13, P = 0.004) are more common in MDD patients, suggesting a higher risk for depression. Gender-specific analyses showed that the <i>MTHFR C677T</i> TT genotype significantly increases the risk of MDD in males compared to females. <i>Conclusion</i>: These findings underscore the significant impact of genetic factors, particularly the association of <i>MTHFR</i> polymorphisms with MDD. The results highlight the importance of personalized treatment approaches considering individual genetic profiles.