BDNF Val66Met Variant as a Genetic Risk Factor for Major Depressive Disorder in Saudis

Objective: Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition in Saudi Arabia, with genetic susceptibility remaining incompletely characterized. Reduced brain-derived neurotrophic factor (BDNF) activity has been implicated in MDD. The Val66Met polymorphism (rs6265), involving the substitution of valine (Val, G allele) with methionine (Met, A allele), impairs activity-dependent BDNF secretion. This study examined the frequency of Val66Met and its association with MDD in a Saudi cohort. Materials and Methods: A case-control study was conducted, including 87 patients with MDD (44 males, 43 females; mean age 44.2 ± 11.5 years) and 87 healthy controls (39 males, 48 females; mean age 28.7 ± 8.4 years). Genotyping was performed using tetra-primer amplification refractory mutation system–polymerase chain reaction. Unadjusted and age- and sex-adjusted logistic regression analyses were applied under genotype-specific, dominant, recessive, and allelic models. Results: The Val/Val (GG) genotype was more frequent in controls than patients (54.0% vs. 34.5%), whereas the Met/Met (AA) genotype was detected exclusively in patients (21.8% vs. 0%; χ 2 = 22.80, p = 1.1 × 10 −5 ). The Met (A) allele frequency was significantly higher in patients (43.7% vs. 23.0%; χ 2 = 15.84, p = 6.9 × 10 −5 ). Unadjusted analysis showed a protective effect of GG (OR = 0.45, 95% CI: 0.24–0.82) and a markedly increased risk associated with AA (OR = 49.81, 95% CI: 2.95–839.90). Dominant carriers (GA + AA) had increased odds of MDD (OR = 2.23), and each A allele conferred a higher risk (OR = 2.60). These associations remained significant after adjustment for age and sex. Conclusion: The BDNF Val66Met polymorphism is associated with MDD susceptibility in Saudis. The Met (A) allele, particularly in homozygosity, confers increased risk, while the Val/Val genotype appears protective, supporting population-specific genetic contributions to depression.