Distribution of SLC6A4 Gene Polymorphisms in a Multi-Ethnic Pakistani Cohort with Major Depressive Disorder

Objective: To determine the distribution of SLC6A4 gene polymorphisms (5-HTTLPR and rs25531) in a multi-ethnic Pakistani population with Major Depressive Disorders. Study Design: Multi-center cross-sectional study. Place and Duration of Study: Tertiary care hospitals in Quetta, Pakistan from Apr 2023 to Oct 2024. Methodology: Four hundred thirty Pakistani patients with Major Depressive Disorder from five ethnic groups (Punjabi, Sindhi, Pathan, Baloch, Kashmiri) were enrolled. Genotyping for 5-HTTLPR and rs25531 polymorphisms was performed using allele-specific PCR followed by restriction fragment length polymorphism. Allele and genotype frequencies were calculated, Hardy-Weinberg equilibrium tested, and inter-ethnic comparisons made. Functional classification was based on tri-allelic system (LA, LG, S). Results: A total of 430 participants were included in the study. Mean age was 32.29 ± 6.80 years. S allele was more common than the L allele, with frequencies of 494 (57.4%) and 366 (42.6%), respectively. Pathan group had the highest frequency of the L allele (47.3%) while Sindhi group had lowest (39.4%). LA allele was common in Pathans (36.5%) and least common in Sindhis (30.8%). Therefore, difference between in allele distribution and ethnic group was statistically significant as p value = 0.012 and differences in treatment response among the three genotype groups were also statistically significant as p value < 0.001. Conclusion: Pakistani population shows unique SLC6A4 genetic architecture with S allele predominance (0.574) and substantial LA allele representation (0.324). The high frequency of low-expression genotypes suggests many Pakistanis may be genetically predisposed to variable SSRI responses. These population-specific data are crucial for developing pharmacogenetic