Japanese Cohort Study and Meta‐Analysis Demonstrate Significant Association Between Serotonin Transporter‐Linked Polymorphic Region and Schizophrenia

ABSTRACT Schizophrenia is a prevalent psychiatric disease that substantially affects health and increases mortality risk. The 5‐hydroxytryptamine system has been implicated in its pathogenesis. The SLC6A4 gene encodes the serotonin transporter, which regulates synaptic 5‐hydroxytryptamine through reuptake into presynaptic neurons. Within its promoter region, there is a 44‐base pair insertion/deletion polymorphism, known as serotonin‐transporter‐linked polymorphic region (5‐HTTLPR). We investigated the association between 5‐HTTLPR polymorphism and schizophrenia in the cohorts, including the largest sample size of Asian schizophrenia patients to date. We included 467 patients with schizophrenia and 361 controls, all of Japanese ancestry. We extracted DNA from peripheral blood samples. After amplification with PCR, we analyzed the association between 5‐HTTLPR genotypes and alleles and schizophrenia. Furthermore, we conducted a meta‐analysis with previous literatures. 5‐HTTLPR genotype distribution differed significantly between patients and controls ( p = 0.007). The short allele was significantly more frequent in schizophrenia patients (odds ratio = 1.39 [95% Cl = 1.08–1.77], p = 0.007). The meta‐analysis demonstrated a significant association between the short allele and schizophrenia (odds ratio = 1.06 [95% Cl = 1.01–1.11], p = 0.024). This study demonstrates a significant association between 5‐HTTLPR polymorphism and schizophrenia. While further research is needed, the findings suggest 5‐HTTLPR may represent a promising target for future therapeutic strategies.