Short allele of 5-HTTLPR linked to increased schizophrenia risk in Japanese cohort and meta-analysis

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Neuropsychopharmacology reports Published June 1, 2026 Medically reviewed June 1, 2026 Study authors: Miyachi Masao, Shirai Toshiyuki, Okada Shohei, Minami Kiriko, Tsukamoto Ryo, Mouri Kentaro, Okazaki … PubMed ↗ DOI ↗ By Dr. Ji-eun Park, MD · Brain, Mind & Pain

Key Takeaway

Interpret the 5-HTTLPR short allele as a modest risk factor for schizophrenia in Japanese populations, but causality is unproven.

This publication combines a cohort study and a meta-analysis examining the association between the 5-HTTLPR polymorphism and schizophrenia in Japanese ancestry individuals. The cohort included 467 patients with schizophrenia and 361 controls. The primary outcome was the association between 5-HTTLPR genotypes/alleles and schizophrenia.

In the cohort, the 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% CI=1.08-1.77, p=0.007). The meta-analysis of available studies showed a significant but modest association between the short allele and schizophrenia (odds ratio=1.06, 95% CI=1.01-1.11, p=0.024).

The authors note that further research is needed. The study establishes an association only; causality is not established. No adverse events or other safety data were reported. The authors suggest that 5-HTTLPR may represent a promising target for future therapeutic strategies, but this remains speculative. Clinicians should interpret these findings cautiously given the modest effect size and the need for replication.

Study Details

Study typeMeta analysis

Sample sizen = 467

EvidenceLevel 1

PublishedJun 2026

PMID41905965

View Original 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.