Association of a 5-HT_5A receptor polymorphism, Pro15Ser, to schizophrenia

Several different lines of evidence suggest that genes involved in serotonergic neurotransmission are factors in the pathogenesis of schizophrenia. For example, 5-HT_5A knockout mice revealed decreased locomotor response to lysergic diethylamide (LSD), which produces a psychotic-like state in healthy people. Recently, we reported a naturally occurring conservative Pro15-Ser substitution in the 5-HT_5A receptor. Here, we evaluate whether this substitution is associated with schizophrenia in a sample including 249 unrelated Japanese schizophrenia patients and 253 unrelated controls. Patients and controls were genotyped for the Pro15Ser polymorphism by a PCR-RFLP assay. Ser15 allele frequencies were 0.07 in patients with schizophrenia and 0.02 in controls (χ² = 17.42, df = 1, P < 0.0001). Thus, we detected a highly significant association of Pro15Ser to schizophrenia in a large population of Japanese schizophrenia patients and controls. Since case-control studies have an inherent potential for false-positive results due to population stratification, this finding is preliminary pending further studies, including studies using the transmission/disequilibrium test to eliminate stratification bias or control loci to assess ethnic matching of cases and controls.