Presenilins are a group of proteins playing an important role in the Notch, ErbB4 and Wnt signaling pathways possibly associated with schizophrenia. The gene coding for presenilin 2 (PSEN2) is located on 1q42 and adjacent to a balanced translocation t (1; 11) (q42; q14.3) that was found to co-segregate within family members of patients with schizophrenia. We thus hypothesized that PSEN2 may contribute to the pathogenesis of schizophrenia. Five functional SNPs (rs1295645, rs11405, rs6759, rs1046240 and rs8383) present in the coding regions of the PSEN2 gene were tested in 410 patients with schizophrenia and 355 controls in a Chinese Han population. Association analysis showed a weak association for rs1295645 and the rs1295645-T allele was involved in increased risk of schizophrenia (corrected p=0.045, OR=1.32, 95% CI 1.04-1.68). The T-C-T-T-T haplotype also showed association with increased risk of the illness (p=1.8x10(-5), OR=3.37, 95% CI 1.33-8.51). Analysis of gene expression demonstrated that PSEN2 mRNA levels in peripheral leukocytes were significantly lower in the patient group than in the control group and that expression levels of the PSEN2 gene were significantly correlated to its genotypes. Analysis of clinical profiles showed an association between the PSEN2 gene and some clinical phenotypes scored using the PANSS. The present results suggest that the PSEN2 gene may be a novel candidate involved in the development of certain psychotic symptoms of schizophrenia although the initial finding needs further replication in a large sample size.