Letter to the Editors: Multiple genetic, environmental and developmental factors have been implicated (Hyman, 1999; Riley et al., 2000) in the etiology of schizophrenia. Axon guidance molecules may be considered candidate genes to explain an early developmental abnormality underlying schizophrenia. Plexin A2, a member of the semaphorin receptor family, is an axon guidance receptor widely expressed in the brain (Takahashi et al., 1999). A genome-wide association study of European schizophrenic patients and controls and found a significant association between schizophrenia and 3 SNPs at the Plexin A2 locus (PLXNA2): rs841865, rs752016 and rs2498028 (Mah et al., 2006). Another study found no association of PLXNA2 and schizophrenia amongst Japanese (Fujii et al., 2007). We sought to replicate this association in a DNA sample of 290 Chinese Han Trios (621 schizophrenic patients and 501 controls) obtained from the National Institute of Mental Health (NIMH; www.nimh.nih.gov). Families were excluded if both parents were schizophrenic. We genotyped the same three SNPs at the PLXNA2 locus: rs841865, rs752016 and rs2498028 using the TaqMan SNP Genotyping Assay (Applied Biosystems, California). Genotype distribution was performed to test deviation from Hardy-Weinberg equilibrium using the Fisher exact test. LD between pairs of SNPs was measured as D’ using Haploview. Structures of haplotypes were analyzed from the parental genotypes based upon LD pattern using the expectation-maximization algorithm (Slatkin and Excoffier, 1996). Conventional TDT statistics were used to analyze transmission disequilibrium between the discrete trait schizophrenia or schizoaffective disorder and the SNPs (Spielman et al., 1993) using the trios from the NIMH with both available parents and one affected offspring. In addition, single marker and haplotype association with schizophrenia were tested using FBAT (Family-Based Association Test) software (Laird et al., 2000; Horvath et al., 2004). FBAT also implements haplotype-based association tests for family-based studies when markers are tightly linked. In our study, all markers were tested as they all had minor allele frequencies greater than 5%. No Mendelian errors were observed in our analysis. The genotype frequencies of the three SNPs tested were in Hardy-Weinberg equilibrium. The association of single SNP and haplotypes with schizophrenia is shown in Figure 1. Results of single SNP-based association and hapltype-based association tests using FBAT are summarized (Fig. 1C, D). No statistical evidence suggests the association between schizophrenia and 3 SNPs at the PLXNA2 locus. Thus, using this population of Chinese Han trios, we were unable to replicate an association at the PLXNA2 locus and schizophrenia (Mah et al., 2006). Figure 1 SNP and linkage analysis at the PlexinA2 locus in Chinese Han Trios In conclusion, we performed a comprehensive analysis of three particular SNPs at the PLXNA2 locus and failed to replicate a previously reported association of this locus and schizophrenia. Further studies are required to verify the potential role of axon guidance molecules in schizophrenia.