A resistance gene in disguise for schizophrenia?

We examined the hypothesis that −485 T, a novel polymorphism in the promoter region of the neuropeptide Y gene which was shown to be associated with schizophrenia in our previous paper, confers susceptibility to the disease. For a case‐control association study, 331 unrelated Japanese schizophrenics (S 1 : milder cases in the previous study, n = 212; and S 2 : additional severer cases, n = 119) and 199 unrelated normal controls were recruited. Contribution of −485 T to the risk and the severity of the illness was examined by (1) comparing the risk in each genotype in the general population, (2) testing correlations between the gene‐dose of −485 T, and the severity of chronic outcome in S 2 assessed with the Positive and Negative Symptom Scale, and (3) comparing the distribution of age at onset in S 1  + S 2 among the three genotypes. −485 T was significantly associated with schizophrenia in S 1  + S 2 . Significant negative correlations were observed between the gene‐dose and the symptom assessment scores in all items. The homozygote of −485 T showed a second peak frequency in the late‐onset group both in males and females, while the homozygote of the alternative allele showed a single peak in the early‐onset group. The higher risk of schizophrenia in the heterozygote than in the homozygote of −485 T in the general population did not support the possibility of linkage disequilibrium with a susceptibility gene. −485 T most likely confers resistance but not susceptibility to schizophrenia. An interaction between a nuclear resistance gene and a presumptive pathogenic gene in the mitochondrial DNA was suggested. © 2006 Wiley‐Liss, Inc.