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A role of histaminergic neuronal systems in schizophrenia was suggested by an association with several polymorphisms located in the coding region of the histamine H2-receptor (H2R) gene (Orange et al, Mol Psychiatry 1996; 1: 466-469). Using either the reference method of direct sequencing or restriction endonuclease digestion of PCR products amplified from DNA, we could not confirm the existence of these polymorphisms in 53 Swedish controls, 52 French controls and 88 French schizophrenics. In contrast, we detected a G543A transition in the coding region of the gene that was not found in the British population. This allelic variation, which was observed in 15% of the controls with no homozygotes, did not change the amino acid sequence of the receptor. We also analyzed a 1.8-kb nucleotide sequence of the promoter region in which we detected two additional polymorphisms that may modulate the expression of the H2R gene. The first one was a A-592G transition located in the minimal promoter of the gene and found in;10% of controls with no homozygotes. The second one was a G-1018A transition located in an enhancer element of the promoter and was found in;20-30% of controls (with;2-4% homozygotes). DNA analysis of the 88 French schizophrenic subjects revealed that the incidence of the three polymorphisms was not significantly different in this population. In conclusion, the present findings may suggest a surprisingly high variability of the H2R gene polymorphisms in different geographical areas but do not support an association of these allelic variations with schizophrenia.