SYSTEMATIC SCREENING FOR MUTATIONS IN THE HUMAN SEROTONIN-2A (5-HT2A)RECEPTOR GENE - IDENTIFICATION OF 2 NATURALLY-OCCURRING RECEPTOR VARIANTS AND ASSOCIATION ANALYSIS IN SCHIZOPHRENIA

A statistically significant association between a silent mutation (102 T/C) in the serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported in a sample of Japanese patients and healthy co ntrols. This finding suggests that genetic predisposition to schizophr enia may be affected by a functional 5-HT,, receptor variant that is i n linkage disequilibrium with 102T/C. In the present study, we have so ught to identify genetic variation in the 5-HT2A receptor gene by scre ening genomic DNA samples from 91 unrelated subjects comprising 45 pat ients with schizophrenia and 46 healthy controls by using single-stran d conformation analysis. We have identified four nucleotide sequence v ariants. Two sequence changes would result in protein alterations: a s ubstitution of threonine by asparagine at position 25 (Thr25Asn), and a substitution of histidine by tyrosine at position 452 (His452Tyr). I n order to test for a possible contribution to the development of schi zophrenia, we have determined allele frequencies in extended samples o f unrelated patients and healthy controls. The two amino acid substitu tions are found with similar frequencies in patients and controls, ind icating that the presence of these variants is not causally related to the development of schizophrenia. However, the reported association o f the non-coding polymorphism 102T/C with the disease has also been de tected in our sample (P = 0.041, odds ratio = 1.28, 95% confidence int erval 1.012-1.623).