Mutational analysis of the 5-HT1B and 5-HT1E serotonin receptor genes in three datasets with schizophrenia

We have investigated two serotonin receptor genes located in the 6q13-q26 area: the 5-ht1e and the 5-ht1b genes. Both receptors belong to the G-protein superfamily and contain the characteristic seven transmembrane regions, are localized in the brain, are intronless, and are negatively coupled to adenylyl cyclase. Both receptors have been studied by mutational analysis techniques by at least one other group [Shimron-Abarbanell et al., 1995; Nothen et al., 1994], in both cases association with schizophrenia was found negative. Therefore, we consider our mutational analysis work a "second pass." For the study of association, we have employed three clinical data sets (n = 180 families) that have supported the existence of a susceptibility gene for schizophrenia in 6q13-26 [Martinez et al., submitted]. We have found in a screening of 97 unrelated individuals (mostly Caucasians) the following new polymorphisms: 1) 5-ht1b. Silent DNA variations: C129T, C705T; missense DNA variations: C662A Thr-Asn, A1099G Ile-Val, G1120AGlu-Lys. We have also detected a variation previously reported by Nothen et al. [1994] (T371G PheCys). We are now investigating the 5′ flanking region. Only C129T had a frequency high enough to perform association (freq. of allele 1 = 0.84 freq. of allele 2 = 0.16) while the rest have a frequency of the minor allele <.02.2) 5-ht1E. Silent DNA variations: C390T, C960T; missense DNA variations: C623T Ala-Val, T785C Ser-Pro, C800A Pro-His. These variations had minor alleles with frequencies <.03. Therefore, for 5-ht1e, a C531T polymorphism (freq. of allele 1 = 0.76, freq. of allele 2 = 0.24) was used for association [Abarbanell et al., 1995]. Transmission disequilibrium tests with C129T (5-ht1b) and with C531T (5-ht1e) showed no association with schizophrenia. For C129T, we had 87 informative parent-offspring combinations. Allele 1 was transmitted 42 times and allele 2, 45 times (n.s.). For C531T, we had 42 informative parent-offspring combinations. Allele 1 was transmitted 20 times and allele 2, 22 times (n.s.). Most of the substitutions detected are too rare to be informative for association testing. However, expressed missense substitutions in 5-ht1b and 5-ht1e receptors can potentially affect ligand binding or interaction with G proteins.