Genetic variation in the seven-pass transmembrane cadherin CELSR1:: lack of association with schizophrenia

Objectives Cadherins play a critical role in morphogenesis and maintenance of neuronal connections in the adult brain. We examined the gene encoding a member of the non-classic seven-pass transmembrane cadherins, CELSR1 for association with schizophrenia. It maps to chromosome 22q13.31, a region in which evidence for linkage to schizophrenia has been reported. The gene has an unusually large first exon of 3544 nucleotides, which encodes the signal peptide and all nine ectodomains in the protein. Methods We screened this exon in 24 schizophrenic patients using denaturing high-performance liquid chromatography followed by sequencing. Genotyping of amino-acid changes was performed with primer extension on a sample of 244 Bulgarian schizophrenic patients from 233 families and all their parents, as well as 180 schizophrenic patients from the UK and 157 controls. Results Three amino-acid changes were identified and shown to be in complete linkage disequilibrium: L556V, S664W and R1126C. There was no preferential transmission of alleles from heterozygous parents to affected offspring. In the UK population the rare alleles were even more common in controls, and this difference almost reached statistical significance for R1126C (chi(2) = 3.63, P=0.057). Conclusions We conclude that variations in the nine ectodomains of CELSR1 do not increase susceptibility to schizophrenia. (C) 2003 Lippincott Williams Wilkins.