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: L556 V, 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 (chi2=3.63, P=0.057). CONCLUSIONS: We conclude that variations in the nine ectodomains of CELSR1 do not increase susceptibility to schizophrenia.

Association analysis of the HOPA12bp polymorphism in schizophrenia and manic depressive illness.

Variations in exon 42 of the HOPA (human opposite paired) gene have been associated with mental retardation, hypothyroidism and psychiatric disorders. We attempted to replicate the association with schizophrenia using 309 parent-offspring trios from Bulgaria and 367 unrelated cases and 368 blood donors from the UK. We also tested 125 bipolar trios from Bulgaria, 112 bipolar trios from the UK and a sample of 178 unrelated bipolar cases and 188 blood donors from the UK. The frequency of HOPA(12bp) in the 556 UK blood donors was 2.6% and it was not significantly different in the UK patients groups, where it ranged from 1.2 to 3.8%. Sixteen mothers transmitted the HOPA(12bp) allele to schizophrenic offspring, while 12 did not transmit, a non-significant difference. There was a trend for under-transmission of the rare allele to bipolar patients (T/NT = 4/10) and they had a lower rate of that allele than schizophrenic patients in the Bulgarian population (1% vs. 4.2%, P = 0.043). However the two diagnostic groups had similar allele frequencies in the UK populations: 2% versus 2.6%, P = 0.6. We conclude that the HOPA polymorphism is unlikely to be a major risk factor in the pathogenesis of these major psychiatric disorders although there could be a small effect in schizophrenia.