The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia

Abstract

The etiology of schizophrenia is unclear, although family, twin, and linkage studies implicate genetic factors. Here, we identified adenomatous polyposis coli (APC), a tumor suppressor gene, as a risk factor for schizophrenia. We compared leukocytic gene expression patterns of six pairs of patients with schizophrenia and healthy controls by microarray. APC expression levels were significantly increased in all patients compared to healthy controls. To confirm the findings of microarray analysis, we measured expression levels of APC in the leukocytes from 30 relapse patients taking antipsychotic medication, 29 first-episode drug-naïve patients, and 30 healthy controls using real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). APC expression levels were significantly increased in leukocytes of schizophrenics both taking and not taking antipsychotic medication and hence the increase of APC expression was not due to antipsychotic medication. APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. Further, we performed the transmission disequilibrium test (TDT) and TDT based on haplotypes to search for the association between schizophrenia and APC by examining 163 parent-offspring trios of Chinese descent. We analyzed three single-nucleotide polymorphisms (SNPs) (rs2229992, rs42427, rs465899) at the exon region of APC. TDT showed that the three SNPs are significantly associated with schizophrenia (TDT v 2 ¼ 4.23, Po0.05; 4.15, Po0.05; 8.49 Po0.01, respectively; HHRRv 2 ¼ 5.54, Po0.05; 4.40, Po0.05; 9.79, Po0.01, respectively). We found a significant association between the APC haplotypes from rs2229992-rs42427-rs465899 and schizophrenia (Global v 2 ¼ 44.376,df ¼ 7, Po0.001). The C-A-T haplotype has a frequency of more than 57% and has a strong association with schizophrenia (v 2 ¼ 15.04, Po0.001). These results indicate that the APC may be a candidate gene conferring susceptibility to schizophrenia and also may be associated with reduced vulnerability to cancer in schizophrenia.

The myelin-pathogenesis puzzle in schizophrenia: a literature review

“…38 Another interesting candidate gene located at 5q21-q22 is the adenomatosis polyposis coli gene, which has been reported to confer risk for schizophrenia and may have a role in the reduced vulnerability to cancer in schizophrenia. 39 One of the most attractive candidate regions for schizophrenia on 5q31-35 that maps several GABA(A) receptor subunit genes, recently gained positive results for an association with the disorder. 40 However, further investigations are warranted considering that a concurrent study in a Japanese schizophrenic population failed to confirm this.…”

Adenomatous polyposis coli plays a key role, in vivo, in coordinating assembly of the neuronal nicotinic postsynaptic complex

“…The present study begins to define these mechanisms in an in vivo model system. The importance of understanding such mechanisms in the vertebrate nervous system is underscored by the association of APC gene mutations with mental retardation, schizophrenia and autism spectrum disorders (Cui et al, 2005;Finch et al, 2005;Zhou et al, 2007).…”

Genome-wide association study of recurrent major depressive disorder in two European case–control cohorts

“…45 APC, a tumor suppressor, gene has been reported to be associated with schizophrenia in a small Chinese family-based sample. 46 The CPLX2, which is involved in synaptogenesis and in the modulation of neurotransmitter release, showed contrasting results in two Asian schizophrenia datasets.…”