Apoptotic Engulfment Pathway and Schizophrenia

Department of Psychiatry and Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(9):e6875. DOI: 10.1371/journal.pone.0006875
Source: PubMed


Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease.
Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples.
From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease.

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    • "This finding strongly implicates the immune system as being involved in the development of schizophrenia. Other findings include candidate genes functioning in cell adhesion [4-6], migration [4,7] and apoptosis [8,9]. Except the findings from rare copy number variations [10-13], the effects of individual genes overall are modest or weak. "
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    • "A SNP of ABCA7 has been found to be associated with schizophrenia [7] and ABCA7’s role in phagocytosis might impact on the deregulation of apoptosis in cortical regions of schizophrenia patients [8], [9]. The defects in the apoptotic pathway of schizophrenia patients may be a factor contributing to dysfunctional autoimmune system and elevated inflammatory cytokines observed in these patients [7]. "
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