MEGF10 association with schizophrenia

Abstract

Background: The 5q21-31 region has been implicated as harboring risk genes for schizophrenia in many linkage studies. In our previous report of stepwise fine mapping of this region, the MEGF10 gene was one of the genes showing consistent associations in our screening subsample. In this study, we carried out independent replication and expression studies of the MEGF10 gene.

Methods: Association studies with 8 SNPs in the MEGF10 gene were performed in the Irish case-control study of schizophrenia (ICCSS) sample (652 case and 617 control subjects). The expression of MEGF10 was also compared between healthy control subjects and schizophrenia patients using postmortem brain cDNA libraries.

Results: In the ICCSS sample, associations with the disease were found in the same risk alleles and haplotypes as that observed in our fine-mapping studies. The major allele (A) of rs27388 was overrepresented in affected individuals (p = .0169), which remained significant after correction for multiple testing. In expression studies, MEGF10 had higher expression levels in the affected than the unaffected (p = .015). Schizophrenia patients with a 1/1 genotype at rs27388 had higher expressions than those patients with 1/2 and 2/2 genotypes (p = .0008).

Conclusions: Evidence from both association and expression studies suggests that MEGF10 is likely associated with schizophrenia. The major allele and 1/1 genotype at rs27388 impose higher risks for the disease.

Figure1

The MEGF10 gene and the LD and haplotype structure of the samples used in this study. A. Gene structure and the relative position of the typed SNPs. Rs27652 was too close to rs27388, it was not shown in the picture. In the figure, exons were illustrated by the long horizontal bars. The 3′ and 5′ UTRs were illustrated by the short bars. B. LD and haplotype structures of the screening subsample. LDs shown were D’. Haplotypes were labeled by letters on the left and their frequencies were listed on the right. Risk haplotype was highlighted. C. LD and haplotype structures of the replication subsample. D. LD and haplotype structures of the ICCSS sample.

Figure 2

ANCOVA analyses of the MEGF10 gene expressions in the Stanley subjects. The expression level was the ΔC_T between MEGF10 and the house keeping gene TBP. The error bars were standard errors. A. Comparison of expressions between the control and schizophrenia subjects. B. Comparison of expressions between the control and schizophrenia subjects with the inclusion of the genotypes of rs27388.