Functional investigation of a schizophrenia GWAS signal at the CDC42 gene.

Objectives: SNP rs2473277 upstream of the cell division cycle 42 (CDC42) gene was associated with schizophrenia in a recent genome-wide association study (GWAS). Reduced expression of CDC42 in schizophrenia has previously been reported. Our objective was to test whether the associated SNP affected CDC42 expression.

Methods: Two available SNP × gene expression datasets were accessed to test the effect of rs2473277 on CDC42 expression: (i) the mRNA by SNP Browser, which presents results of a genome-wide linkage study of gene expression, and (ii) the Genevar HapMap expression dataset. rs2473277 is in strong linkage disequilibrium (LD) with the SNP rs2473307 (r(2) =0.96), which is predicted to affect transcription factor binding. rs2473307 was directly tested for allelic effects on gene expression using a gene reporter assay in a human neuronal cell line.

Results: In both datasets, the schizophrenia risk allele at rs2473277 was associated with a reduction in CDC42 mRNA levels. In the reporter gene assay the risk allele at rs2473307 similarly reduced gene expression.

Conclusions: We found evidence that rs2473307, in strong LD with the schizophrenia associated SNP rs2473277, is a functional variant at CDC42 that may increase risk for schizophrenia by reducing expression of CDC42.