Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes

Abstract

There is genetic evidence that schizophrenia is a polygenic disorder with a large number of loci of small effect on disease susceptibility. Genome-wide association studies (GWASs) of schizophrenia have had limited success, with the best finding at the MHC locus at chromosome 6p. A recent effort of the Psychiatric GWAS consortium (PGC) yielded five novel loci for schizophrenia. In this study, we aim to highlight additional schizophrenia susceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394 schizophrenia cases and 12 462 controls) with expression QTLs (eQTLs) and differential gene expression in whole blood of schizophrenia patients and controls. We examined the 6192 single-nucleotide polymorphisms (SNPs) with significance threshold at P<0.001. eQTLs were calculated for these SNPs in a sample of healthy controls (n=437). The transcripts significantly regulated by the top SNPs from the GWAS meta-analysis were subsequently tested for differential expression in an independent set of schizophrenia cases and controls (n=202). After correction for multiple testing, the eQTL analysis yielded 40 significant cis-acting effects of the SNPs. Seven of these transcripts show differential expression between cases and controls. Of these, the effect of three genes (RNF5, TRIM26 and HLA-DRB3) coincided with the direction expected from meta-analysis findings and were all located within the MHC region. Our results identify new genes of interest and highlight again the involvement of the MHC region in schizophrenia susceptibility.

Figure 1

Distribution of eQTL effects. A region of 1 MB around the center of the expression probe was taken as a threshold for cis-effects. The plot shows a histogram of frequency of eQTL effects (SNP-probe combinations) in this region. Effects in the MHC region are displayed in blue, effects elsewhere on the genome in green.

Figure 2

eQTL effects versus SNP rank. The −log10(p) value of eQTL effects (SNP-probe combinations) are plotted against the original rank of the SNP in the schizophrenia meta-analysis top 6192. Effects in the MHC region are displayed in blue, effects elsewhere on the genome in green.