Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes

Abstract

Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates <0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P = 0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P = 5.00 × 10(-4); odds ratio 2.60, P = 0.049).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author.

Figure 1.

Genes in genome-wide significant schizophrenia meta-analysis loci enrich for cortical structures of the brain. We used DEPICT and RNA-Seq data from the GTEx Project to assess whether genes in genome-wide significant schizophrenia loci were highly expressed in any of 37 tissue/brain area annotations. Genes within the associated loci were highly expressed in 5 brain areas, most predominantly in the frontal cortex. Enrichments are grouped according to tissue-type annotations and significance, and annotations colored in black exhibited false discovery rates below 5%.

Figure 2.

Genes prioritized for schizophrenia exhibited higher expression during postnatal development compared to prenatal development. The 62 genes prioritized in genome-wide significant schizophrenia loci (dashed line) exhibit higher expression during postnatal stages (early infancy through adulthood) compared to prenatal stages (early to late prenatal development; fold-change 1.29, one-sided paired t-test P = 0.005) across the different brain structures (gray lines). These findings contrast previous findings primarily based on exome sequencing data by Gilman et al. (24) showing higher expression of likely causal schizophrenia genes during prenatal stages (dotted line). These analyses were based on log₂ transformed BrainSpan Developmental Transcriptome (40) RNA-Seq gene expression data. Error bars represent standard deviation across brain structures.