Abstract
Genome-wide association studies have linked common variation in ZNF804A with an increased risk of schizophrenia. However, little is known about the biology of ZNF804A and its role in schizophrenia. Here, we investigate the function of ZNF804A using a variety of complementary molecular techniques. We show that ZNF804A is a nuclear protein that interacts with neuronal RNA splicing factors and RNA-binding proteins including RBFOX1, which is also associated with schizophrenia, CELF3/4, components of the ubiquitin-proteasome system and the ZNF804A paralog, GPATCH8. GPATCH8 also interacts with splicing factors and is localized to nuclear speckles indicative of a role in pre-messenger RNA (mRNA) processing. Sequence analysis showed that GPATCH8 contains ultraconserved, alternatively spliced poison exons that are also regulated by RBFOX proteins. ZNF804A knockdown in SH-SY5Y cells resulted in robust changes in gene expression and pre-mRNA splicing converging on pathways associated with nervous system development, synaptic contact, and cell adhesion. We observed enrichment (P = 1.66 × 10–9) for differentially spliced genes in ZNF804A-depleted cells among genes that contain RBFOX-dependent alternatively spliced exons. Differentially spliced genes in ZNF804A-depleted cells were also enriched for genes harboring de novo loss of function mutations in autism spectrum disorder (P = 6.25 × 10–7, enrichment 2.16) and common variant alleles associated with schizophrenia (P = .014), bipolar disorder and schizophrenia (P = .003), and autism spectrum disorder (P = .005). These data suggest that ZNF804A and its paralogs may interact with neuronal-splicing factors and RNA-binding proteins to regulate the expression of a subset of synaptic and neurodevelopmental genes.
Highlights
Schizophrenia is a highly heritable neuropsychiatric disorder that is often associated with poor quality of life and premature mortality.[1,2,3] Risk is conferred by many common alleles of individually weak effect, as well as rare alleles, some of stronger effect
We found that genes that were differentially spliced in ZNF804A-depleted cells were highly enriched for RBFOX targets (P = 3.31 × 10–9, OR 2.32) whereas no enrichment was found among the differentially expressed (DEX) genes
Given the extensive evidence for pleiotropy across neuropsychiatric disorders,[2] we examined the enrichment of DEX and differentially spliced genes for common variants associated with schizophrenia, schizophrenia and bipolar disorder, and autism spectrum disorder (ASD)
Summary
Schizophrenia is a highly heritable neuropsychiatric disorder that is often associated with poor quality of life and premature mortality.[1,2,3] Risk is conferred by many common alleles of individually weak effect (collectively accounting for up to 40% of disease liability4), as well as rare alleles, some of stronger effect. Genome-wide association studies (GWAS) have identified large numbers of common genetic variants associated with an increased risk in schizophrenia,[5,6,7,8] with the most recent study reporting 179 independent associations mapping to 145 independent loci.[7] One of the first variants implicated in schizophrenia through GWAS was rs1344706, within intron 2 of ZNF804A. Following the original GWAS, the association between rs1344706 and schizophrenia has been independently replicated in large meta-analyses of schizophrenia and in a combined analysis of schizophrenia and bipolar disorder.[7,8,9,10,11] GWAS alone do not definitively identify causal variants, rs1344706 is one of only 5 single-nucleotide polymorphisms (SNPs), all intronic, that collectively have a 95% posterior probability of including the causal SNP at this locus.[7] The
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