Chromatin accessibility mapping for GWAS risk loci reveals compound genetic effects of neurodevelopment and neurodegenerative disorders in human neurons
Genome binding/occupancy profiling by high throughput sequencing
Summary
Here, in NEUROG2-induced human neurons, we identified 31 credible risk SNPs in 26 schizophrenia (SZ) risk loci that displayed allele-specific open chromatin (ASoC) and were likely to be functional. For the VPS45 locus showing the strongest ASoC, CRISPR/Cas9 editing of ASoC SNP (rs2027349) altered the local expression of VPS45 and AC244033.2 (a lncRNA), and a distal gene, C1orf54. Notably, the global expression changes in neurons correlated with post-mortem brain expression signatures of neuropsychiatric disorders. Neurons carrying risk allele exhibited increased dendritic complexity, synaptic puncta density and hyperactivity, which were partially reversed by knocking-down each cis-regulated gene (VPS45, AC244033.2, or C1orf54), suggesting phenotypic contribution from all three genes.
Overall design
In NEUROG2-induced human neurons, we identified 31 credible risk SNPs in 26 schizophrenia (SZ) risk loci that displayed allele-specific open chromatin (ASoC) and were likely to be functional. For the VPS45 locus showing the strongest ASoC, CRISPR/Cas9 editing of ASoC SNP (rs2027349) altered the local expression of VPS45 and AC244033.2 (a lncRNA), and a distal gene, C1orf54. Our study reveals a compound effect of multiple genes at a single SZ locus that impairs neurodevelopment and synaptic function, providing a mechanistic link between a noncoding SZ risk variant and disease-related cellular phenotypes.
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