Multiple genes in a single GWAS risk locus synergistically mediate aberrant synaptic development and function in human neurons

The mechanistic tie between genome-wide association study (GWAS)-implicated risk variants and disease-relevant cellular phenotypes remains largely unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons as a neurodevelopmental model, we identify multiple schizophrenia (SZ) risk variants that display allele-specific open chromatin (ASoC) and are likely to be functional. Editing the strongest ASoC SNP, rs2027349, near vacuolar protein sorting 45 homolog (VPS45) alters the expression of VPS45, lncRNA AC244033.2, and a distal gene, C1orf54. Notably, the transcriptomic changes in neurons are associated with SZ and other neuropsychiatric disorders. Neurons carrying the risk allele exhibit increased dendritic complexity and hyperactivity. Interestingly, individual/combinatorial gene knockdown shows that these genes alter cellular phenotypes in a non-additive synergistic manner. Our study reveals that multiple genes at a single GWAS risk locus mediate a compound effect on neural function, providing a mechanistic link between a non-coding risk variant and disease-related cellular phenotypes.