Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | 100399 |
| Journal | Cell Genomics |
| Volume | 3 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 13 2023 |
Funding
We thank Molecular Genetics of Schizophrenia (MGS) investigators for collecting samples that were used for deriving hiPSCs. Funding was provided by NIH grants R01AA023797 and R01MH125528 (to Z.P.P.); R01MH110531 (to X.H.); R01MH097216 (to P.P); and R01MH106575 , R01MH116281 , and R01AG063175 (to J.D.). We thank Molecular Genetics of Schizophrenia (MGS) investigators for collecting samples that were used for deriving hiPSCs. Funding was provided by NIH grants R01AA023797 and R01MH125528 (to Z.P.P.); R01MH110531 (to X.H.); R01MH097216 (to P.P); and R01MH106575, R01MH116281, and R01AG063175 (to J.D.). S.Z. analyzed the ATAC-seq, bulk, and scRNA-seq data and performed genetic/genomic analyses. S.Z. and H.Z. performed the experiments, analyzed data, and wrote the manuscript. M.P.F. performed immunostaining, neural imaging and analyses, and wrote the manuscript. A.K. helped with neuron differentiation. V.A.B. and L.E.D. performed neural imaging and analyses. M.D.S. and N.H.P. assisted with immunostaining and analysis. A.R.S. helped with clinical phenotypes, data interpretation, and manuscript writing. Z.P.P. guided the neuron differentiation. Y.Z. helped with the CROP-seq data analysis and X.S. helped with the GWAS SNP enrichment analysis. X.H. supervised the data analyses of Y.Z. and X.S. and wrote the manuscript. P.P. supervised the neuronal phenotype analyses and wrote the manuscript. J.D. conceived the study, supervised the experiments and analyses, and wrote the manuscript. The authors declare no competing interests.
Keywords
- CRISPR-Cas9 gene editing
- CROP-seq
- GWAS
- Micro-C
- allele-specific open chromatin
- chromatin accessibility
- common risk variants
- human iPS cells
- isogenic
- neuron
- neuropsychiatric disorders
- noncoding variants
- scRNA-seq
- schizophrenia
- synergistic
ASJC Scopus subject areas
- Genetics
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
