Interrogation of noncoding schizophrenia risk variants using CRISPR-based functional genomics

Abstract

Schizophrenia (SCZ) is a highly heritable complex disorder influenced by coding and noncoding genetic variation. Its genetic causes, particularly those involving noncoding variation, are largely unknown. High-throughput CRISPR screens enable dissection of disease-associated loci and identification of noncoding regulatory elements and variants that modulate gene expression. We screened SCZ GWAS loci linked to genes that are also associated in whole-exome sequencing studies to identify regulatory elements and variants impacting expression of disease-relevant genes. We used CRISPRi paired with HCR-FlowFISH to epigenetically silence 333 putative regulatory elements and measure the downstream effects on gene expression of causal SCZ genes, FAM120A, SV2A, and STAG1, in iPSCs and iPSC-derived neurons (iNeurons). We identified 78 regulatory elements that significantly alter expression of a SCZ gene, including noncoding enhancers/silencers as well as promoters of genes and lncRNAs. Pooled prime editing screens interrogated noncoding variant influence on gene expression for SCZ-associated variants and uncharacterized common variants from diverse population studies. We find that a common variant in the promoter of SV2A, rs112851681:A>G (MAF = 3.56%, 1000 Genomes) enhances transcriptional activity in iPSCs and iNeurons. These findings show distinct noncoding mechanisms that map within GWAS signals, and provide a path forward for interrogating noncoding regulatory elements and variants in disease loci.

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BibTeX RIS

BibTeX

@misc{hamilton2026interrogation,
  title = {{Interrogation of noncoding schizophrenia risk variants using CRISPR-based functional genomics}},
  author = {M. C. Hamilton and J. W. Riley and A. C. Nelson and B. Li and S. F. Dornbaum and A. Safi and X. Cui and I. R. Jones and A. A. Coley and K. T. Hagy and R. Rai and A. Barrera and A. S. Allen and Y. Shen and R. I. Sherwood and M. I. Love and P. F. Sullivan and C. A. Gersbach and G. E. Crawford},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.03.749158},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749158v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - Interrogation of noncoding schizophrenia risk variants using CRISPR-based functional genomics
AU  - M. C. Hamilton
AU  - J. W. Riley
AU  - A. C. Nelson
AU  - B. Li
AU  - S. F. Dornbaum
AU  - A. Safi
AU  - X. Cui
AU  - I. R. Jones
AU  - A. A. Coley
AU  - K. T. Hagy
AU  - R. Rai
AU  - A. Barrera
AU  - A. S. Allen
AU  - Y. Shen
AU  - R. I. Sherwood
AU  - M. I. Love
AU  - P. F. Sullivan
AU  - C. A. Gersbach
AU  - G. E. Crawford
PY  - 2026
DA  - 2026/09/03
PB  - bioRxiv
DO  - 10.64898/2026.09.03.749158
UR  - https://www.biorxiv.org/content/10.64898/2026.09.03.749158v1
AB  - Schizophrenia (SCZ) is a highly heritable complex disorder influenced by coding and noncoding genetic variation. Its genetic causes, particularly those involving noncoding variation, are largely unknown. High-throughput CRISPR screens enable dissection of disease-associated loci and identification of noncoding regulatory elements and variants that modulate gene expression. We screened SCZ GWAS loci linked to genes that are also associated in whole-exome sequencing studies to identify regulatory elements and variants impacting expression of disease-relevant genes. We used CRISPRi paired with HCR-FlowFISH to epigenetically silence 333 putative regulatory elements and measure the downstream effects on gene expression of causal SCZ genes, FAM120A, SV2A, and STAG1, in iPSCs and iPSC-derived neurons (iNeurons). We identified 78 regulatory elements that significantly alter expression of a SCZ gene, including noncoding enhancers/silencers as well as promoters of genes and lncRNAs. Pooled prime editing screens interrogated noncoding variant influence on gene expression for SCZ-associated variants and uncharacterized common variants from diverse population studies. We find that a common variant in the promoter of SV2A, rs112851681:A>G (MAF = 3.56%, 1000 Genomes) enhances transcriptional activity in iPSCs and iNeurons. These findings show distinct noncoding mechanisms that map within GWAS signals, and provide a path forward for interrogating noncoding regulatory elements and variants in disease loci.
ER  -

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