bioRxiv : the preprint server for biologySep 24, 2026

Testing the effects of noncoding genetic risk factors for schizophrenia using gene-editing tools

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Sep 25, 2026

Abstract

Seventy-eight regulatory elements were identified that significantly alter the expression of schizophrenia-associated genes.

Schizophrenia is influenced by both coding and noncoding genetic variation, yet many genetic causes remain unclear.
High-throughput CRISPR screens were used to examine regulatory elements linked to genes associated with schizophrenia.
The study focused on epigenetically silencing 333 putative regulatory elements to assess their impact on gene expression.
Findings included the identification of noncoding enhancers, silencers, promoters, and lncRNAs that affect gene expression.
A common variant in the promoter of the gene SV2A was found to enhance transcriptional activity in specific cell types.

Simplified

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.

Full Text

Full text is available at the source.

View Full Text ↗

Featured in

CRISPR Gene EditingIssue #56

A single IV dose corrected thalassemia in mice — no drug selection required

↗

Testing the effects of noncoding genetic risk factors for schizophrenia using gene-editing tools

Abstract

Full Text

Featured in

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the crispr gene editing brief