Systematic Functional Interrogation of Neurodevelopmental Disorder Risk Variants

Abstract

Neurodevelopmental disorders (NDDs) are highly polygenic, yet the functional consequences of most associated non-coding variants remain unclear. We used a massively parallel reporter assay (MPRA) to test 727 NDD-associated non-coding variants in human neural progenitors, identifying 38 expression-modulating variants (emVars) with regulatory activity. These emVars were predicted to alter transcription factor binding motifs linked to neurodevelopmental signaling and cellular metabolism. We mapped emVars to candidate target genes using expression quantitative trait loci and activity-by-contact (ABC) models. We then used CRISPR droplet sequencing (CROP-seq) in human pluripotent stem cell-derived neurons to identify endogenous target genes and characterize their downstream transcriptional effects. CROP-seq preferentially supported ABC predictions, identified additional regulatory relationships, and revealed convergence on developmentally regulated programs involving neuronal connectivity, synaptic function, and mitochondrial biology. Together, these results connect NDD risk variants to endogenous target genes and shared neurodevelopmental transcriptional programs.

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BibTeX RIS

BibTeX

@misc{gomez2026systematic,
  title = {{Systematic Functional Interrogation of Neurodevelopmental Disorder Risk Variants}},
  author = {A. Gomez and J. C. McAfee and H. Min and T. Ulloa Avila and S. Jones and J. L. Bell and Y. Gao and E. Hu and H. Li and S. Lee and R. Sadovnik and Z. Fan and N. Yang and A. S. Beltran and H. Won},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.21.760732},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760732v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - Systematic Functional Interrogation of Neurodevelopmental Disorder Risk Variants
AU  - A. Gomez
AU  - J. C. McAfee
AU  - H. Min
AU  - T. Ulloa Avila
AU  - S. Jones
AU  - J. L. Bell
AU  - Y. Gao
AU  - E. Hu
AU  - H. Li
AU  - S. Lee
AU  - R. Sadovnik
AU  - Z. Fan
AU  - N. Yang
AU  - A. S. Beltran
AU  - H. Won
PY  - 2026
DA  - 2026/10/21
PB  - bioRxiv
DO  - 10.64898/2026.10.21.760732
UR  - https://www.biorxiv.org/content/10.64898/2026.10.21.760732v1
AB  - Neurodevelopmental disorders (NDDs) are highly polygenic, yet the functional consequences of most associated non-coding variants remain unclear. We used a massively parallel reporter assay (MPRA) to test 727 NDD-associated non-coding variants in human neural progenitors, identifying 38 expression-modulating variants (emVars) with regulatory activity. These emVars were predicted to alter transcription factor binding motifs linked to neurodevelopmental signaling and cellular metabolism. We mapped emVars to candidate target genes using expression quantitative trait loci and activity-by-contact (ABC) models. We then used CRISPR droplet sequencing (CROP-seq) in human pluripotent stem cell-derived neurons to identify endogenous target genes and characterize their downstream transcriptional effects. CROP-seq preferentially supported ABC predictions, identified additional regulatory relationships, and revealed convergence on developmentally regulated programs involving neuronal connectivity, synaptic function, and mitochondrial biology. Together, these results connect NDD risk variants to endogenous target genes and shared neurodevelopmental transcriptional programs.
ER  -

Abstract

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