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Mutations of schizophrenia risk gene SETD1A dysregulate synaptic function in human neurons

GSE278808 Homo sapiens (human) RNA-seq (gene expression) 26 samples Submitted 2025/12/04 Platform GPL20301Platform GPL24676
At a glance

RNA-seq (gene expression) · human · 26 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Homo sapiens (human)
Samples
26 samples: 6 conditions, mostly in duplicateGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
Mutations of schizophrenia risk gene SETD1A dysregulate synaptic function in human neuronsMolecular psychiatry · 2025
Summary (written by the submitters)
Schizophrenia (SCZ) is a complex neuropsychiatric disorder associated with both common risk variants of small effect sizes and rare risk variants of high penetrance. Rare protein truncating variants (PTVs) in SETD1A (SET Domain Containing 1A) show a strong association with SCZ; however, it remains largely unclear how rare PTVs in SETD1A contribute to the pathophysiology of SCZ.
Read the full summary ↓
To understand the impact of SETD1A rare PTVs in human neurons, we CRISPR/Cas9-engineered five isogenic pairs of human induced pluripotent stem cells (iPSCs), with a recurrent heterozygous patient-specific PTV mutation c.4582-2delAG in two donor lines and a heterozygous frameshift mutation c.4596_4597insG (p. Leu1533fs) in three donor lines. These two mutations are predicted to cause a premature stop codon in exon 16 of SETD1A, leading to the loss of the conserved SET domain that is critical for its histone methyltransferase activity. We found that these presumably loss-of-function (LoF) mutations caused the SETD1A mRNAs to be degraded by nonsense-mediated decay (NMD), accompanied by a reduction of full-length SETD1A protein level in iPSCs. We then characterized the morphological, electrophysiological, and transcriptomic impacts of the SETD1A+/- LoF mutations in iPSC-derived human excitatory neurons induced by NGN2. We found that the SETD1A+/- exon-16 LoF mutations altered dendrite complexity, dysregulated synaptic transmission, and synaptic plasticity, likely by dysregulating genes involved in synaptic function. These results provide mechanistic insights into how SETD1A+/- exon-16 patient-specific LoF mutations affect neuron phenotypes that may be relevant to the pathophysiology of SCZ.
Published in
Mutations of schizophrenia risk gene SETD1A dysregulate synaptic function in human neurons
Su X, Zhang H, Hong Y et al. · Molecular psychiatry 2025 · PMID 40962831 · doi:10.1038/s41380-025-03246-z
This dataset
Open GSE278808 in finder → Find more human RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE278808_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1168956 and SRA study SRP536635. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 40962831) ↗
Study design
6 conditions, mostly in duplicate
Ngn2_CD07_SETD1A_fs_control, ×3 Ngn2_CD07_SETD1A_fs_mutant, ×3 Ngn2_CD15_SETD1A_fs_control, ×2 Ngn2_CD15_SETD1A_fs_mutant, ×2 Ngn2_CD19_SETD1A_fs_control, ×2 Ngn2_CD19_SETD1A_fs_mutant, ×2 Ngn2_CD07_SETD1A_del_control [EX16KI_7C1] ×1 Ngn2_CD07_SETD1A_del_control [EX16KI_7C2] ×1 +10 more

Supports a case/control comparison: 13 samples read as cases, 13 as controls.

How we read this: 6 replicated groups read from 26 sample titles; they account for 14 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
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