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Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders [022]

ABSTRACT: Most causal variants for neuropsychiatric disorders (NPD) remain unknown. A major hurdle is that disease variants may act in specific contexts, such as during neuronal activation, which is difficult to study in vivo at the population level. We profiled single-nucleus neuron-activation multiomics in human induced pluripotent stem cell-derived neurons from 100 donors, revealing the NPD-relevant transcriptomic and epigenomic landscape of neuronal activation. We identified abundant genetic variants associated with activity-dependent gene expression and chromatin accessibility, the latter explaining larger proportions of NPD heritability. Integrating multiomics data with genome-wide association studies further revealed NPD risk variants and genes with effects detected only upon stimulation, such as activity-dependent cholesterol metabolism. Our work highlights the power of cell stimulation to reveal context-specific "hidden" genetic effects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289956 | GEO | 2025/02/20

REPOSITORIES: GEO

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Project description:Genome-wide association studies (GWAS) have identified many risk genes for neuropsychiatric disorders (NPD) such as schizophrenia (SCZ). However, functional interpretation of these GWAS findings remains challenging; a major hurdle is that polygenic risk may manifest its effect conditionally upon neural activation, i.e., context-dependent. Human induced pluripotent stem cell (hiPSC)-derived neurons are a tractable cellular model for ascertaining context-dependent polygenic effects, e.g., neural activation that may mimic the physiological effects of environmental stimuli. Here, we modelled neural activation by depolarisation using high potassium chloride (KCl) in co-cultured excitatory/inhibitory neurons of 100 hiPSC lines (28 from SCZ donors), followed by assaying single-cell multiomes (scRNA/ATAC-seq) of over 700,000 nuclei from neurons at 0 hr (unstimulated), 1 hr (early response), and 6 hr (later response) of high KCI exposure. We linked genes with open chromatin peaks for each main neural subtype (GABAergic inhibitory, NEFM+ or NEFM-excitatory neurons) and confirmed a significant correlation between peak accessibility and target gene expression. Compared to static genes/peaks, dynamic ones, specifically those activity-upregulated, were more enriched for NPD GWAS risk, with the most robust enrichment for SCZ. Based on the dynamic gene expression pattern across the three time points, we found NPD risk genes tend to be continuously upregulated (i.e., with up-up dynamics). We further analysed context-specific SCZ-associated differentially expressed genes (DEGs) using MAST for single neurons of 28 SCZ cases and 72 controls. We found that 3-5%, 4-6%, and 15-23% of genes were SCZ-associated DEGs in NEFM+ excitatory, NEFM- excitatory, and GABAergic neurons, respectively, most of which were cell activity-specific. Notably, we found that SCZ-associated DEGs in high-activity neurons were more enriched for synapse-related GO terms and NPD risk genes. Interestingly, upstream regulatory sequences of the stimulation-specific SCZ-associated DEGs were enriched for binding sites of TCF4, which is a strong GWAS risk gene and was considered the master regulator of other SCZ-related genes. Moreover, the upregulated genes in SCZ cases in the stimulated (only at 6hr) NEFM+ excitatory neurons showed strong enrichment for GO terms related to cholesterol synthesis. Single-neuron DEG analysis for 28 SCZ cases and 28 matched controls gave similar results. Our study suggests that many NPD genes may only elicit disease-relevant effects upon neuronal activation, providing novel insights into how polygenic risk factors interact with environmental stimuli for NPD.

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Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders [022]

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