Eye-brain connections through genetics and single-cell techniques

Title:

Systematic dissection of pleiotropic loci and critical regulons in exhibitory neurons and microglia relevant to neuropsychiatric and occular diseases

Brief description

Background: Single-cell multimodal techniques have advanced our understanding of disease-relevant loci identified in genome-wide association studies (GWASs). However, the functional interpretation of these variants remains challenging. It is still unclear how these variants modulate core gene-regulatory networks in specific cell types to influence complex diseases.

Methods: We leveraged a computational framework to integrate bulk and single-cell multiomic (scRNA-seq and scATAC-seq) profiles with GWAS summary statistics for identifying critical transcription factor (TF)-regulatory regulons through which genetic variants influence eight neuropsychiatric and five ocular diseases. Various genetic methods were utilized to uncover pleiotropic loci, risk genes, and key pathways for the diseases.

Results: Our analysis revealed five latent factors explaining 61.7% of genetic variances across the 13 eye and brain diseases, showing diverse correlational patterns among these conditions. We identified 45 pleiotropic loci with 91 candidate genes contributing to disease risk. Integration of the GWAS and single-cell sequencing data implicated excitatory neurons and microglia in eye-brain connections. Network-based polygenic enrichment analysis identified 15 disease-relevant pleiotropic regulons in exhibitory neurons, including BCL11A, STAT4, and GLS1, and 16 disease-relevant pleiotropic regulons in microglia, such as SPI1, FOXP2, and MEF2C. Exhibitory neuron-specific regulons were functionally involved in axon guidance and synaptic activity, while microglia-specific regulons related to immune response and cell activation.

Conclusions: Our study reinforces the genetic link between psychiatric and ocular diseases and provides biological insights into the potential regulatory mechanisms and implications for future therapeutic development.

Keywords:

GWAS, Genetic correlation, Pleiotropy, Psychiatric disorders, Ocular diseases

Workflow of current study

Correspondence should be addressed to:

Yunlong Ma, Ph.D Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania; E-mail: [email protected]

Citation

1. Ma et al., Sytematic dissection of pleiotropic loci and critical regulons in exhibitory neurons and microglia relevant to neuropsychiatric and ocular diseases, Research Square, 2024.

Other references:

2. Ma et al., Polygenic network enrichment identifies cellular context-specific regulons relevant to diseases by integration of single-cell multiomic data, medRvix, 2024.

3. Ma et al., Integration of human organoids single-cell transcriptomic profiles and human genetics repurposes critical cell type-specific drug targets for severe COVID-19, Cell Proliferation, 2024. Ma et al., Cell Proliferation, 2024, and see related Github codes.

4. Ma et al., Polygenic regression uncovers trait-relevant cellular contexts through pathway activation transformation of single-cell RNA sequencing data, Cell Genomics, 2023. see Ma et al., Cell Genomics, 2023, and see related Github codes.

5. Ma et al., Integrating single-cell sequencing data with GWAS summary statistics reveals CD16+monocytes and memory CD8+T cells involved in severe COVID-19. Genome Medicine, 2022. see Ma et al., Genome Medicine, 2022, and see related Github codes.