SingleBrain: A Meta-Analysis of Single-Nucleus eQTLs Linking Genetic Risk to Brain Disorders

Most genetic risk variants for neurological diseases are located in non-coding regulatory regions, where they may often act as expression quantitative trait loci (eQTLs), modulating gene expression and influencing disease susceptibility. However, eQTL studies in bulk brain tissue or specific cell types lack the resolution to capture the brains cellular diversity. Single-nucleus RNA sequencing (snRNA-seq) offers high-resolution mapping of eQTLs across diverse brain cell types. Here, we performed a meta-analysis, "SingleBrain," integrating publicly available snRNA-seq and genotype data from four cohorts, totaling 5.8 million nuclei from 983 individuals. We mapped cis-eQTLs across major brain cell types and subtypes and employed statistical colocalization and Mendelian randomization to identify genes mediating neurological disease risk. We observed up to a 10-fold increase in cis-eQTLs compared to previous studies and uncovered novel cell type-specific genes linked to Alzheimers disease, Parkinsons disease, and schizophrenia that were previously undetectable in bulk tissue analyses. Additionally, we prioritized putative causal variants for each locus through fine-mapping and integration with cell type-specific enhancer and promoter regulatory elements. SingleBrain represents a comprehensive single-cell eQTL resource, advancing insights into the genetic regulation of brain disorders.