Disease-associated variants are enriched for altering cell-type-specific gene co-expression relationships

Genes act within complex regulatory networks, and genetic variants can perturb these networks by altering gene co-expression. Here, we performed co-expression quantitative trait locus (co-eQTL) mapping using single-cell RNA-seq from the sc-eQTLGen consortium (1,330 donors, >2 million cells), enabling sensitive detection and prioritization of informative variant-gene-gene triplets. We identified co-eQTLs for 398 eGenes where a nearby genetic variant affected both the genes expression (cis-gene) and its co-expression with other genes, often implicating upstream regulators. For 181 genes, we inferred a likely upstream transcription factor, with motif disruption predicted for 41 genes. These upstream genes are more often loss-of-function intolerant and show more network connections, providing an explanation for why co-eQTL variants are 2.8x more strongly associated with immune diseases than classical eQTLs. These findings position co-eQTLs as mechanistic links between genetic variation and disease, revealing how variants can rewire cell-type-specific gene networks.