biostudies-literatureNathan ANIAID NIH HHSNHGRI NIH HHSNIAMS NIH HHS120-128https://www.ebi.ac.uk/biostudies/studies/S-EPMC9842455biostudies-literatureUnknown606(7912)Non-coding genetic variants may cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by differences in gene regulation across fluid functional cell states within cell types. These states-for example, neurotransmitter-driven programs in astrocytes or perivascular fibroblast differentiation-are obscured in eQTL studies that aggregate cells^1,2. Here we modelled eQTLs at single-cell resolution in one complex cell type: memory T cells. Using more than 500,000 unstimulated memory T cells from 259 Peruvian individuals, we show that around one-third of 6,511 cis-eQTLs had effects that were mediated by continuous multimodally defined cell states, such as cytotoxicity and regulatory capacity. In some loci, indepeNatureSingle-cell eQTL models reveal dynamic T cell state dependence of disease loci.PMC9842455U01 HG009379R01 AR063759U01 HG012009U19 AI111224T32 AR007530T32 HG002295P01 AI148102R01 AI049313UH2 AR067677Lecca LNathan ABaglaenko YMurray MBRaychaudhuri SMoody DBIshigaki KPrice ALValencia CBeynor JILuo YSuliman SAsgari SAmariuta TfalseSingle-cell eQTL models reveal dynamic T cell state dependence of disease loci.Non-coding genetic variants may cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by differences in gene regulation across fluid functional cell states within cell types. These states-for example, neurotransmitter-driven programs in astrocytes or perivascular fibroblast differentiation-are obscured in eQTL studies that aggregate cells^1,2. Here we modelled eQTLs at single-cell resolution in one complex cell type: memory T cells. Using more than 500,000 unstimulated memory T cells from 259 Peruvian individuals, we show that around one-third of 6,511 cis-eQTLs had effects that were mediated by continuous multimodally defined cell states, such as cytotoxicity and regulatory capacity. In some loci, indepe2022-01-01T00:00:00Z2022 Jun2026-05-10T06:54:08.357Z2025-04-07T03:18:39.466ZS-EPMC98424553554567810.1038/s41586-022-04713-1