Title
Single-cell eQTL models reveal dynamic T cell state dependence of disease loci
Date Issued
02 June 2022
Access level
open access
Resource Type
journal article
Author(s)
Nathan A.
Asgari S.
Ishigaki K.
Valencia C.
Amariuta T.
Luo Y.
Beynor J.I.
Baglaenko Y.
Suliman S.
Price A.L.
Murray M.B.
Moody D.B.
Raychaudhuri S.
Publisher(s)
Nature Research
Abstract
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 cells1,2. 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, independent eQTL variants had opposing cell-state relationships. Autoimmune variants were enriched in cell-state-dependent eQTLs, including risk variants for rheumatoid arthritis near ORMDL3 and CTLA4; this indicates that cell-state context is crucial to understanding potential eQTL pathogenicity. Moreover, continuous cell states explained more variation in eQTLs than did conventional discrete categories, such as CD4+ versus CD8+, suggesting that modelling eQTLs and cell states at single-cell resolution can expand insight into gene regulation in functionally heterogeneous cell types.
Start page
120
End page
128
Volume
606
Issue
7912
Language
English
OCDE Knowledge area
Patología Genética humana
Scopus EID
2-s2.0-85129832364
PubMed ID
Source
Nature
ISSN of the container
00280836
Sponsor(s)
Agradecemos a HE Randolph y LB Barreiro por compartir conocimientos y acceso al conjunto de datos de PBMC sobre influenza. Este trabajo está financiado en parte por fondos de los Institutos Nacionales de Salud (U19AI111224, UH2AR067677, T32HG002295, T32AR007530, U01HG009379, R01AI049313, R01AR063759 y U01HG012009)
Sources of information: Directorio de Producción Científica Scopus