Mapping interindividual dynamics of innate immune response at single-cell resolution

Natsuhiko Kumasaka, Raghd Rostom, Ni Huang, Krzysztof Polanski, Kerstin B. Meyer, Sharad Patel, Rachel Boyd, Celine Gomez, Sam N. Barnett, Nikolaos I. Panousis, Jeremy Schwartzentruber, Maya Ghoussaini, Paul A. Lyons, Fernando J. Calero-Nieto, Berthold Göttgens, Josephine L. Barnes, Kaylee B. Worlock, Masahiro Yoshida, Marko Z. Nikolić, Emily StephensonGary Reynolds, Muzlifah Haniffa, John C. Marioni, Oliver Stegle, Tzachi Hagai*, Sarah A. Teichmann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution.

Original languageEnglish
Pages (from-to)1066-1075
Number of pages10
JournalNature Genetics
Volume55
Issue number6
DOIs
StatePublished - Jun 2023

Funding

FundersFunder number
Biotechnology and Biological Sciences Research Council
National Institute for Health and Care Research
UK Coronavirus Immunology Consortium
University College London
UK Research and Innovation
Evelyn Trust20/75
Wellcome Trust206328, 206194, 206328/Z/17/Z
Birkbeck MRCMR/W00111X/1
Rosetrees TrustM944
Medical Research CouncilMR/S036113/1
Action Medical ResearchGN2911
Israel Science Foundation435/20
Wellcome SangerWT206194
UK Regenerative Medicine PlatformMR/5005579/1
Chan Zuckerberg InitiativeDAF2020-217532

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