Journal Article

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

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

2023

Overview

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. GASPACHO is a statistical method that identifies nonlinear dynamic genetic effects using single-cell RNA-seq data. Analysis of an antiviral response in human fibroblasts identifies 1,275 expression QTLs, many of which colocalize with risk loci for autoimmune and infectious diseases.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/100 / 38/91 / 45 / 45/43 / 631/114/794 / 631/208/212/2019 / 631/208/514/1949 / 692/699/249/1313 / 692/699/255 / Agriculture / Animal Genetics and Genomics / Antiviral drugs / Autoimmune Diseases / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell cycle / Confounding (Statistics) / COVID-19 / Cytokines / Fibroblasts / Gaussian process / Gene expression / Gene Function / Gene mapping / Gene sequencing / Genetic diversity / Genetic effects / Genetic variance / Genome-wide association studies / Genome-Wide Association Study / Genomes / Heterogeneity / Human Genetics / Humans / Immune response / Immune system / Immunity (Disease) / Immunity, Innate / Infections / Infectious diseases / Innate immunity / Mapping / Nonlinear dynamics / Quantitative trait loci / Ribonucleic acid / RNA / Statistical methods / Statistics / Susceptibility / technical-report / Viral infections