Large scale single-cell transcriptome analysis to identify how environmental stimuli can influence the downstream molecular consequences of immune disease-associated genetic risk variants
M.G.P. van der Wijst, M.R. Dam, H. Brugge, D.H. de Vries, L. Franke
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Over 10% of people suffer from an immune-mediated disease. Both genetic and environmental risk factors contribute to the development of these diseases. In the last decade, genome-wide association studies have identified over a 1000 genetic variants (single nucleotide polymorphisms, SNPs) that increase the risk to develop an immune-mediated disease. In contrast, little is known on the environmental risk factors contributing to the development of these diseases, although several viral and bacterial infectious triggers have been implicated in the initiation of these diseases. Based on previous proof-of-concept studies, we hypothesize that the downstream expression effects of many disease risk-SNPs are cell-type and environmental stimulus-dependent. Therefore, to identify these cell-type specific downstream effects of disease risk-SNPs on gene expression, we will conduct single-cell RNA sequencing on 1000 peripheral blood mononuclear cells (PBMCs) from 100 extensively phenotyped, healthy individuals. Subsequently, to study the (cell-type specific) interplay between disease risk-SNPs and specific infectious stimuli on downstream expression effects in an unbiased manner, we will analyze the single-cell transcriptome of 1000 PBMCs of these same 100 individuals, each being stimulated by 10 different viral, bacterial or fungal infectious triggers. By performing this large scale analysis (1,100,000 single cells), we aim to identify which infectious stimuli are over-represented per immune-mediated disease and in which (potentially previously unknown) cell-types. As such, this study may give us new insights into the causes of developing an immune-mediated disease, and this, may offer new targets for therapeutic intervention.
This study was supported by an ERC starting grant (grant #637640)