Genetic variation is a sizeable driver of complex diseases and cellular profiles. However, these genetic effects are also modulated by biological variables such as genetic ancestry, disease, sex, age and cell type, as well as environmental variables like geographical region. Revealing the context-dependent influence of genetic variation on gene expression is crucial for establishing the molecular mechanisms that drive complex human traits. Single-cell data provides the unique opportunity to reveal dynamic genetic regulation across cell types that are altered by biological and environmental contributors.
Therefore, we estimated genetic effects in peripheral blood mononuclear cells (PBMCs) from >3,000 samples and >10 million cells spanning genetic ancestries, ages, sexes and geographical regions. We identified thousands of genetic effects, including many that are context dependent across cell type, genetic ancestry, age, sex and geography.
In addition, we will test for co-localisation of immune and blood phenotype genome-wide association study loci with our context-dependent genetic regulation loci to reveal mechanisms of disease susceptibility genetics. Importantly, the context-dependent nature of this analysis will provide critical insights into additional variables that may interact with genetic variants and contribute to disease susceptibility.
Our results demonstrate the complex interplay between genetics, biological variables and environmental contributors and demonstrate the critical need of generating diverse single-cell data that spans multiple measures of biological and environmental variation. Our results provide the foundation to reveal the biological underpinnings of diseases, identify pharmaceutical targets and hopefully, improve health outcomes for overlooked communities.