Abstract
AbstractThe immune system plays a crucial role in many human diseases. In this context, genome-wide association studies (GWAS) offer valuable insights to elucidate the role of immunity in health and disease. The present multi-omics study aimed to identify genetic determinants of immune cell type distributions in the blood of healthy individuals and to assess whether the distributions of these cells may play a role for autoimmune and COVID-19 disease risk.To this end, the frequencies of different immune cells in 483 healthy individuals from the Berlin Aging Study II were quantified using flow cytometry, and GWAS was performed for 92 immune cell phenotypes. Additionally, we performed linear regression analyses of immune cell distributions using polygenic risk scores (PRS) based on prior GWAS for five autoimmune diseases as well as for COVID-19 infection and post-COVID syndrome (“long COVID”).We validated seven previously described immune loci and identified 13 novel loci showing genome-wide significant (α=5.00E-8) association with different immune cell phenotypes. The most significant novel signal was conferred by theSLC52A3locus, encoding for a riboflavin transporter protein, which was associated with naïve CD57+ CD8+ T cells (p=4.13E-17) and colocalized withSLC52A3expression. Several novel loci contained immunologically plausible candidate genes, e.g., variants nearTBATAandB3GAT1representing genes associated with T cell phenotypes. The PRS of type 1 diabetes were significantly associated with CD8+ T cells at different differentiation states (p≤7.02E-4), and PRS of long COVID were associated with early-differentiated CD4+ T cells (p≤1.54E-4).In conclusion, our extensive immune cell GWAS analyses highlight several novel genetic loci of likely relevance for immune system function. Furthermore, our PRS analyses point to a shared genetic basis between immune cell distributions in healthy adults and T1D (CD8+ T cells) as well as long COVID (CD4+ T cells).
Publisher
Cold Spring Harbor Laboratory