Genetic determinants and phenotypic consequences of blood T-cell proportions in 207,000 diverse individuals

T-cells play a critical role in multiple aspects of human health and disease, yet large-scale studies of the genetic determinants of human T-cell abundance have been limited because T-cell–specific measurements are not widely available in clinical or research settings. We directly estimated T-cell fractions from whole genome sequencing (WGS) data in over 200,000 individuals from the multi-ethnic TOPMed and All of Us studies by leveraging read-depth patterns across the V(D)J recombination region of the T-cell receptor alpha (TRA) locus. We identified 27 loci associated with T-cell fraction. Using electronic health records, we found clinical phenotypes associated with T-cell fraction, with notable changes enriched in respiratory diseases. Estimating T-cell fraction from sequencing provided new insights into the genetic regulation of T-cells and the phenotypic consequences of T-cell fraction variation across the human phenome.

Hannah Poisner, Annika Faucon, Nancy Cox, Alexander G. Bick