Tandem repeat variation shapes immune cell type-specific gene expression

Tandem repeats (TRs)-highly polymorphic, repetitive sequences across the human genome-are important regulators of gene expression but remain underexplored due to challenges in accurate genotyping and analysis¹. Here we generate whole-genome and single-cell RNA sequencing from more than 5.4 million blood-derived cells across 1,925 individuals in two cohorts², and perform meta-analysis to characterize the impact of variation in more than 1.7 million TR loci on immune cell type-specific gene expression. We identify more than 69,000 single-cell expression quantitative trait loci, 30.7% of which are specific to 1 of 28 immune cell types, and reveal dynamic regulatory effects using cell-state inference. Matched single-cell assay for transposase-accessible chromatin with high-throughput sequencing profiles from more than 3.4 million nuclei in 922 individuals³ uncover chromatin accessibility quantitative trait loci for nearly one-third of expression-associated TRs, supporting coordinated effects on cis-regulatory architecture. Fine-mapping implicates 1,490 TRs as candidate causal drivers of gene expression in 6.1% of tested genes, and colocalization analyses highlight more than 200 genes in which TRs likely mediate genetic associations with immune and haematological traits. Together, these results provide a genome-wide, multiomic view of TR-mediated regulation in the human immune system, establishing TRs as key contributors to cell type-specific regulatory variation and complex trait architecture.