Population-scale single-nucleus multi-omic profiling of skeletal muscle reveals extensive context-specific genetic regulation.

Abstract

Skeletal muscle tissue underlies several polygenic metabolic traits and diseases. Identifying their genetic mechanisms requires pinpointing cell types, regulatory elements, target genes and causal variants. Here we use genetic multiplexing to generate population-scale single-nucleus chromatin accessibility (single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq)) and transcriptome (single-nucleus RNA sequencing (snRNA-seq)) maps across 287 frozen human skeletal muscle biopsies. We identify 13 cell types and integrate genetic variation to discover >7,000 expression quantitative trait loci (eQTLs) and >100,000 chromatin accessibility QTLs (caQTLs) across cell types, including context-specific eQTL/caQTL with significant G × C interaction. We identify nearly 2,000 eGenes colocalized with caQTL and construct causal directional maps for chromatin accessibility and gene expression. Almost 3,500 genome-wide association study (GWAS) signals across 38 relevant traits colocalize with sn-eQTL/caQTL, most in a cell-specific manner. These signals typically colocalize with caQTL and not eQTL, highlighting the importance of population-scale chromatin profiling for GWAS functional studies. The results of this study illuminate the genetic regulatory architecture of human skeletal muscle.