Trait-associated noncoding variant regions affect <i>TBX3</i> regulation and cardiac conduction.

Abstract

Genome-wide association studies have implicated common genomic variants in the gene desert upstream of <i>TBX3</i> in cardiac conduction velocity. Whether these noncoding variants affect expression of <i>TBX3</i> or neighboring genes and how they affect cardiac conduction is not understood. Here, we use high-throughput STARR-seq to test the entire 1.3 Mb human and mouse <i>TBX3</i> locus, including two cardiac conduction-associated variant regions, for regulatory function. We identified multiple accessible and functional regulatory DNA elements that harbor variants affecting their activity. Both variant regions drove gene expression in the cardiac conduction tissue in transgenic reporter mice. Genomic deletion from the mouse genome of one of the regions caused increased cardiac expression of only <i>Tbx3,</i> PR interval shortening and increased QRS duration. Combined, our findings address the mechanistic link between trait-associated variants in the gene desert, <i>TBX3</i> regulation and cardiac conduction.