Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure

Genome-wide association studies in large population cohorts have now mapped thousands of variants and loci for numerous polygenic traits and diseases. However, with some exceptions, mechanistic understanding of which precise variants affect which genes and in which tissues to modulate trait variation is still lacking. Here, we propose genomic analyses of any complex trait using gene expression and chromatin accessibility across multiple tissues, to identify the TFs and regulatory variants within active enhancers regulating specific genes in individual tissues to explain trait heritability. We apply these methods to blood pressure, a classical polygenic trait, to show that variant heritability contributions of kidney, adrenal, heart and arterial tissues are 3.7%, 5.6%, 6.9%, and 9.8%, respectively, from a total of ~500,000 regulatory variants in the four tissues. We demonstrate that these variants are enriched in enhancers binding specific TFs in each tissue. Our findings suggest that gene regulatory networks perturbed by common regulatory variants in a tissue relevant to a phenotype is the primary source of interindividual variation of BP. These studies provide an approach to scan each human tissue for its physiological contribution to a polygenic trait. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) for human snap frozen tissue samples.