New mechanistic insights from alignment of accessible chromatin and renal lineage factor DNA-binding with genetics of kidney function
Johannes Schödel et al.
Genome-wide association studies for kidney function identified hundreds of genomic signals overlapping non-coding regions. Prioritizing regulated target genes is key to clarify mechanisms and discover novel therapeutic routes into kidney function preservation. Comprehensive alignment of variants credibly associated with estimated glomerular filtration rate with accessible chromatin across 29 human tissues revealed substantial overlap with regulatory DNA-elements in the liver and the kidney. Variants were enriched in regulatory elements bound by the lineage-transcription factor HNF-1β in renal tubules, resolving several association signals to their likely regulated genes. Our work revealed a polymorphic NDRG1 enhancer that differentially interacted with HNF-1β and regulated cell growth and migration of human tubule cells. Our study follows genetic association to the cellular mechanisms in humans and underscores the utility of intersecting genetic information of common traits with lineage-specific transcription factor binding in a tissue-specific way for determining regulatory mechanisms.

