Chromatin Conformation Links Distal Target Genes to CKD Loci.
Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chromosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis. Expression quantitative trait loci analysis revealed that mRNA levels of many target genes are genotype dependent. Pathway analyses showed that target genes were enriched in processes crucial for renal function, identifying dysregulated geranylgeranyl diphosphate biosynthesis as a potential disease mechanism. Overall, our data annotated multiple genes to previously reported CKD-associated single-nucleotide polymorphisms and provided evidence for interaction between these loci and target genes. This pipeline provides a novel technique for hypothesis generation and complements classic GWAS interpretation. Future studies are required to specify the implications of our dataset and further reveal the complex roles that common variants have in complex diseases, such as CKD.
['Brandt|Maarten M|MM|', 'Meddens|Claartje A|CA|', 'Louzao-Martinez|Laura|L|', 'van den Dungen|Noortje A M|NAM|', 'Lansu|Nico R|NR|', 'Nieuwenhuis|Edward E S|EES|', 'Duncker|Dirk J|DJ|', 'Verhaar|Marianne C|MC|', 'Joles|Jaap A|JA|', 'Mokry|Michal|M|', 'Cheng|Caroline|C|']
D000818:Animals D053898:Biosynthetic Pathways D002478:Cells, Cultured D002843:Chromatin D004247:DNA D030541:Databases, Genetic D042783:Endothelial Cells D020022:Genetic Predisposition to Disease D005838:Genotype D006706:Homeostasis D006801:Humans D007684:Kidney Tubules D051379:Mice D009690:Nucleic Acid Conformation D020641:Polymorphism, Single Nucleotide D040641:Quantitative Trait Loci D012333:RNA, Messenger D051436:Renal Insufficiency, Chronic D017422:Sequence Analysis, DNA
DNA regulatory elements circular chromosome conformation capture (4C) sequencing 3D chromatin structure STARR-seq chronic kidney disease transcriptional regulation