THE BIOLOGICAL AND FUNCTIONAL CHARACTERISATION OF GENES RESPONSIBLE FOR MONOGENIC DISORDERS OF THE KIDNEY

Abstract Background and Aims Single mutations in over 620 genes are known as drivers of approximately 330 monogenic disorders of the kidney. These disorders are estimated to account for up to 10% of chronic kidney disease cases. Due to their disease-causing nature, these genes are particularly clinically relevant targets for molecular analysis, but, so far, there has been no systematic analysis of their expression profile and biological functions in the human kidney. We aimed to characterise and compare the genes responsible for monogenic disorders of the kidney with other non-monogenic protein-coding genes. Method We used RNA-sequencing profile of 430 kidneys to explore the characteristics of 530 monogenic genes whose expression was available for analysis in the dataset. The property of genes was characterised using in silico databases such as Genome Reference Consortium Human Build 37 (GRCh37), Drug Gene Interaction database (DGIdb) and the Human Protein Atlas (HPA). The PANTHER (protein analysis through evolutionary relationships) database was used to determine the biological network of interactions between the monogenic genes. A Fast Gene Set Enrichment Analysis (FGSEA) was carried out using single-cell RNA-sequencing data for eight cell types of the kidney from Young et al. Finally, we carried out a two-stage mendelian randomisation to discover a causal link between gene expression and estimated glomerular filtration rate (eGFR) and blood pressure (BP). We used the summary statistics from UK Biobank and the CKDGen consortium for BP and eGFR respectively. Results The expression of monogenic genes was both higher and more specific to the kidney, than other protein-coding kidney genes. The pathway analysis found both fetal and organ development to be overrepresented in this set of genes, when compared to non-monogenic kidney genes. We also found that monogenic genes are significantly overrepresented for cell-type specific expression in the proximal tubule and underrepresented in podocytes. Our Mendelian randomisation analysis identified a causal effect between the expression of 50 monogenic genes and either eGFR, systolic or diastolic blood pressure. Conclusion Our studies revealed differences in the renal expression profile of monogenic genes and protein-coding genes. The proximal tubule segment of the nephron is a particularly enriched segment of the nephron for monogenic disorders. Kidney expression of 50 of the monogenic genes is causally related to changes in eGFR and blood pressure in the general population.