Identification of genetic determinants of kidney function and chronic kidney disease

Abstract

The genome wide association study (GWAS) identified hundreds of genomic regions associated with kidney function and chronic kidney disease biomarkers. In many cases, it is still uncertain whether these loci reflect true kidney function or simply variation in biomarker metabolism. This thesis investigates both complexity and specificity of genetic effects on kidney-related traits. The research focused on loci with consistent associations across multiple kidney function markers (eGFRcrea, BUN, eGFRcys) using the homogeneous CHRIS study population. Chapter 2 focused on identifying mediators and environmental modifiers at established kidney function loci, revealing novel links between genetic variants and systemic physiological pathways including magnesium and coagulation traits. Chapter 3 genetically characterized a highly pleiotropic locus at FAM47E–SHROOM3 region, integrating haplotype association analysis with multi-omics data to uncover regulatory mechanisms spanning renal and other metabolic traits. The work was leveraged in Chapter 4 by introducing Haplomics, a computational pipeline for automated haplotype-based analyses across multiple loci, enabling systematic dissection of genetic regions. Additionally, the thesis explored the genetic architecture of bile acid metabolism in Chapter 5. Collectively, this thesis provides novel insights into the molecular mechanisms linking genetic variants to kidney function and introduces conceptual frameworks for genetic investigations for other complex diseases.