Genome-wide association studies in pediatric chronic kidney disease

Abstract

The genome-wide association study (GWAS) has become an established scientific method that provides an unbiased screen for genetic loci potentially associated with phenotypes of clinical interest, such as chronic kidney disease (CKD). Thus, GWAS provides opportunities to gain new perspectives regarding the genetic architecture of CKD progression by identifying new candidate genes and targets for intervention. As such, it has become an important arm of translational science providing a complementary line of investigation to identify novel therapeutics to treat CKD. In this review, we describe the method and the challenges of performing GWAS in the pediatric CKD population. We also provide an overview of successful GWAS for kidney disease, and we discuss the established pediatric CKD cohorts in North America and Europe that are poised to identify genetic risk variants associated with CKD progression.

Keywords: Chronic kidney disease; Genetics; Genome-wide association study (GWAS); Pediatric; Translational medicine.

Figure 1

Red—CEU (Caucasian ancestry), Purple—YRI (African ancestry), Green—CHB/YPT (Asian ancestry). The genotyped individuals are shown black dots. Principal component analyses are shown in Panel A: the ESCAPE/4C cohorts (N= 934). We note the cluster near the CEU region for most participants recruited from Western and Central European countries. There is a sub-cluster just below, representing Turkish participants and in Panel B In Panel B, the CKiD cohort (n=444). Near the CEU region there are a cluster of subjects of European ancestry and there is a cluster near YRI representing African Americans. [13]

Figure 2

Kaplan-Meier kidney allograft survival curves in recipient of donor kidney with (red line) and without (blue line) two APOL1 risk variant alleles [30].

Figure 3

Meta-analysis of GWAS results –log₁₀ (P value) versus genomic position plots for CKD (estimated GFR creatinine <60ml/min/1.73m²) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, and RS). Abbreviations: ARIC, Atherosclerosis Risk in Communities Study; CHS, Cardiovascular Health Study; CKD, chronic kidney disease; FHS, Framingham Heart Study; GFR, glomerular filtration rate; RS, Rotterdam Study. [34].

Figure 4

Depiction of the worldwide geospatial distribution for an IgAN genetic risk score. Lowest risk scores (green) in Africa and highest (red) in Asia and the Americas (inset). [42].