IgA Nephropathy Genetic Risk Score to Estimate the Prevalence of IgA Nephropathy in UK Biobank

Abstract

Background: IgA nephropathy (IgAN) is the commonest glomerulonephritis worldwide. Its prevalence is difficult to estimate, as people with mild disease do not commonly receive a biopsy diagnosis. We aimed to generate an IgA nephropathy genetic risk score (IgAN-GRS) and estimate the proportion of people with hematuria who had IgAN in the UK Biobank (UKBB).

Methods: We calculated an IgAN-GRS using 14 single-nucleotide polymorphisms (SNPs) drawn from the largest European Genome-Wide Association Study (GWAS) and validated the IgAN-GRS in 464 biopsy-proven IgAN European cases from the UK Glomerulonephritis DNA Bank (UKGDB) and in 379,767 Europeans in the UKBB. We used the mean of IgAN-GRS to calculate the proportion of potential IgAN in 14,181 with hematuria and other nonspecific renal phenotypes from 379,767 Europeans in the UKBB.

Results: The IgAN-GRS was higher in the IgAN cohort (4.30; 95% confidence interval [95% CI: 4.23-4.38) than in controls (3.98; 3.97-3.98; P < 0.0001). The mean GRS in UKBB participants with hematuria (n = 12,858) was higher (4.04; 4.02-4.06) than UKBB controls (3.98; 3.97-3.98; P < 0.0001) and higher in those with hematuria, hypertension, and microalbuminuria (n = 1323) (4.07; 4.02-4.13) versus (3.98; 3.97-3.98; P = 0.0003). Using the difference in these means, we estimated that IgAN accounted for 19% of noncancer hematuria and 28% with hematuria, hypertension, and microalbuminuria in UKBB.

Conclusions: We used an IgAN-GRS to estimate the prevalence of IgAN contributing to common phenotypes that are not always biopsied. The noninvasive use of polygenic risk in this setting may have further utility to identify likely etiology of nonspecific renal phenotypes in large population cohorts.

Keywords: Genetic Risk Scores; IgA nephropathy; chronic kidney disease; epidemiology; hematuria.

Graphical abstract

Figure 1

Graph of estimated prevalence of IgA nephropathy (IgAN) in different mixture (hematuria, hypertension [HTN], microalbuminuria [micalb]) (with 95% confidence intervals represented by error bars). Controls: UK Biobank (UKBB) healthy individuals (without IgAN, hypertension, diabetes, albuminuria, renal disease). IgAN-related phenotypes: hematuria, hypertension, microalbuminuria. Cases: IgAN cases from UKBB and UK Glomerulonephritis DNA Bank (UKGDB) combined. Red numbers represent the genetic risk score (GRS) of phenotype that could be explained by IgAN calculated using the following formula: Proportion = (phenotype GRS – control GRS) / (IgAN-GRS – control GRS).

Figure 2

Proof of concept. Simulated mixture of IgA nephropathy (IgAN) and UK Biobank (UKBB) control in different percentage mixture. Data are sampled with replacement from IgAN cases (UK Glomerulonephritis DNA Bank [UKGDM] and UKBB) and UKBB control to generate these mixtures. The mean genetic risk score (GRS) is then calculated (red) and the estimated prevalence was calculated using our equation. The simulation mixture matches the calculated estimated prevalence.

Figure 3

Density plot demonstrating the distribution of IgA genetic risk scores of UK Biobank (UKBB) controls (green line, n = 151,103) and IgA nephropathy (IgAN) cases (red line, n = 586) from UKBB and the UK Glomerulonephritis DNA Bank cohort.