GWAS of Hematuria.

BACKGROUND AND OBJECTIVES

Glomerular hematuria has varied causes but can have a genetic basis, including Alport syndrome and IgA nephropathy.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used summary statistics to identify genetic variants associated with hematuria in White British UK Biobank participants. Individuals with glomerular hematuria were enriched by excluding participants with genitourinary conditions. A strongly associated locus on chromosome 2 (-) was identified. The region was reimputed using the Trans-Omics for Precision Medicine Program followed by sequential rounds of regional conditional analysis, conditioning on previous genetic signals. Similarly, we applied conditional analysis to identify independent variants in the MHC region on chromosome 6 using imputed haplotypes.

RESULTS

In total, 16,866 hematuria cases and 391,420 controls were included. Cases had higher urinary albumin-creatinine compared with controls (women: 13.01 mg/g [8.05-21.33] versus 12.12 mg/g [7.61-19.29]; <0.001; men: 8.85 mg/g [5.66-16.19] versus 7.52 mg/g [5.04-12.39]; <0.001) and lower eGFR (women: 88±14 versus 90±13 ml/min per 1.72 m; <0.001; men: 87±15 versus 90±13 ml/min per 1.72 m; <0.001), supporting enrichment of glomerular hematuria. Variants at six loci (, , , , , and ) met genome-wide significance (<5E-8). At chromosome 2, p.Ser969X (rs35138315; minor allele frequency=0.00035; <7.95E-35; odds ratio, 87.3; 95% confidence interval, 47.9 to 159.0) had the most significant association, and two variants in the locus remained associated with hematuria after conditioning for this variant: p.Gly695Arg (rs200287952; minor allele frequency=0.00021; <2.16E-7; odds ratio, 45.5; 95% confidence interval, 11.8 to 168.0) and a common intron 25 variant (not previously reported; rs58261427; minor allele frequency=0.214; <2.00E-9; odds ratio, 1.09; 95% confidence interval, 1.06 to 1.12). Of the haplotypes, (; minor allele frequency=0.14; <4.41E-24; odds ratio, 0.84; 95% confidence interval, 0.82 to 0.88) displayed the most statistically significant association. For remaining loci, we identified three novel associations, which were replicated in the deCODE dataset for dipstick hematuria (nearest genes: , , and ).

CONCLUSIONS

Our study identifies six loci associated with hematuria, including independent variants in - and . Additionally, three novel loci are reported, including an association with an intronic variant in expressed in the podocyte.

PODCAST

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_04_26_CJN13711021.mp3.