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Abstract: SA-OR11

Genome-Wide Association Studies of a Composite Renal Phenotype Reveal Pleiotropic Effects and a Novel Locus

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic


  • Barua, Moumita, Toronto General Hospital, Toronto, Ontario, Canada
  • Gagliano Taliun, Sarah A., Universite de Montreal, Montreal, Quebec, Canada
  • Paterson, Andrew, The Hospital for Sick Children, Toronto, Ontario, Canada

Our previous genome-wide association study (GWAS) of hematuria using ICD codes in the UK Biobank identified 6 loci, some of which overlap with loci for albuminuria suggesting pleiotropy. Hematuria cases had higher systolic blood pressure, higher urine albumin:creatinine (uACR) ratios and lower eGFR compared to controls, supporting enrichment for hematuria due to glomerular pathologies. Although most GWAS analyze one trait at a time, many clinical syndromes are defined by combinations of outcomes. Therefore, generating a combined phenotype may improve power to detect loci influencing multiple traits.


The composite outcome of hematuria and albuminuria was chosen to enrich for glomerular disease. We performed a case-control GWAS in the white British subset of the UK Biobank. Cases had both hematuria defined by ICD codes and albuminuria defined as uACR >3 mg/mmol. Controls did not have either an ICD code for hematuria nor an uACR >3 mg/mmol.


2,429 cases and 343,509 controls were included. eGFR was significantly lower in cases (F: 88.6±16.5 mL/min/1.72m2, M: 82.2±20.1 mL/min/1.72m2 by CKD EPI) compared to controls (F: 90.6±13.1 mL/min/1.72m2, M: 90.6±12.6 mL/min/1.72m2) in both sexes. Variants at 4 loci met genome-wide significance (p<5x10-8) with the following nearest genes: COL4A4-COL4A3, TRIM27, ETV1 and CUBN. TRIM27 is part of the extended MHC locus. Our previous GWAS of hematuria reported COL4A3-COL4A3 variants and HLA-B*0801 within MHC, but the latter is not in linkage disequilibrium (LD) with the TRIM27 variant. Additional loci are identified for the composite outcome including CUBN (previously associated with albuminuria) and a novel signal at chromosome 7 (ETV1, (nearest gene), rs146676616, p=1.3x10-8, alternate allele (G) frequency in cases versus controls: 1.77% versus 0.91%, OR=2.61, 95% CI=1.87-3.63).


GWAS for the composite outcome of hematuria and albuminuria identifies 4 loci. Three were not identified in our previous GWAS of hematuria enriched for glomerular causes. These include variants with closest genes TRIM27, within the extended MHC locus but not in LD with HLA-B*0801 reported previously, CUBN and a novel signal at chromosome 7. Analysis of composite phenotypes has the potential to identify novel loci which have pleiotropic effects.


  • Government Support – Non-U.S.