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Abstract: SA-PO554

Elucidating the Genetic Architecture of Microscopic Hematuria

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Mhaske, Aditi, University College London Department of Renal Medicine, London, London, United Kingdom
  • Sadeghi-Alavijeh, Omid, University College London Department of Renal Medicine, London, London, United Kingdom
  • Downie, Mallory Lorraine, University College London Department of Renal Medicine, London, London, United Kingdom
  • Chan, Melanie M., University College London Department of Renal Medicine, London, London, United Kingdom
  • Gale, Daniel P., University College London Department of Renal Medicine, London, London, United Kingdom
Background

Microscopic hematuria is commonly found during routine urine analysis and may be unrelated to exercise, trauma to the urogenital tract and menstruation. The most common glomerulopathies associated with this finding are IgA nephropathy and type IV collagen defects including Alport syndrome (AS). To elucidate the genetic architecture and identify potential disease-causing variants we used the whole genome sequencing and the phenotypic information from the 100,000 Genomes Project (100KGP) database.

Methods

Genome wide association studies (GWAS) were performed on two cohorts. Cohort one represent the 137 probands recruited with familial hematuria, cohort two comprised 3459 patients with hospital episode statistics (HES) data coding for at least one episode of microscopic hematuria. Both cohorts were ancestry matched to ~45,000 controls inclusive of individuals with diverse genetic ancestry. Enrichment of common, low-frequency (minor allele frequency [MAF] > 0.1%) and rare (MAF < 0.1%) single-nucleotide variant (SNV), indel and rare structural variant (SV) alleles on a genome-wide and per-gene basis was sought using a generalised linear mixed model approach to account for population structure.

Results

In the gene-based analyses we identified COL4A4 (p=6.21E-10, MAF=0.00040) as significantly associated with hematuria. This signal was driven by a stop gain variant that exhibits a founder effect in collagenopathies (rs35138315). The genome wide variant analysis of over 9 million variants in both cohorts did not reveal any statistically significant loci.

Conclusion

This study provides insights on the genetic landscape of hematuria in a national health system. The pathogenic rs35138315 mutation in COL4A4 was also reported recently in a larger cohort of hematuria patients from the UK Biobank. Variants in COL4A4 account for a large proportion of microscopic hematuria at the population level.

Figure 1 - Rare variant manhattan showing COL4A4 as being significantly associated with hematuria