Abstract: PUB195
Genome-Wide Association StudyMeta-Analysis to Uncover the Molecular Etiology of Posterior Urethral Valves
Session Information
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits
Authors
- Vendrig, Lisanne M., Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Lim, Tze Yin, Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, United States
- Tanck, Michael Wt, Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, Netherlands
- Maj, Carlo, Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
- Chan, Melanie M.Y., Medical Research Council Laboratory of Medical Sciences, Imperial College London, London, United Kingdom
- Sanna-Cherchi, Simone, Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, United States
- Hilger, Alina, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany
- van der Zanden, Loes Fm, IQ Health Science Department, Radboud university medical center, Nijmegen, Netherlands
- Westland, Rik, Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
Background
Posterior urethral valves (PUV) are the commonest cause of kidney failure in boys. Although a genetic origin is suspected for PUV, its molecular etiology remains largely unknown. Hence, we performed a genome-wide association study (GWAS) meta-analysis of three study cohorts to better characterize the role of common variants in PUV.
Methods
Summary statistics from two previously published GWAS (Van der Zanden, 2022; Chan, 2022) were combined with an additional unpublished cohort. In total, 1,037 PUV cases and 17,170 matched controls were included. All cases and controls were male and of European ancestry. Variants were called using DNA microarray genotyping (948 cases, 8,823 controls) or whole-genome sequencing (89 cases, 8,347 controls). Quality control included standard measures. Genome-wide logistic regression analysis was performed with principal components as covariates. 4,694,037 autosomal variants were analyzed using the inverse-variance approach in METAL.
Results
14 loci showed suggestive association (P < 10-5) with PUV. The variant with the strongest association (OR 0.70, 95% CI 0.61-0.80, P = 1.81 x 10-7) was located at the Chr1q21.1 region that is associated with known genomic disorders (OMIM #612474/612475). Large and rare duplications at this locus have been previously implicated in PUV. Further post-GWAS analyses are pending.
Conclusion
In this large-scale European GWAS meta-analysis in PUV, suggestive association was seen at 14 loci. The strongest association was found within a genomic disorder locus for PUV, potentially influencing gene dosage. Additional analyses will be performed and presented.