A study published today in eLife suggests that genetic variation affecting developmental genes not previously associated with urethral development may contribute to the congenital condition that is the most common cause of kidney failure in young males.
The discovery may help scientists understand the causes of a rare condition called posterior urethral valves (PUV), which affects 1 in 4,000 males and leads to blockage of the urethra and a buildup of urine in the bladder that can lead to kidney damage. About a third of individuals with this condition develop kidney failure before the age of 30. Affected individuals often have surgery to remove blockages, but most still have urinary problems even after surgery. Therefore, new insights into the cause of the condition are needed in order to better understand how urology evolves in health and disease and to inform new treatment approaches in the future.
“PUV does not follow a Mendelian inheritance pattern, with each parent contributing one of two possible alleles for a trait, and scientists have not identified a single genetic cause,” explains lead author Dr. Melanie Chan, who conducted the study as a clinical trial. Fellow of the College of Nephrology, Department of Nephrology, London, UK. “This suggests that the genetic basis for this condition is more complex.”
To identify genetic causes, Chan and colleagues analyzed the genomes of 132 unrelated males with PUV and 23,727 individuals without the condition who were recruited into the 100,000 Genomes Project in the UK. Among them were individuals of diverse genetic origins, including people from South Asia, Africa and Europe. They found two genetic variants associated with PUV risk. One was a common genetic variant located on chromosome 12q24.21 and the other was a rare genetic variant on chromosome 6p21. They confirmed the link between these genetic differences and disease in a separate group of individuals of European ancestry that included 395 males with PUV and 4,152 individuals without the disease.
The team then mapped the variation to 12q24.21 to a gene called TBX5, This can turn other genes on or off. They also mapped the 6p21.1 variation to a gene called PTK7, which plays an essential role in cell growth. When they looked at cells from developing human embryos, they found that the proteins encoded by the genes are active in the developing urinary tract. This finding suggests that changes in these proteins may interfere with normal urethral development.
Finally, they showed that structural changes in chromosomes, including inverted portions of DNA or other changes that alter regulation of gene expressionhas also been linked to PUV.
Our study is the first to identify rare and common genetic variation strongly associated with PUV, as well as structural differences in chromosomes that may contribute to the disease. It provides new insights into the causes of this poorly understood disorder.”
Dr. Melanie Chan, lead author
The authors add that the small number of individuals included in this genetic analysis reduces its statistical power for detecting very rare genetic variations associated with PUV. Additionally, they say more studies are needed to verify exactly how these genetic changes cause PUV.
But senior author Professor Daniel Gill, Head of St Peter’s of Nephrology in the Department of Nephrology at University College London, says the study demonstrates the importance of including people with diverse genetic backgrounds in genome-wide studies for rare conditions. He noted that often, genetic studies may consist of European populations only, making them less likely to identify genetic variants that may be important in other groups.
“Increasing diversity in genetic studies is both scientifically and ethically beneficial,” says Professor Gill. “It increases the power of studies to find and verify rare genetic variants and allows the discovery of genetic variants that disproportionately affect individuals of Asian, African or non-European ancestry. It also helps ensure that people around the world benefit equally from treatment.” driven by genetic discoveries.”
Chan, MMY, et al. (2022) A whole-genome sequencing association study identifies the diverse origins of TBX5 and PTK7 as sensitivity genes for posterior urethral valves. eLife. doi.org/10.7554/eLife.74777.