Background: Polycystic kidney disease (PKD) affects 12 million individuals worldwide. Although genomics has been transformative in PKD diagnostics, there is considerable unexplained variance in disease severity. Post state-of-the-art genetic screening, 8-10% of PKD patients with a Mendelian-like family history do not achieve a molecular diagnosis.
Hypothesis: PKD is the result of a combination of previously established monogenic causes but also polygenic factors. Rare variant burden and polygenic factors may explain a portion of observed variation of disease severity.
Opportunity: Ireland has a genetically homogenous population, the highest birth rates in Europe and a clinical infrastructure that facilitates recruitment. The Beaumont Hospital Renal Genetics Clinic receives referrals from all Irish renal units, facilitating extensive recruitment of PKD cases.
Approach: We will address knowledge gaps via three complementary work packages. In Work Package 1, we will create a deeply phenotyped population of 379 Irish PKD patients, genetically stratified into those with/without a molecular diagnosis. In Work Package 2, we will undertake genetic analysis of 550 individuals with PKD (from work package 1) to determine the role of polygenic burden, calculated from both common and rare variation as well as rare variant burden, as modifiers of PKD risk and prognosis. Results will be meta analysed with >1000 US PKD patients. In Work Package 3 we will use genetic linkage and whole exome sequencing to identify new genes involved in the pathogenesis of PKD where current state of the art genetic testing has failed to identify a molecular diagnosis in large Irish families.
Impact: This project will challenge the current paradigm that PKD genetics is completely explained by monogenic segregation patterns and has potential to identify new PKD genes. This project will impact the clinic by providing the framework to combine known disease-causing mutations with broad genetic background, to inform on prognosis and treatment.
