Polygenic risk affects the penetrance of monogenic kidney disease

BACKGROUND: Chronic kidney disease (CKD) is a genetically complex disease determined by an interplay of monogenic, polygenic, and environmental risks. Most forms of monogenic kidney diseases have incomplete penetrance and variable expressivity. It is presently unknown if some of the variability in penetrance can be attributed to polygenic factors. METHODS: Using the UK Biobank (N=469,835 participants) and the All of Us (N=98,622 participants) datasets, we examined two most common forms of monogenic kidney disorders, autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious variants in the PKD1 or PKD2 genes, and COL4A-associated nephropathy (COL4A-AN caused by deleterious variants in COL4A3, COL4A4, or COL4A5 genes). We used the eMERGE-III electronic CKD phenotype to define cases (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or kidney failure) and controls (eGFR >90 mL/min/1.73m2 in the absence of kidney disease diagnoses). The effects of the genome-wide polygenic score (GPS) for CKD were tested in monogenic variant carriers and non-carriers using logistic regression controlling for age, sex, diabetes, and genetic ancestry. RESULTS: As expected, the carriers of known pathogenic and rare predicted loss-of-function variants in PKD1 or PKD2 had a high risk of CKD (OR(meta)=17.1, 95% CI: 11.1–26.4, P=1.8E-37). The GPS was comparably predictive of CKD in both ADPKD variant carriers (OR(meta)=2.28 per SD, 95%CI: 1.55–3.37, P=2.6E-05) and non-carriers (OR(meta)=1.72 per SD, 95% CI=1.69–1.76, P< E-300) independent of age, sex, diabetes, and genetic ancestry. Compared to the middle tertile of the GPS distribution for non-carriers, ADPKD variant carriers in the top tertile had a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile had only a 3-fold increased risk of CKD. Similarly, the GPS was predictive of CKD in both COL4-AN variant carriers (OR(meta)=1.78, 95% CI=1.22–2.58, P=2.38E-03) and non-carriers (OR(meta)=1.70, 95%CI: 1.68–1.73 P<E-300). The carriers in the top tertile of the GPS had a 2.5-fold higher risk of CKD while the risk for carriers in the bottom tertile was similar to the middle tertile of non-carriers. CONCLUSIONS: Variable penetrance of kidney disease in ADPKD and COL4-AN is partially explained by differences in polygenic risk profiles. Accounting for polygenic factors has the potential to improve risk stratification in monogenic kidney disease and may have implications for genetic counseling.