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- Title
Polygenic risk alters the penetrance of monogenic kidney disease.
- Authors
Khan, Atlas; Shang, Ning; Nestor, Jordan G.; Weng, Chunhua; Hripcsak, George; Harris, Peter C.; Gharavi, Ali G.; Kiryluk, Krzysztof
- Abstract
Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease. Polygenic factors may partially explain the observed variability in the penetrance of monogenic diseases. Here, the authors show that a polygenic risk score for chronic kidney disease is significantly associated with a higher risk of renal dysfunction in the two most common monogenic forms of kidney disease, suggesting that accounting for polygenic factors improves risk stratification in monogenic kidney disease.
- Subjects
UNITED Kingdom; MONOGENIC &; polygenic inheritance (Genetics); KIDNEY diseases; POLYCYSTIC kidney disease; EXOMES; DISEASE risk factors; CHRONIC kidney failure
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43878-9