Abstract

Chronic kidney disease (CKD) is a growing health burden currently affecting 10–15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.

Estimated glomerular filtration rate (eGFR) is a measure of kidney function and used to characterize chronic kidney disease. Here, Graham et al. identify 53 novel loci for eGFR in a GWAS meta-analysis, a subset of which are associated with other common diseases, such as diabetes and hypertension, based on PheWAS.

Details

Title
Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis
Author
Graham, Sarah E 1   VIAFID ORCID Logo  ; Nielsen, Jonas B 1   VIAFID ORCID Logo  ; Zawistowski, Matthew 2   VIAFID ORCID Logo  ; Zhou, Wei 3 ; Fritsche, Lars G 2   VIAFID ORCID Logo  ; Gabrielsen, Maiken E 4 ; Skogholt, Anne Heidi 5 ; Surakka Ida 1 ; Hornsby, Whitney E 1 ; Fermin Damian 6 ; Larach, Daniel B 7 ; Kheterpal Sachin 7 ; Brummett, Chad M 7 ; Lee, Seunggeun 2   VIAFID ORCID Logo  ; Kang, Hyun Min 2 ; Abecasis, Goncalo R 2 ; Romundstad Solfrid 8 ; Stein, Hallan 9 ; Sampson, Matthew G 6   VIAFID ORCID Logo  ; Hveem Kristian 10 ; Willer, Cristen J 11   VIAFID ORCID Logo 

1  University of Michigan, Department of Internal Medicine: Cardiology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
2  University of Michigan, Department of Biostatistics: Center for Statistical Genetics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
3  University of Michigan, Department of Computational Medicine and Bioinformatics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
4  Norwegian University of Science and Technology, K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Norwegian University of Science and Technology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393) 
5  Norwegian University of Science and Technology, K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Norwegian University of Science and Technology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Norwegian University of Science and Technology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393) 
6  University of Michigan, Department of Pediatrics: Pediatric Nephrology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
7  University of Michigan, Department of Anesthesiology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
8  Norwegian University of Science and Technology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Levanger Hospital, Health Trust Nord-Trøndelag, Department of Internal Medicine, Levanger, Norway (GRID:grid.414625.0) (ISNI:0000 0004 0627 3093) 
9  Norwegian University of Science and Technology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); St Olav Hospital, Department of Nephrology, Trondheim, Norway (GRID:grid.5947.f) 
10  Norwegian University of Science and Technology, K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Norwegian University of Science and Technology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Norwegian University of Science and Technology, HUNT Research Centre, Department of Public Health and General Practice, Levanger, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393) 
11  University of Michigan, Department of Internal Medicine: Cardiology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Department of Computational Medicine and Bioinformatics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Department of Human Genetics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
Publication year
2019
Publication date
2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-09861-z
ProQuest document ID
2393015071
Copyright
© The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.