Multiple new genetic loci associated with kidney function and Chronic Kidney Disease: The CKDGen Consortium

A Köttgen; C Pattaro; C Böger; C Fuchsberger; M Olden; N Glazer; A Parsa; X Gao; Q Yang; M Chen; A Teumer; D Chasman; L Kao; I Heid; C Fox

doi:10.1055/s-0030-1266452

Multiple new genetic loci associated with kidney function and Chronic Kidney Disease: The CKDGen Consortium

A Köttgen ¹, C Pattaro ², C Böger ³, C Fuchsberger ², M Olden ³, N Glazer ⁴, A Parsa ⁵, X Gao ⁶, Q Yang ⁷, M Chen ⁷, A Teumer ⁸, D Chasman ⁹, L Kao ¹⁰, I Heid ¹¹, C Fox ¹²

¹Uniklink Freiburg and Johns Hopkins University, Freiburg
²European Academy of Bolzano, Bolzano
³University Medical Center Regensburg, Regensburg
⁴University of Washington, Seattle
⁵University of Maryland, Baltimore
⁶Washington University, St. Louis
⁷Boston University, Boston
⁸Greifswald University, Greifswald
⁹Harvard University, Boston
¹⁰Johns Hopkins University, Baltimore
¹¹University Medical Center Regensburg and Helmholtz Zentrum Munchen, Regensburg
¹²NHLBI's Framingham Heart Study, Framingham

Abstract

Introduction and Aims: Chronic kidney disease (CKD) is a significant public health problem of increasing prevalence. Previous studies support a genetic contribution to CKD. We therefore aimed to identify genetic risk variants for CKD and reduced estimated glomerular filtration rate (eGFR) using genome-wide association studies in the CKDGen Consortium. Methods: Data from 67,093 Caucasian participants of 20 population-based studies (AGES, Amish, ARIC, ASPS, BLSA, CHS, ERF, FamHS, FHS, KORA, Korcula, Micros, Orcades, NSPHS, RS, SHIP, Vis, and WGHS Studies) were included. We performed meta-analysis of genome-wide association results combining beta-estimates using a fixed effects model. Approximately 2.5 million genotyped and imputed single nucleotide polymorphisms (SNPs) per participant were interrogated to identify new susceptibility loci for reduced renal function, estimated by serum creatinine (eGFRcrea), cystatin C (eGFRcys), and CKD (eGFRcrea <60ml/min/1.73m²; n=5,807 CKD cases). Results: Twenty-three genome-wide significant loci (p≤5×10–8 after meta-analysis of the 20 discovery studies) were followed up in 22,982 additional participants of 14 independent replication samples. By incorporating association evidence for different markers of renal function, serum creatinine and cystatin C, we identified 13 novel genomic loci associated with renal function and CKD (such as variants in or near GCKR and SLC7A9; p-value range: 3*10–11 to 1*10–17) and 7 loci likely related to creatinine metabolism (such as variants in or near SLC22A2 and SLC6A13; p-value range: 1*10–8 to 1*10–15). We also confirmed previously identified associations between SNPs in or near UMOD, SHROOM3, and STC1 with eGFR and CKD. SNPs at several of the novel loci were significantly associated with altered gene expression. Conclusions: We identified common risk variants in several novel genomic CKD susceptibility regions. These results may further our understanding of kidney function physiology by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport, and metabolic functions of the kidney.