TY - JOUR
T1 - Polygenic risk scores for kidney function and their associations with circulating proteome, and incident kidney diseases
AU - Yu, Zhi
AU - Jin, Jin
AU - Tin, Adrienne
AU - Köttgen, Anna
AU - Yu, Bing
AU - Chen, Jingsha
AU - Surapaneni, Aditya
AU - Zhou, Linda
AU - Ballantyne, Christie M.
AU - Hoogeveen, Ron C.
AU - Arking, Dan E.
AU - Chatterjee, Nilanjan
AU - Grams, Morgan E.
AU - Coresh, Josef
N1 - Publisher Copyright:
© 2021 American Society of Nephrology. All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-Analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed a significant association with all outcomes. Hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.
AB - Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-Analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed a significant association with all outcomes. Hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.
KW - Chronic kidney disease
KW - End stage kidney disease
KW - Genetics
KW - Kidney function
KW - Polygenic risk score
KW - Proteomics
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U2 - 10.1681/ASN.2020111599
DO - 10.1681/ASN.2020111599
M3 - Article
C2 - 34548389
AN - SCOPUS:85120694644
SN - 1046-6673
VL - 32
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -