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 - Funding Information:
Funders: National Human Genome Research Institute, (Grant / Award Number: 'R01 HG010480') Deutsche Forschungsgemeinschaft, (Grant / Award Number: '431984000 – SFB 1453') National Institute of Diabetes and Digestive and Kidney Diseases, (Grant / Award Number: 'U01 DK085689','U01 DK106981') National Heart, Lung, and Blood Institute, (Grant / Award Number: 'HHSN268201700001I','HHSN268201700002I','HHSN268201700003I','HHSN268201700004I','HHSN2682 01700005I','R01 HL134320','U01 2U01HL096812','U01 2U01HL096814','U01 2U01HL096899','U01 2U01HL096902','U01 2U01HL096917') Financial Disclosure: No C. Ballantyne reports Consultancy Agreements with Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, Astra Zeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma Inc, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, Sanofi-Synthelabo; Research Funding from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, Roche Diagnostic; and Scientific Advisor or Membership with Amarin, Amgen, Arrowhead, Astra Zeneca, Corvidia, Esperion, and Matinas BioPharma. R. Hoogeveen reports Consultancy Agreements with and Research Funding from Denka Seiken. D. Arking reports Scientific Advisor or Membership with Association for the Eradication of Heart Attach (AEHA) Scientific Advisory Board. M. Grams reports Honoraria from Academic institutions for giving grand rounds and ASN for Young Investigator Award; Scientific Advisor or Membership with AJKD, CJASN, JASN Editorial Fellowship Committee, NKF Scientific Advisory Board, KDIGO Executive Committee, USRDS Scientific Advisory Board; Other Interests/Relationships with NKF --which receives funding from Relypsa, Abbvie, and Thrasos; and Received travel support from DCI to speak at the annual meeting and KDIGO for participation in scientific meetings and the executive committee. J. Coresh reports Consultancy Agreements with Ultragenyx, Kaleido, Healthy.io; Ownership Interest in Health.io; Research Funding from National Institutes of Health (NIH), National Kidney Foundation (NKF which receives industry support); and Scientific Advisor or Membership with Healthy.io, and National Kidney Foundation. A. Kottgen reports Honoraria from Sanofi Genzyme; Scientific Advisor or Membership with Journal of the American Society of Nephrology, American Journal of Kidney Diseases, Kidney International, Nature Reviews Nephrology, and American Kidney Fund. All remaining authors have no conflict of interest to declare.
Funding Information:
Funding from National Institutes of Health (NIH), National Kidney Foundation (NKF which
Funding Information:
Foundation) – Project-ID 431984000 – SFB 1453. CMB is supported by National Heart, Lung,
Funding Information:
supported by National Human Genome Research Institute grant R01 HG010480. The
Funding Information:
The work of AK is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research
Funding Information:
and Blood Institute grant R01 HL134320. JC is supported by National Institute of Diabetes and
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 -