TY - JOUR
T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals
AU - LifeLines Cohort Study
AU - V. A. Million Veteran Program
AU - Wuttke, Matthias
AU - Li, Yong
AU - Li, Man
AU - Sieber, Karsten B.
AU - Feitosa, Mary F.
AU - Gorski, Mathias
AU - Tin, Adrienne
AU - Wang, Lihua
AU - Chu, Audrey Y.
AU - Hoppmann, Anselm
AU - Kirsten, Holger
AU - Giri, Ayush
AU - Chai, Jin-Fang
AU - Sveinbjornsson, Gardar
AU - Tayo, Bamidele O.
AU - Nutile, Teresa
AU - Fuchsberger, Christian
AU - Marten, Jonathan
AU - Cocca, Massimiliano
AU - Ghasemi, Sahar
AU - Xu, Yizhe
AU - Horn, Katrin
AU - Noce, Damia
AU - van der Most, Peter J.
AU - Sedaghat, Sanaz
AU - Yu, Zhi
AU - Akiyama, Masato
AU - Afaq, Saima
AU - Ahluwalia, Tarunveer S.
AU - Almgren, Peter
AU - Amin, Najaf
AU - Ärnlöv, Johan
AU - Bakker, Stephan J. L.
AU - Bansal, Nisha
AU - Baptista, Daniela
AU - Bergmann, Sven
AU - Biggs, Mary L.
AU - Biino, Ginevra
AU - Boehnke, Michael
AU - Boerwinkle, Eric
AU - Boissel, Mathilde
AU - Bottinger, Erwin P.
AU - Boutin, Thibaud S.
AU - Brenner, Hermann
AU - Brumat, Marco
AU - Burkhardt, Ralph
AU - Butterworth, Adam S.
AU - Campana, Eric
AU - Milaneschi, Yuri
AU - Penninx, Brenda W. J. H.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
AB - Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85066607502&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31152163
U2 - https://doi.org/10.1038/s41588-019-0407-x
DO - https://doi.org/10.1038/s41588-019-0407-x
M3 - Article
C2 - 31152163
SN - 1061-4036
VL - 51
SP - 957
EP - 972
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -