Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Research
2019
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| _version_ | 1826275183378300928 |
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| author | Teumer, A Li, Y Ghasemi, S Prins, BP Wuttke, M Hermle, T Giri, A Sieber, KB Qiu, C Kirsten, H Tin, A Chu, AY Bansal, N Feitosa, MF Wang, L Chai, J-F Cocca, M Fuchsberger, C Gorski, M Hoppmann, A Horn, K Li, M Marten, J Noce, D Nutile, T Sedaghat, S Sveinbjornsson, G Tayo, BO van der Most, PJ Xu, Y Yu, Z Gerstner, L Ärnlöv, J Bakker, SJL Baptista, D Biggs, ML Boerwinkle, E Brenner, H Burkhardt, R Carroll, RJ Chee, M-L Chee, M-L Chen, M Cheng, C-Y Cook, JP Coresh, J Corre, T Danesh, J de Borst, MH De Grandi, A Lindgren, CM |
| author_facet | Teumer, A Li, Y Ghasemi, S Prins, BP Wuttke, M Hermle, T Giri, A Sieber, KB Qiu, C Kirsten, H Tin, A Chu, AY Bansal, N Feitosa, MF Wang, L Chai, J-F Cocca, M Fuchsberger, C Gorski, M Hoppmann, A Horn, K Li, M Marten, J Noce, D Nutile, T Sedaghat, S Sveinbjornsson, G Tayo, BO van der Most, PJ Xu, Y Yu, Z Gerstner, L Ärnlöv, J Bakker, SJL Baptista, D Biggs, ML Boerwinkle, E Brenner, H Burkhardt, R Carroll, RJ Chee, M-L Chee, M-L Chen, M Cheng, C-Y Cook, JP Coresh, J Corre, T Danesh, J de Borst, MH De Grandi, A Lindgren, CM |
| author_sort | Teumer, A |
| collection | OXFORD |
| description | Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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| first_indexed | 2024-03-06T22:54:50Z |
| format | Journal article |
| id | oxford-uuid:60039a64-5a00-427e-982c-c76d72c2073b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:54:50Z |
| publishDate | 2019 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:60039a64-5a00-427e-982c-c76d72c2073b2022-03-26T17:50:47ZGenome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:60039a64-5a00-427e-982c-c76d72c2073bEnglishSymplectic ElementsNature Research2019Teumer, ALi, YGhasemi, SPrins, BPWuttke, MHermle, TGiri, ASieber, KBQiu, CKirsten, HTin, AChu, AYBansal, NFeitosa, MFWang, LChai, J-FCocca, MFuchsberger, CGorski, MHoppmann, AHorn, KLi, MMarten, JNoce, DNutile, TSedaghat, SSveinbjornsson, GTayo, BOvan der Most, PJXu, YYu, ZGerstner, LÄrnlöv, JBakker, SJLBaptista, DBiggs, MLBoerwinkle, EBrenner, HBurkhardt, RCarroll, RJChee, M-LChee, M-LChen, MCheng, C-YCook, JPCoresh, JCorre, TDanesh, Jde Borst, MHDe Grandi, ALindgren, CMIncreased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria. |
| spellingShingle | Teumer, A Li, Y Ghasemi, S Prins, BP Wuttke, M Hermle, T Giri, A Sieber, KB Qiu, C Kirsten, H Tin, A Chu, AY Bansal, N Feitosa, MF Wang, L Chai, J-F Cocca, M Fuchsberger, C Gorski, M Hoppmann, A Horn, K Li, M Marten, J Noce, D Nutile, T Sedaghat, S Sveinbjornsson, G Tayo, BO van der Most, PJ Xu, Y Yu, Z Gerstner, L Ärnlöv, J Bakker, SJL Baptista, D Biggs, ML Boerwinkle, E Brenner, H Burkhardt, R Carroll, RJ Chee, M-L Chee, M-L Chen, M Cheng, C-Y Cook, JP Coresh, J Corre, T Danesh, J de Borst, MH De Grandi, A Lindgren, CM Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. |
| title | Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. |
| title_full | Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. |
| title_fullStr | Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. |
| title_full_unstemmed | Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. |
| title_short | Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. |
| title_sort | genome wide association meta analyses and fine mapping elucidate pathways influencing albuminuria |
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