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Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage

BACKGROUND: The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage. RESULTS: Through transcriptome-wide associ...

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Autores principales: Schlosser, Pascal, Zhang, Jingning, Liu, Hongbo, Surapaneni, Aditya L., Rhee, Eugene P., Arking, Dan E., Yu, Bing, Boerwinkle, Eric, Welling, Paul A., Chatterjee, Nilanjan, Susztak, Katalin, Coresh, Josef, Grams, Morgan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291807/
https://www.ncbi.nlm.nih.gov/pubmed/37365616
http://dx.doi.org/10.1186/s13059-023-02993-y
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author Schlosser, Pascal
Zhang, Jingning
Liu, Hongbo
Surapaneni, Aditya L.
Rhee, Eugene P.
Arking, Dan E.
Yu, Bing
Boerwinkle, Eric
Welling, Paul A.
Chatterjee, Nilanjan
Susztak, Katalin
Coresh, Josef
Grams, Morgan E.
author_facet Schlosser, Pascal
Zhang, Jingning
Liu, Hongbo
Surapaneni, Aditya L.
Rhee, Eugene P.
Arking, Dan E.
Yu, Bing
Boerwinkle, Eric
Welling, Paul A.
Chatterjee, Nilanjan
Susztak, Katalin
Coresh, Josef
Grams, Morgan E.
author_sort Schlosser, Pascal
collection PubMed
description BACKGROUND: The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage. RESULTS: Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are supported as putatively causal. We then prioritize 153 of these genomic regions using additional colocalization analyses. Our genome-wide findings are supported by existing knowledge (animal models for MANBA, DACH1, SH3YL1, INHBB), exceed the underlying GWAS signals (28 region-trait combinations without significant GWAS hit), identify independent gene/protein-trait associations within the same genomic region (INHBC, SPRYD4), nominate tissues underlying the associations (tubule expression of NRBP1), and distinguish markers of kidney filtration from those with a role in creatinine and cystatin C metabolism. Furthermore, we follow up on members of the TGF-beta superfamily of proteins and find a prognostic value of INHBC for kidney disease progression even after adjustment for measured glomerular filtration rate (GFR). CONCLUSION: In summary, this study combines multimodal, genome-wide association studies to generate a catalog of putatively causal target genes and proteins relevant to kidney function and damage which can guide follow-up studies in physiology, basic science, and clinical medicine. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-02993-y.
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spelling pubmed-102918072023-06-27 Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage Schlosser, Pascal Zhang, Jingning Liu, Hongbo Surapaneni, Aditya L. Rhee, Eugene P. Arking, Dan E. Yu, Bing Boerwinkle, Eric Welling, Paul A. Chatterjee, Nilanjan Susztak, Katalin Coresh, Josef Grams, Morgan E. Genome Biol Research BACKGROUND: The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage. RESULTS: Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are supported as putatively causal. We then prioritize 153 of these genomic regions using additional colocalization analyses. Our genome-wide findings are supported by existing knowledge (animal models for MANBA, DACH1, SH3YL1, INHBB), exceed the underlying GWAS signals (28 region-trait combinations without significant GWAS hit), identify independent gene/protein-trait associations within the same genomic region (INHBC, SPRYD4), nominate tissues underlying the associations (tubule expression of NRBP1), and distinguish markers of kidney filtration from those with a role in creatinine and cystatin C metabolism. Furthermore, we follow up on members of the TGF-beta superfamily of proteins and find a prognostic value of INHBC for kidney disease progression even after adjustment for measured glomerular filtration rate (GFR). CONCLUSION: In summary, this study combines multimodal, genome-wide association studies to generate a catalog of putatively causal target genes and proteins relevant to kidney function and damage which can guide follow-up studies in physiology, basic science, and clinical medicine. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-02993-y. BioMed Central 2023-06-26 /pmc/articles/PMC10291807/ /pubmed/37365616 http://dx.doi.org/10.1186/s13059-023-02993-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Schlosser, Pascal
Zhang, Jingning
Liu, Hongbo
Surapaneni, Aditya L.
Rhee, Eugene P.
Arking, Dan E.
Yu, Bing
Boerwinkle, Eric
Welling, Paul A.
Chatterjee, Nilanjan
Susztak, Katalin
Coresh, Josef
Grams, Morgan E.
Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage
title Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage
title_full Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage
title_fullStr Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage
title_full_unstemmed Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage
title_short Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage
title_sort transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291807/
https://www.ncbi.nlm.nih.gov/pubmed/37365616
http://dx.doi.org/10.1186/s13059-023-02993-y
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