Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

Xiaoguang Xu; James Eales; Artur Akbarov; Hui Guo; Lorenz Becker; David Talavera; Fehzan Ashraf; Jabran Nawaz; Sanjeev Pramanik; John Bowes; Xiao Jiang; John Dormer; Matthew Denniff; A Antczak; Monika Sszulinska; Ingrid Wise; Priscilla R Prestes; Maciej Glyda; Pawel Bogdanski; Ewa Zukowska-Szczechowska; Carlo Berzuini; Adrian S. Woolf; Nilesh Samani; Fadi J. Charchar; Maciej Tomaszewski

doi:10.1038/s41467-018-07260-4

Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

Xiaoguang Xu, James Eales, Artur Akbarov, Hui Guo, Lorenz Becker, David Talavera, Fehzan Ashraf, Jabran Nawaz, Sanjeev Pramanik, John Bowes, Xiao Jiang, John Dormer, Matthew Denniff, A Antczak, Monika Sszulinska, Ingrid Wise, Priscilla R Prestes, Maciej Glyda, Pawel Bogdanski, Ewa Zukowska-SzczechowskaCarlo Berzuini, Adrian S. Woolf, Nilesh Samani, Fadi J. Charchar, Maciej Tomaszewski

Research output: Contribution to journal › Article › peer-review

Abstract

Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.

Original language	English
Article number	4800
Journal	Nature Communications
Volume	9
Issue number	1
Early online date	22 Nov 2018
DOIs	https://doi.org/10.1038/s41467-018-07260-4
Publication status	Published - 22 Nov 2018

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Xu, X., Eales, J., Akbarov, A., Guo, H., Becker, L., Talavera, D., Ashraf, F., Nawaz, J., Pramanik, S., Bowes, J., Jiang, X., Dormer, J., Denniff, M., Antczak, A., Sszulinska, M., Wise, I., Prestes, P. R., Glyda, M., Bogdanski, P., ... Tomaszewski, M. (2018). Molecular insights into genome-wide association studies of chronic kidney disease-defining traits. Nature Communications, 9(1), Article 4800. https://doi.org/10.1038/s41467-018-07260-4

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title = "Molecular insights into genome-wide association studies of chronic kidney disease-defining traits",

abstract = "Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.",

author = "Xiaoguang Xu and James Eales and Artur Akbarov and Hui Guo and Lorenz Becker and David Talavera and Fehzan Ashraf and Jabran Nawaz and Sanjeev Pramanik and John Bowes and Xiao Jiang and John Dormer and Matthew Denniff and A Antczak and Monika Sszulinska and Ingrid Wise and Prestes, {Priscilla R} and Maciej Glyda and Pawel Bogdanski and Ewa Zukowska-Szczechowska and Carlo Berzuini and Woolf, {Adrian S.} and Nilesh Samani and Charchar, {Fadi J.} and Maciej Tomaszewski",

year = "2018",

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doi = "10.1038/s41467-018-07260-4",

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Xu, X , Eales, J, Akbarov, A, Guo, H, Becker, L, Talavera, D, Ashraf, F, Nawaz, J, Pramanik, S, Bowes, J , Jiang, X, Dormer, J, Denniff, M, Antczak, A, Sszulinska, M, Wise, I, Prestes, PR, Glyda, M, Bogdanski, P, Zukowska-Szczechowska, E, Berzuini, C , Woolf, AS, Samani, N, Charchar, FJ & Tomaszewski, M 2018, 'Molecular insights into genome-wide association studies of chronic kidney disease-defining traits', Nature Communications, vol. 9, no. 1, 4800. https://doi.org/10.1038/s41467-018-07260-4

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T1 - Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

AU - Xu, Xiaoguang

AU - Eales, James

AU - Akbarov, Artur

AU - Guo, Hui

AU - Becker, Lorenz

AU - Talavera, David

AU - Ashraf, Fehzan

AU - Nawaz, Jabran

AU - Pramanik, Sanjeev

AU - Bowes, John

AU - Jiang, Xiao

AU - Dormer, John

AU - Denniff, Matthew

AU - Antczak, A

AU - Sszulinska, Monika

AU - Wise, Ingrid

AU - Prestes, Priscilla R

AU - Glyda, Maciej

AU - Bogdanski, Pawel

AU - Zukowska-Szczechowska, Ewa

AU - Berzuini, Carlo

AU - Woolf, Adrian S.

AU - Samani, Nilesh

AU - Charchar, Fadi J.

AU - Tomaszewski, Maciej

PY - 2018/11/22

Y1 - 2018/11/22

N2 - Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.

AB - Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.

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U2 - 10.1038/s41467-018-07260-4

DO - 10.1038/s41467-018-07260-4

M3 - Article

C2 - 30467309

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4800

ER -

Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

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