s41467-018-07260-4.pdf (1.71 MB)
Download file

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

Download (1.71 MB)
journal contribution
posted on 25.07.2019, 15:21 by X Xu, JM Eales, A Akbarov, H Guo, L Becker, D Talavera, F Ashraf, J Nawaz, S Pramanik, J Bowes, X Jiang, J Dormer, M Denniff, A Antczak, M Szulinska, I Wise, PR Prestes, M Glyda, P Bogdanski, E Zukowska-Szczechowska, C Berzuini, AS Woolf, NJ Samani, FJ Charchar, M Tomaszewski
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.

Funding

M.T. acknowledges support of British Heart Foundation project grant PG/17/35/33001 and Kidney Research UK grant RP_017_20180302. F.J.C. and A.S.W. acknowledge grant support from Kidney Research UK RP_021_20170302; Medical Research Council MR/K026739/1 and National Health and Medical Research Council Australia grant APP1123472. Access to GWAS-genotyped and RNA-sequenced TCGA kidneys and GTEx data has been granted by NIH (approvals 50804-2 and 50805-2).

History

Citation

Nature Communications, 2018, volume 9, Article number: 4800

Author affiliation

/Organisation

Version

VoR (Version of Record)

Published in

Nature Communications

Publisher

Nature Research (part of Springer Nature)

eissn

2041-1723

Acceptance date

17/10/2018

Copyright date

2018

Available date

25/07/2019

Publisher version

https://www.nature.com/articles/s41467-018-07260-4

Notes

The data supporting the findings from these investigations are available within the article and the supplementary data files or are available upon reasonable request to the authors. The normalised (prior to PEER-adjustment) gene expression data from the TRANSLATE study are deposited in the public domain at the Dryad digital repository (https://doi.org/10.5061/dryad.10r1pt0). A reporting summary for this Article is available as a Supplementary Information file.

Language

en

Usage metrics

Categories

Keywords

Licence

Exports