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

Xu, Xiaguang, Eales, James M., Akbarov, Artur, Guuo, Hui, Becker, Lorenz, Talavera, David, Ashraf, Fehzan, Nawaz, Jabran, Pramanik, Sanjeev, Bowes, John, Jiang, Xiao, Dormer, John, Denniff, Matthew, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Prestes, Priscilla R., Glyda, Maciej, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Berzuini, Carlo, Woolf, Adrian S., Samani, Nilesh J., Charchar, Fadi J., and Tomaszewski, Maciej (2018) Molecular insights into genome-wide association studies of chronic kidney disease-defining traits. Nature Communications, 9. 4800.

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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.

Item ID: 56472
Item Type: Article (Research - C1)
ISSN: 2041-1723
Copyright Information: Copyright © The Author(s) 2018
Additional Information:

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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

Funders: British Heart Foundation (BHF), Kidney Research UK (KRUK), Medical Research Council (MRC), National Health and Medical Research Council (NHMRC)
Projects and Grants: BHF PG/17/35/33001, KRUK RP_017_20180302, KRUK RP_021_20170302, MRC MR/K026739/1, NHMRC APP1123472
Date Deposited: 03 Dec 2018 03:29
FoR Codes: 06 BIOLOGICAL SCIENCES > 0604 Genetics > 060404 Epigenetics (incl Genome Methylation and Epigenomics) @ 50%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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