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