Trans-ethnic genome-wide association study provides insight into effector genes and molecular mechanisms for kidney function and highlights a causal effect on kidney-specific disease aetiologies

Morris, A. P.; Le, T. H.; Wu, H.; Akbarov, A.; van der Most, P. P.; Mahajan, A.; Hemani, G.; Gaulton, K. J.; Nadkarni, G.; Valladares-Salgado, A.; Wacher-Rodarte, N.; Mychaleckyj, J. C.; Dueker, N. D.; Guo, X.; Hai, Y.; Haessler, J.; Kamatani, Y.; Stilp, A.; Zhu, G.; Cook, J. P.; Arnlov, J.; Blanton, S. H.; de Borst, M.; Bottinger, E. P.; Buchanan, T. A.; Charchar, F. J.; Damman, J.; Eales, J. M.; Gharavi, A. G.; Giedraitis, V.; Heath, A. C.; Ipp, E.; Kiryluk, K.; Kubo, M.; Larsson, A.; Lindgren, C.; Lu, Y.; Madden, P. A.; Kramer, H. J.; Montgomery, G. W.; Papanicolaou, G. J.; Raffel, L. J.; S

doi:10.1101/420273

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bioRxiv · 10.1101/420273

Trans-ethnic genome-wide association study provides insight into effector genes and molecular mechanisms for kidney function and highlights a causal effect on kidney-specific disease aetiologies

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Abstract

Chronic kidney disease (CKD) affects [~]10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

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Morris, A. P., Le, T. H., Wu, H., Akbarov, A., van der Most, P. P., Mahajan, A., Hemani, G., Gaulton, K. J., Nadkarni, G., Valladares-Salgado, A., Wacher-Rodarte, N., Mychaleckyj, J. C., Dueker, N. D., Guo, X., Hai, Y., Haessler, J., Kamatani, Y., Stilp, A., Zhu, G., Cook, J. P., Arnlov, J., Blanton, S. H., de Borst, M., Bottinger, E. P., Buchanan, T. A., Charchar, F. J., Damman, J., Eales, J. M., Gharavi, A. G., Giedraitis, V., Heath, A. C., Ipp, E., Kiryluk, K., Kubo, M., Larsson, A., Lindgren, C., Lu, Y., Madden, P. A., Kramer, H. J., Montgomery, G. W., Papanicolaou, G. J., Raffel, L. J., S. 2018-09-18. Trans-ethnic genome-wide association study provides insight into effector genes and molecular mechanisms for kidney function and highlights a causal effect on kidney-specific disease aetiologies. https://doi.org/10.1101/420273

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