Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
Creators: name: Zhu, Gu
name: van Zuydam, Natalie
name: Haessler, Jeffrey
name: Martin, Nicholas G.
name: Whitfield, John B.
name: Chu, Pei-Lun
name: Puri, Sanjana
name: Schellinger, Jeffrey N.
name: Lind, Lars
name: Franceschini, Nora
name: Papanicolaou, George J.
name: Lindgren, Cecilia M.
name: Montgomery, Grant W.
name: Ingelsson, Erik
name: Kooperberg, Charles
name: Mahajan, Anubha
name: Madden, Pamela A.F.
name: Giedraitis, Vilmantas
name: Stilp, Adrienne M.
name: Matsuda, Koichi
name: Thornton, Timothy A.
name: Sofer, Tamar
name: Cechova, Sylvia
name: Rodan, Aylin R.
name: Morris, Andrew P.
name: Flessner, Michael F.
name: Cai, Jianwen
name: Larsson, Anders
name: Reiner, Alex P.
name: Kubo, Michiaki
name: Sundström, Johan
name: Le, Thu H.
name: Laurie, Cathy C.
name: Arnlov, Johan
name: Kamatani, Yoichiro
name: Okada, Yukinori
name: Gaulton, Kyle J.
name: Heath, Andrew C.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2016

description: Supplemental Data Supplemental Data include five figures, fourteen tables, and Supplemental Acknowledgments and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg.2016.07.012. Supplemental Data Document S1. Figures S1–S5, Tables S1–S14, and Supplemental Acknowledgments Document S1. Figures S1–S5, Tables S1–S14, and Supplemental Acknowledgments Download Document S2. Article plus Supplemental Data Document S2. Article plus Supplemental Data Download Web Resources 1000 Genomes, http://www.1000genomes.org ENCODE, https://www.encodeproject.org/ Ensembl Genome Browser, http://www.ensembl.org/index.html EPACTS, http://genome.sph.umich.edu/wiki/EPACTS fGWAS, https://github.com/joepickrell/fgwas Gencode, http://www.gencodegenes.org GWAMA, http://www.geenivaramu.ee/en/tools/gwama IMPUTE2, http://mathgen.stats.ox.ac.uk/impute/impute_v2.html International HapMap Project, http://hapmap.ncbi.nlm.nih.gov/ LDlink, http://analysistools.nci.nih.gov/LDlink/ METAL, http://www.sph.umich.edu/csg/abecasis/metal/ Minimac, http://genome.sph.umich.edu/wiki/Minimac OMIM, http://www.omim.org/ Roadmap, http://www.roadmapepigenomics.org/ Variant Effect Predictor, http://useast.ensembl.org/Homo_sapiens/Tools/VEP We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10−8) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of “credible sets” of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.