Genetic association for renal traits among participants of African ancestry reveals new loci for renal function

• Published in: PLoS genetics 2011-09, Vol.7 (9), p.e1002264
• Main Authors: Liu, Ching-Ti, Garnaas, Maija K, Tin, Adrienne, Kottgen, Anna, Franceschini, Nora, Peralta, Carmen A, de Boer, Ian H, Lu, Xiaoning, Atkinson, Elizabeth, Ding, Jingzhong, Nalls, Michael, Shriner, Daniel, Coresh, Josef, Kutlar, Abdullah, Bibbins-Domingo, Kirsten, Siscovick, David, Akylbekova, Ermeg, Wyatt, Sharon, Astor, Brad, Mychaleckjy, Josef, Li, Man, Reilly, Muredach P, Townsend, Raymond R, Adeyemo, Adebowale, Zonderman, Alan B, de Andrade, Mariza, Turner, Stephen T, Mosley, Thomas H, Harris, Tamara B, Rotimi, Charles N, Liu, Yongmei, Kardia, Sharon L R, Evans, Michele K, Shlipak, Michael G, Kramer, Holly, Flessner, Michael F, Dreisbach, Albert W, Goessling, Wolfram, Cupples, L Adrienne, Kao, W Linda, Fox, Caroline S
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport - genetics; Adult; African Americans; Aged; Animals; Biology; Biomedical research; Black People - genetics; Children & youth; Chronic kidney failure; Demographic aspects; Female; Gene Knockdown Techniques; Genealogy; Genetic aspects; Genetic Association Studies; Genetic Loci; Genetic variation; Genetics; Genome-Wide Association Study; Genomes; Glomerular Filtration Rate - genetics; Heart; Hospitals; Humans; KCNQ1 Potassium Channel - genetics; Kidney - physiology; Kidney diseases; Kidney Failure, Chronic - genetics; Male; Medicine; Microscopy; Middle Aged; Neoplasm Proteins - genetics; Phenotype; Polymorphism, Single Nucleotide - genetics; Public health; Quantitative trait loci; Questioning; Risk factors; Statistical methods; Studies; Zebrafish - genetics; Zebrafish - growth & development
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1002264

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR 30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.