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

Ching Ti Liu, Maija K. Garnaas, Adrienne Tin, Anna Kottgen, Nora Franceschini, Carmen A. Peralta, Ian H. de Boer, Xiaoning Lu, Elizabeth Atkinson, Jingzhong Ding, Michael Nalls, Daniel Shriner, Josef Coresh, Abdullah Kutlar, Kirsten Bibbins-Domingo, David Siscovick, Ermeg Akylbekova, Sharon Wyatt, Brad Astor, Josef MychaleckjyMan Li, Muredach P. Reilly, Raymond R. Townsend, Adebowale Adeyemo, Alan B. Zonderman, Mariza de Andrade, Stephen T. Turner, Thomas H. Mosley, Tamara B. Harris, Charles N. Rotimi, Yongmei Liu, Sharon L.R. Kardia, Michele K. Evans, Michael G. Shlipak, Holly Kramer, Michael F. Flessner, Albert W. Dreisbach, Wolfram Goessling, L. Adrienne Cupples, W. Linda Kao, Caroline S. Fox

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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 <60 mL/min/1.73 m 2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >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.

Original languageEnglish (US)
Article numbere1002264
JournalPLoS Genetics
Volume7
Issue number9
DOIs
StatePublished - Sep 1 2011

Fingerprint

glomerular filtration rate
renal function
Glomerular Filtration Rate
ancestry
Single Nucleotide Polymorphism
kidneys
African Americans
Kidney
loci
African American
Zebrafish
Danio rerio
Morpholinos
kidney diseases
Chronic Renal Insufficiency
Genome
Genes
gene
genome
genes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Liu, C. T., Garnaas, M. K., Tin, A., Kottgen, A., Franceschini, N., Peralta, C. A., ... Fox, C. S. (2011). Genetic association for renal traits among participants of African Ancestry reveals new loci for renal function. PLoS Genetics, 7(9), [e1002264]. https://doi.org/10.1371/journal.pgen.1002264

Genetic association for renal traits among participants of African Ancestry reveals new loci for renal function. / 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.

In: PLoS Genetics, Vol. 7, No. 9, e1002264, 01.09.2011.

Research output: Contribution to journalArticle

Liu, CT, Garnaas, MK, Tin, A, Kottgen, A, Franceschini, N, Peralta, CA, de Boer, IH, Lu, X, Atkinson, E, Ding, J, Nalls, M, Shriner, D, Coresh, J, Kutlar, A, Bibbins-Domingo, K, Siscovick, D, Akylbekova, E, Wyatt, S, Astor, B, Mychaleckjy, J, Li, M, Reilly, MP, Townsend, RR, Adeyemo, A, Zonderman, AB, de Andrade, M, Turner, ST, Mosley, TH, Harris, TB, Rotimi, CN, Liu, Y, Kardia, SLR, Evans, MK, Shlipak, MG, Kramer, H, Flessner, MF, Dreisbach, AW, Goessling, W, Cupples, LA, Kao, WL & Fox, CS 2011, 'Genetic association for renal traits among participants of African Ancestry reveals new loci for renal function', PLoS Genetics, vol. 7, no. 9, e1002264. https://doi.org/10.1371/journal.pgen.1002264
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. / Genetic association for renal traits among participants of African Ancestry reveals new loci for renal function. In: PLoS Genetics. 2011 ; Vol. 7, No. 9.
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abstract = "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 <60 mL/min/1.73 m 2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >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.",
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T1 - Genetic association for renal traits among participants of African Ancestry reveals new loci for renal function

AU - Liu, Ching Ti

AU - Garnaas, Maija K.

AU - Tin, Adrienne

AU - Kottgen, Anna

AU - Franceschini, Nora

AU - Peralta, Carmen A.

AU - de Boer, Ian H.

AU - Lu, Xiaoning

AU - Atkinson, Elizabeth

AU - Ding, Jingzhong

AU - Nalls, Michael

AU - Shriner, Daniel

AU - Coresh, Josef

AU - Kutlar, Abdullah

AU - Bibbins-Domingo, Kirsten

AU - Siscovick, David

AU - Akylbekova, Ermeg

AU - Wyatt, Sharon

AU - Astor, Brad

AU - Mychaleckjy, Josef

AU - Li, Man

AU - Reilly, Muredach P.

AU - Townsend, Raymond R.

AU - Adeyemo, Adebowale

AU - Zonderman, Alan B.

AU - de Andrade, Mariza

AU - Turner, Stephen T.

AU - Mosley, Thomas H.

AU - Harris, Tamara B.

AU - Rotimi, Charles N.

AU - Liu, Yongmei

AU - Kardia, Sharon L.R.

AU - Evans, Michele K.

AU - Shlipak, Michael G.

AU - Kramer, Holly

AU - Flessner, Michael F.

AU - Dreisbach, Albert W.

AU - Goessling, Wolfram

AU - Cupples, L. Adrienne

AU - Kao, W. Linda

AU - Fox, Caroline S.

PY - 2011/9/1

Y1 - 2011/9/1

N2 - 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 <60 mL/min/1.73 m 2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >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.

AB - 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 <60 mL/min/1.73 m 2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >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.

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