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

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.

Pubmed ID: 21931561

Authors

  • 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
  • CKDGen Consortium
  • Rotimi CN
  • Liu Y
  • Kardia SL
  • Evans MK
  • Shlipak MG
  • Kramer H
  • Flessner MF
  • Dreisbach AW
  • Goessling W
  • Cupples LA
  • Kao WL
  • Fox CS

Journal

PLoS genetics

Publication Data

September 20, 2011

Associated Grants

  • Agency: NIA NIH HHS, Id: 1R01AG032098-01A1
  • Agency: NCRR NIH HHS, Id: 2M01RR010284
  • Agency: PHS HHS, Id: HHSN268200782096C
  • Agency: NHLBI NIH HHS, Id: HL 46380
  • Agency: NCRR NIH HHS, Id: M01RR00080
  • Agency: NHLBI NIH HHS, Id: N01 HC-15103
  • Agency: NHLBI NIH HHS, Id: N01 HC-55222
  • Agency: NHLBI NIH HHS, Id: N01-HB-72982
  • Agency: NHLBI NIH HHS, Id: N01-HB-72991
  • Agency: NHLBI NIH HHS, Id: N01-HB-72992
  • Agency: NHLBI NIH HHS, Id: N01-HB-72993
  • Agency: NHLBI NIH HHS, Id: N01-HB-72994
  • Agency: NHLBI NIH HHS, Id: N01-HB-72995
  • Agency: NHLBI NIH HHS, Id: N01-HB-72996
  • Agency: NHLBI NIH HHS, Id: N01-HB-72997
  • Agency: NHLBI NIH HHS, Id: N01-HB-72998
  • Agency: NHLBI NIH HHS, Id: N01-HB-73000
  • Agency: NHLBI NIH HHS, Id: N01-HB-73001
  • Agency: NHLBI NIH HHS, Id: N01-HB-73002
  • Agency: NHLBI NIH HHS, Id: N01-HB-73003
  • Agency: NHLBI NIH HHS, Id: N01-HB-73004
  • Agency: NHLBI NIH HHS, Id: N01-HB-73005
  • Agency: NHLBI NIH HHS, Id: N01-HB-73006
  • Agency: NHLBI NIH HHS, Id: N01-HB-97051
  • Agency: NHLBI NIH HHS, Id: N01-HB-97053
  • Agency: NHLBI NIH HHS, Id: N01-HB-97054
  • Agency: NHLBI NIH HHS, Id: N01-HB-97056
  • Agency: NHLBI NIH HHS, Id: N01-HB-97058
  • Agency: NHLBI NIH HHS, Id: N01-HB-97060
  • Agency: NHLBI NIH HHS, Id: N01-HB-97061
  • Agency: NHLBI NIH HHS, Id: N01-HB-97062
  • Agency: NHLBI NIH HHS, Id: N01-HB-97064
  • Agency: NHLBI NIH HHS, Id: N01-HB-97066
  • Agency: NHLBI NIH HHS, Id: N01-HB-97068
  • Agency: NHLBI NIH HHS, Id: N01-HB-97069
  • Agency: NHLBI NIH HHS, Id: N01-HB-97070
  • Agency: NHLBI NIH HHS, Id: N01-HB-97071
  • Agency: NHLBI NIH HHS, Id: N01-HB-97072
  • Agency: NHLBI NIH HHS, Id: N01-HB-97073
  • Agency: NHLBI NIH HHS, Id: N01-HB-97085
  • Agency: NHLBI NIH HHS, Id: N01-HC-05187
  • Agency: NHLBI NIH HHS, Id: N01-HC-25195
  • Agency: NHLBI NIH HHS, Id: N01-HC-35129
  • Agency: NHLBI NIH HHS, Id: N01-HC-45133
  • Agency: NHLBI NIH HHS, Id: N01-HC-45134
  • Agency: NHLBI NIH HHS, Id: N01-HC-45204
  • Agency: NHLBI NIH HHS, Id: N01-HC-45205
  • Agency: NHLBI NIH HHS, Id: N01-HC-48047
  • Agency: NHLBI NIH HHS, Id: N01-HC-48048
  • Agency: NHLBI NIH HHS, Id: N01-HC-48049
  • Agency: NHLBI NIH HHS, Id: N01-HC-48050
  • Agency: NHLBI NIH HHS, Id: N01-HC-55015
  • Agency: NHLBI NIH HHS, Id: N01-HC-55016
  • Agency: NHLBI NIH HHS, Id: N01-HC-55018
  • Agency: NHLBI NIH HHS, Id: N01-HC-55019
  • Agency: NHLBI NIH HHS, Id: N01-HC-55020
  • Agency: NHLBI NIH HHS, Id: N01-HC-55021
  • Agency: NHLBI NIH HHS, Id: N01-HC-55022
  • Agency: NHLBI NIH HHS, Id: N01-HC-65226
  • Agency: NHLBI NIH HHS, Id: N01-HC-75150
  • Agency: NHLBI NIH HHS, Id: N01-HC-85079
  • Agency: NHLBI NIH HHS, Id: N01-HC-85080
  • Agency: NHLBI NIH HHS, Id: N01-HC-85081
  • Agency: NHLBI NIH HHS, Id: N01-HC-85082
  • Agency: NHLBI NIH HHS, Id: N01-HC-85083
  • Agency: NHLBI NIH HHS, Id: N01-HC-85084
  • Agency: NHLBI NIH HHS, Id: N01-HC-85085
  • Agency: NHLBI NIH HHS, Id: N01-HC-85086
  • Agency: NHLBI NIH HHS, Id: N01-HC-95095
  • Agency: NHLBI NIH HHS, Id: N01-HC-95100
  • Agency: NHLBI NIH HHS, Id: N01-HC-95159
  • Agency: NHLBI NIH HHS, Id: N01-HC-95160
  • Agency: NHLBI NIH HHS, Id: N01-HC-95161
  • Agency: NHLBI NIH HHS, Id: N01-HC-95162
  • Agency: NHLBI NIH HHS, Id: N01-HC-95163
  • Agency: NHLBI NIH HHS, Id: N01-HC-95164
  • Agency: NHLBI NIH HHS, Id: N01-HC-95165
  • Agency: NHLBI NIH HHS, Id: N01-HC-95166
  • Agency: NHLBI NIH HHS, Id: N01-HC-95167
  • Agency: NHLBI NIH HHS, Id: N01-HC-95168
  • Agency: NHLBI NIH HHS, Id: N01-HC-95169
  • Agency: NHLBI NIH HHS, Id: N01-HC-95170
  • Agency: NHLBI NIH HHS, Id: N01-HC-95171
  • Agency: NHLBI NIH HHS, Id: N01-HC-95172
  • Agency: NIA NIH HHS, Id: N01AG62101
  • Agency: NIA NIH HHS, Id: N01AG62103
  • Agency: NIA NIH HHS, Id: N01AG62106
  • Agency: NIA NIH HHS, Id: R01 AG028321
  • Agency: NIA NIH HHS, Id: R01 AG032098
  • Agency: NHLBI NIH HHS, Id: R01 HL076784
  • Agency: NHLBI NIH HHS, Id: R01-HL-071205
  • Agency: NHLBI NIH HHS, Id: R01-HL087660
  • Agency: NHLBI NIH HHS, Id: R01HL092577-01A1
  • Agency: NIGMS NIH HHS, Id: S06GM008016-320107
  • Agency: NIGMS NIH HHS, Id: S06GM008016-380111
  • Agency: NHLBI NIH HHS, Id: U01 HL053916
  • Agency: NHLBI NIH HHS, Id: U01 HL053934
  • Agency: NHLBI NIH HHS, Id: U01 HL053937
  • Agency: NHLBI NIH HHS, Id: U01 HL053938
  • Agency: NHLBI NIH HHS, Id: U01 HL053941
  • Agency: NHLBI NIH HHS, Id: U01 HL063429
  • Agency: NHLBI NIH HHS, Id: U01 HL063463
  • Agency: NHLBI NIH HHS, Id: U01 HL064360
  • Agency: NHLBI NIH HHS, Id: U01 HL077813
  • Agency: NHLBI NIH HHS, Id: U01 HL080295

Mesh Terms

  • Adaptor Proteins, Vesicular Transport
  • Adult
  • African Continental Ancestry Group
  • Aged
  • Animals
  • Female
  • Gene Knockdown Techniques
  • Genetic Association Studies
  • Genetic Loci
  • Genome-Wide Association Study
  • Glomerular Filtration Rate
  • Humans
  • KCNQ1 Potassium Channel
  • Kidney
  • Kidney Failure, Chronic
  • Male
  • Middle Aged
  • Neoplasm Proteins
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Zebrafish