CKDGen Consortium Meta-Analysis Data

Li et al., 2017

https://pubmed.ncbi.nlm.nih.gov/27920155/

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7E-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4E-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Data set description

• EA indicate analyses performed among participants of European ancestry

• AA indicate analyses performed among participants of African ancestry

• DM and nonDM indicate results from analyses stratified by diabetes status

• All other analyses were performed in the overall group

• Within each file, the data are presented as follows:

  • chr: chromosome
  • bp_hg19: base pair position from hg19
  • rsID: rs-identifier
  • allele1: coded allele
  • allele2: noncoded allele
  • beta: is the beta-coefficient for allele1 (rounded to 2 significant digits)
  • se: is the standard error (rounded to 2 significant digits)
  • pval: is the p-value (rounded to 2 significant digits)
  • N: is the sample size
  • 1KG_(EUR/AFR)_MAF: is the frequency of the minor allele from the 1000G analyses in European or African ancestry
  • ExAC_(EUR/AFR)_MAF: is the frequency of the minor allele from ExAC in European or African ancestry

Phenotypes

• eGFRcrea overall, EA, Nmax=111,666
• eGFRcrea DM, EA, Nmax=14,308
• eGFRcrea nonDM, EA, Nmax=94,677
• eGFRcys overall, EA, Nmax=32,861
• UACR, EA, Nmax=31,164
• eGFRcrea overall, AA, Nmax=9,067
• eGFR DM, AA, Nmax=2,162
• eGFRcrea nonDM, AA, Nmax=6,597
• eGFRcys overall, AA, Nmax=4,440
• UACR, AA, Nmax=4,387

Citation

Reference The preferred citation is as follows:

Li M, Li Y, Weeks O, et al. SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. J Am Soc Nephrol. 2017 Mar;28(3):981-994.

DOI: https://doi.org/10.1681/ASN.2016020131

Files

• LiEtAl2017.tar.gz
• Li_etal_2017_full.pdf
• Published_UACR_AA.csv.gz
• Published_UACR_EA.csv.gz
• Published_eGFRcrea_DM_AA.csv.gz
• Published_eGFRcrea_DM_EA.csv.gz
• Published_eGFRcrea_nonDM_AA.csv.gz
• Published_eGFRcrea_nonDM_EA.csv.gz
• Published_eGFRcrea_overall_AA.csv.gz
• Published_eGFRcrea_overall_EA.csv.gz
• Published_eGFRcys_overall_AA.csv.gz
• Published_eGFRcys_overall_EA.csv.gz