Abstract 55: Novel Genetic Risk Variants for Kidney Function: A Large-Scale Exome Array Analysis of 111,666 European Ancestry Individuals
Introduction: Chronic kidney disease (CKD) is a worldwide public health problem. Although genome-wide association studies (GWAS) have identified 29 loci for estimated glomerular filtration rate (eGFR, a measure of kidney function), they account for only a small proportion of the variation in eGFR. Exonic genetic variants with minor allele frequency (MAF) < 5% had not been represented well in existing GWAS.
Hypothesis: Multiple low frequency (MAF 1-5%) and rare (MAF<1%) exonic variants are associated with eGFR.
Methods: We meta-analyzed the association result from 24 studies between eGFR as estimated from serum creatinine with the MDRD equation and up to 134,329 genetic variants genotyped on the Illumina HumanExome Beadchip (“Exome Array”) in up to 111,666 European ancestry participants. We conducted inverse-variance weighted fixed-effect meta-analysis for single variants. To test for within-gene enrichment of rare exonic variants, we performed gene-based collapsing tests (T1 and sequence kernel association test [SKAT]) incorporating variants annotated as nonsynonymous or splice site with MAF < 1%.
Results: Among 29 known kidney function loci, 28 of them achieved exome array wide significance (p < 3.7x10-7, Bonferroni correction). We identified 8 novel loci associated with eGFR that achieved exome array wide significance. The most significant association was found in the PPM1J gene (MAF=13%, p=1.17E-14), which encodes the serine/threonine protein phosphatase. The lowest frequency variant that achieved exome array wide significance is at EDEM3 (MAF=2%, p=5.25E-08), which is involved in endoplasmic reticulum-associated degradation. We also identified a novel gene-based association with eGFR (pskat=5.4x10-8).
Conclusions: Using the exome array, we have not identified single rare exonic variants associated with eGFR. With the identification of common and low-frequency variants and one gene with enrichment of rare coding variants associated with eGFR, our findings provide further insight into the genetic architecture of kidney function and offer the potential to provide new insights into the pathogenesis of CKD.
Author Disclosures: M. Li: None.
- © 2015 by American Heart Association, Inc.