A Genome-Wide Association Study of Nephrolithiasis in the Japanese Population Identifies Novel Susceptible Loci at 5q35.3, 7p14.3, and 13q14.1

Abstract

Nephrolithiasis is a common nephrologic disorder with complex etiology. To identify the genetic factor(s) for nephrolithiasis, we conducted a three-stage genome-wide association study (GWAS) using a total of 5,892 nephrolithiasis cases and 17,809 controls of Japanese origin. Here we found three novel loci for nephrolithiasis: RGS14-SLC34A1-PFN3-F12 on 5q35.3 (rs11746443; P = 8.51×10 ⁻¹², odds ratio (OR) = 1.19), INMT-FAM188B-AQP1 on 7p14.3 (rs1000597; P = 2.16×10 ⁻¹⁴, OR = 1.22), and DGKH on 13q14.1 (rs4142110; P = 4.62×10 ⁻⁹, OR = 1.14). Subsequent analyses in 21,842 Japanese subjects revealed the association of SNP rs11746443 with the reduction of estimated glomerular filtration rate (eGFR) ( P = 6.54×10 ⁻⁸), suggesting a crucial role for this variation in renal function. Our findings elucidated the significance of genetic variations for the pathogenesis of nephrolithiasis.

Author Summary

Although nephrolithiasis is one of the most common nephro-urological disorders with high prevalence (4%–9%) and extremely high recurrence rate (60% within ten years), little is known about the role of common variations in its pathogenesis. Through a GWAS using a total of 5,892 cases and 17,809 controls, we identified three novel nephrolithiasis loci: rs11746443, rs1000597, and rs4142110 ( P<1×10 ⁻⁸). The top two significant SNPs, rs11746443 and rs1000597, are located upstream of the SLC34A1 and the AQP1 genes that play important roles in kidney function and the urine-concentration process, respectively. We also found that SNP rs11746443 is associated with the reduction of estimated glomerular filtration rate (eGFR), indicating the role of this variation in kidney function. Although nephrolithiasis is considered as one of the lifestyle-related diseases, the results of dietary intervention studies to reduce the recurrence incidence have been unsuccessful. Our findings could contribute to a better understanding of the pathogenesis of nephrolithiasis and lead to the development of new therapeutics.