Genome-wide association analysis identifies multiple loci associated with kidney disease-related traits in Korean populations

Abstract

Chronic kidney disease (CKD) is an important social health problem characterized by a decrease in the kidney glomerular filtration rate (GFR). In this study, we analyzed genome-wide association studies for kidney disease-related traits using data from a Korean adult health screening cohort comprising 7,064 participants. Kidney disease-related traits analyzed include blood urea nitrogen (BUN), serum creatinine, estimated GFR, and uric acid levels. We detected two genetic loci (SLC14A2 and an intergenic region) and 8 single nucleotide polymorphisms (SNPs) associated with BUN, 3 genetic loci (BCAS3, C17orf82, ALDH2) and 6 SNPs associated with serum creatinine, 3 genetic loci (BCAS3, C17orf82/TBX2, LRP2) and 7 SNPs associated with GFR, and 14 genetic loci (3 in ABCG2/PKD2, 2 in SLC2A9, 3 in intergenic regions on chromosome 4; OTUB1, NRXN2/SLC22A12, CDC42BPG, RPS6KA4, SLC22A9, and MAP4K2 on chromosome 11) and 84 SNPs associated with uric acid levels. By comparing significant genetic loci associated with serum creatinine levels and GFR, rs9895661 in BCAS3 and rs757608 in C17orf82 were simultaneously associated with both traits. The SNPs rs11710227 in intergenic regions on chromosome 3 showing significant association with BUN is newly discovered. Genetic variations of multiple gene loci are associated with kidney disease-related traits, and differences in associations between kidney disease-related traits and genetic variation are dependent on the population. The meanings of the mutations identified in this study will need to be reaffirmed in other population groups in the future.

Fig 1

Genome-wide association analysis -log10 (P-value) vs. genomic position plots (Manhattan plot) for BUN (A), serum creatinine (B), GFR (C), and uric acid (D) in the discovery cohort. Genetic loci significantly associated (P < 1.45 × 10⁻⁷ in the discovery set) with BUN were found on chromosomes 3, 7, and 18. Genetic loci significantly associated with serum creatinine were found on chromosomes 12 and 17. Genetic loci significantly associated with GFR were found on chromosomes 2 and 17. Genetic loci significantly associated with uric acid were found on chromosomes 4 and 11.

Fig 2

Quantile-quantile plots of the association test results (expected vs. observed -log10 (P-value)) for BUN (A), serum creatinine (B), GFR (C), and uric acid (D) in the discovery cohort. The red line shows the expected distribution under the null hypothesis of no association at any locus, and the gray area shows the 95% confidence limits of the null hypothesis distribution.

Fig 3. Genetic architecture of genome-wide susceptibility loci significantly associated with kidney disease-related traits in the discovery cohorts.

(A) SLC14A2 on chromosome 18 for BUN. (B): Null intergenic region on chromosome 3 for BUN. (C) BCAS3 on chromosome 17 for creatinine. (D) ALDH2 and HECTD4 on chromosome 12 for creatinine. (E) BCAS3 on chromosome 17 for GFR. (F) LRP2 on chromosome 2 for GFR. (G) ABCG2 on chromosome 4 for uric acid. (H): SLC2A9 on chromosome 4 for uric acid. (I) intergenic region on chromosome 4 for uric acid. (J) OTUB1 on chromosome 11 for uric acid. (K) NRXN2/SLC22A12 on chromosome 11 for uric acid. (L) SLC22A9 on chromosome 11 for uric acid. The calculated -log10 P values are shown according to genomic position. P values were obtained from the discovery set. Among the SNPs, the most significant SNP with the lowest P value is colored purple. LD values (based on the HapMap CEU sample) are displayed as different colors is marked in colors: red (r2 to top SNP 0.8–0.0), orange (0.4–0.6), green (0.4–0.6), sky blue (0.2–0.4), and dark blue (<0.2). Gene annotations are based on Build 36. The directions of the arrows indicate the direction of transcription.