Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study

Abstract

Background: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. Methods: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. Results: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of ­activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10^–6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10^–8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. Conclusion: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

Association of genetic risk score and chronic kidney disease in a Japanese population

“… †Odds ratio (95% confidence interval) indicates the risk elevation per every 10‐unit increment of the GRS. The GRS was constructed based on the count of the risk alleles of 18 eGFR‐associated SNPs on 17 and 18 that were identified in a recent GWAS in a Japanese population …”

“…After a quality check, genotype imputation was conducted based on the 1000 Genome reference panel, phase 3, using Minimac 3 software (https://genome.sph.umich.edu/wiki/Minimac3). The details of the procedure for quality control have been described elsewhere …”

“…The GRS was constructed by summing up the number of the risk alleles (0, 1 or 2) of 18 eGFR‐associated SNPs on chromosome 17 and 18, corresponding to the locus for the BCAS3 and NFATC1 gene, respectively, that reached genome‐wide significance ( P < 5 × 10 −8 ) in both the discovery and the replication phase, in consideration of robust and reliable predictor of renal function decline in Japanese population . (Table S1, Supporting Information).…”

MRTF: Basic Biology and Role in Kidney Disease

“…These studies revealed that approx. 20% of CKD cases can be linked to certain single gene variants, while others have a polygenic background with an overall heritability of 30–50% [ 194 , 195 , 196 , 197 , 198 ]. However, only 5% of these are localized in coding regions of the genes, pointing to the role of dysregulated expression.…”

SHROOM3, the gene associated with chronic kidney disease, affects the podocyte structure

“…Our GWAS study provided evidence for the genetic association of SHROOM3 to the eGFR decliner. While a similar analysis has been conducted in a Japanese population of 14,539 as a discovery cohort, the role of SHROOM3 has not been confirmed 15 . This is presumably due to differences in sample size and cohort.…”