Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population
Authors: Tanikawa Chizu , Kamatani Yoichiro , Terao Chikashi , Usami Masayuki , Takahashi Atsushi , Momozawa Yukihide , Suzuki Kichiya , Ogishima Soichi , Shimizu Atsushi , Satoh Mamoru , Matsuo Keitaro , Mikami Haruo , Naito Mariko , Wakai Kenji , Yamaji Taiki , Sawada Norie , Iwasaki Motoki , Tsugane Shoichiro , Kohri Kenjiro , Yu Alan S.L. , Yasui Takahiro , Murakami Yoshinori , Kubo Michiaki , Matsuda Koichi 
Published: April 2019

Significance Statement
Although there is evidence that genetic factors may play a substantial role in the risk of urolithiasis, the genetic basis for this condition remains largely unidentified. Previous genome-wide association studies (GWAS) have identified only six gene loci as risk-related. In this work, the authors performed a GWAS using 11,130 cases and 187,639 controls from the Japanese population, identifying 14 significant loci associated with urolithiasis, of which nine are novel. Ten of the 14 loci showed a significant association with one or more of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, eGFR, serum uric acid, and serum calcium). All 14 loci were associated with elements of the metabolic or crystallization pathways, providing insight into the molecular pathogenesis of urolithiasis.

Background
A family history of urolithiasis is associated with a more than doubling of urolithiasis risk, and a twin study estimating 56% heritability of the condition suggests a pivotal role for host genetic factors. However, previous genome-wide association studies (GWAS) have identified only six risk-related loci.

Methods
To identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan.

Results
The analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%).

Conclusions
Our findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.