Chizu Tanikawa1, Yoichiro Kamatani2, Chikashi Terao2, Masayuki Usami3, Atsushi Takahashi2,4, Yukihide Momozawa2, Kichiya Suzuki5, Soichi Ogishima5, Atsushi Shimizu6, Mamoru Satoh6, Keitaro Matsuo7,8, Haruo Mikami9, Mariko Naito10,11, Kenji Wakai10, Taiki Yamaji12, Norie Sawada12, Motoki Iwasaki12, Shoichiro Tsugane13, Kenjiro Kohri3, Alan S L Yu14,15, Takahiro Yasui3, Yoshinori Murakami16, Michiaki Kubo2, Koichi Matsuda17. 1. Laboratory of Genome Technology, Human Genome Center. 2. Division of Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. 3. Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 4. Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan. 5. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan. 6. Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan. 7. Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. 8. Department of Epidemiology and. 9. Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan. 10. Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan. 11. Department of Oral Epidemiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. 12. Division of Epidemiology and. 13. Center for Public Health Sciences, National Cancer Center, Tokyo, Japan; and. 14. Division of Nephrology and Hypertension and. 15. The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas. 16. Division of Molecular Pathology, Institute of Medical Science, and. 17. Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan; kmatsuda@edu.k.u-tokyo.ac.jp.
Abstract
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.
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.
Authors: Mayandi Sivaguru; Jessica J Saw; Elena M Wilson; John C Lieske; Amy E Krambeck; James C Williams; Michael F Romero; Kyle W Fouke; Matthew W Curtis; Jamie L Kear-Scott; Nicholas Chia; Bruce W Fouke Journal: Nat Rev Urol Date: 2021-05-24 Impact factor: 14.432
Authors: M Reza Jabalameli; Fiona M Fitzpatrick; Roberto Colombo; Sarah A Howles; Gary Leggatt; Valerie Walker; Akira Wiberg; Edmund R S Kunji; Sarah Ennis Journal: Mol Genet Genomic Med Date: 2021-08-04 Impact factor: 2.183