Novel risk loci identified in a genome-wide association study of urolithiasis in a Japanese population

Chizu Tanikawa, Yoichiro Kamatani, Chikashi Terao, Masayuki Usami, Atsushi Takahashi, Yukihide Momozawa, Kichiya Suzuki, Soichi Ogishima, Atsushi Shimizu, Mamoru Satoh, Keitaro Matsuo, Haruo Mikami, Mariko Naito, Kenji Wakai, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Shoichiro Tsugane, Kenjiro Kohri, Alan S.L. Yu & 4 others Takahiro Yasui, Yoshinori Murakami, Michiaki Kubo, Koichi Matsuda

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)855-864
Number of pages10
JournalJournal of the American Society of Nephrology
Volume30
Issue number5
DOIs
Publication statusPublished - 01-05-2019

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Urolithiasis
Genome-Wide Association Study
Population
Electrolytes
Crystallization
Kidney
Confidence Intervals
Hyperuricemia
Twin Studies
Hypertriglyceridemia
Metabolic Networks and Pathways
Uric Acid
Serum
Self Report
Medical Records
Japan
Body Mass Index
Obesity
Odds Ratio
Calcium

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

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. / Novel risk loci identified in a genome-wide association study of urolithiasis in a Japanese population. In: Journal of the American Society of Nephrology. 2019 ; Vol. 30, No. 5. pp. 855-864.
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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.",
author = "Chizu Tanikawa and Yoichiro Kamatani and Chikashi Terao and Masayuki Usami and Atsushi Takahashi and Yukihide Momozawa and Kichiya Suzuki and Soichi Ogishima and Atsushi Shimizu and Mamoru Satoh and Keitaro Matsuo and Haruo Mikami and Mariko Naito and Kenji Wakai and Taiki Yamaji and Norie Sawada and Motoki Iwasaki and Shoichiro Tsugane and Kenjiro Kohri and Yu, {Alan S.L.} and Takahiro Yasui and Yoshinori Murakami and Michiaki Kubo and Koichi Matsuda",
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Tanikawa, C, Kamatani, Y, Terao, C, Usami, M, Takahashi, A, Momozawa, Y, Suzuki, K, Ogishima, S, Shimizu, A, Satoh, M, Matsuo, K, Mikami, H, Naito, M, Wakai, K, Yamaji, T, Sawada, N, Iwasaki, M, Tsugane, S, Kohri, K, Yu, ASL, Yasui, T, Murakami, Y, Kubo, M & Matsuda, K 2019, 'Novel risk loci identified in a genome-wide association study of urolithiasis in a Japanese population', Journal of the American Society of Nephrology, vol. 30, no. 5, pp. 855-864. https://doi.org/10.1681/ASN.2018090942

Novel risk loci identified in a genome-wide association study of urolithiasis in a Japanese population. / 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.

In: Journal of the American Society of Nephrology, Vol. 30, No. 5, 01.05.2019, p. 855-864.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel risk loci identified in a genome-wide association study of urolithiasis in a Japanese population

AU - Tanikawa, Chizu

AU - Kamatani, Yoichiro

AU - Terao, Chikashi

AU - Usami, Masayuki

AU - Takahashi, Atsushi

AU - Momozawa, Yukihide

AU - Suzuki, Kichiya

AU - Ogishima, Soichi

AU - Shimizu, Atsushi

AU - Satoh, Mamoru

AU - Matsuo, Keitaro

AU - Mikami, Haruo

AU - Naito, Mariko

AU - Wakai, Kenji

AU - Yamaji, Taiki

AU - Sawada, Norie

AU - Iwasaki, Motoki

AU - Tsugane, Shoichiro

AU - Kohri, Kenjiro

AU - Yu, Alan S.L.

AU - Yasui, Takahiro

AU - Murakami, Yoshinori

AU - Kubo, Michiaki

AU - Matsuda, Koichi

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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