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J Am Soc Nephrol. 2019 May;30(5):855-864. doi: 10.1681/ASN.2018090942. Epub 2019 Apr 11.

Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.

Author information

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.

KEYWORDS:

genetics and development; human genetics; kidney stones

PMID:
30975718
PMCID:
PMC6493984
[Available on 2020-05-01]
DOI:
10.1681/ASN.2018090942

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