Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population
Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population
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DOI：
10.1681/asn.2018090942
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发表时间：
2019-05-01
影响因子：
13.6
通讯作者：
Matsuda, Koichi
中科院分区：
文献类型：
--
作者：
Tanikawa, Chizu;Kamatani, Yoichiro;Matsuda, Koichi
背景 尿石症家族史与尿石症风险增加一倍以上相关，一项双胞胎研究估计该病有 56% 的遗传力，表明宿主遗传因素起着关键作用。然而，之前的全基因组关联研究 (GWAS) 仅识别出 6 个风险相关位点。 方法 为了识别日本人群中新的尿石症相关位点，我们对 11,130 例病例和 187,639 名对照进行了大规模 GWAS，随后对 2289 例病例和 3817 名对照进行了重复分析。尿石症的诊断由临床医生或使用医疗记录或自我报告确认。我们还使用来自日本 BioBank 的多达 160,000 个样本评估了尿石症基因座与 16 个数量性状的关联，包括代谢、肾脏相关和电解质性状（例如体重指数、脂质储存、eGFR、血清尿酸和血清钙）。结果分析确定了 14 个显着基因座，包括 9 个新基因座。十个区域显示出与至少一种数量性状显着相关，包括代谢、肾脏相关和电解质性状，表明尿石症和这些数量性状具有共同的遗传基础。四个新位点与代谢特征、肥胖、高甘油三酯血症或高尿酸血症相关。其余十个位点与肾脏或电解质相关特征相关；这些可能会影响结晶。加权遗传风险评分分析表明，与参照组（后 20%）相比，最高风险组（前 20%）的比值比为 1.71（95% 置信区间，1.42 至 2.06）- 2.13（95% 置信区间，2.00 至 2.27）。 结论 我们的研究结果提供了证据，表明与代谢和结晶途径调节相关的宿主遗传因素有助于尿石症。
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.