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Genetic susceptibility of urolithiasis: comprehensive results from genome-wide analysis

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Abstract

Background

The pathogenesis of urolithiasis is multi-factorial and genetic factors have been shown to play a significant role in the development of urolithiasis. We tried to apply genome-wide Mendelian randomization (MR) analysis and figure out reliable gene susceptibility of urolithiasis from the largest samples to date in two independent genome-wide association studies (GWAS) database of European ancestry.

Methods

We extracted summary statistics of expression quantitative trait locus (eQTL) from eQTLGen consortium. Urolithiasis phenotype information was obtained from both FinnGen Biobank and UK Biobank. Multiple two-sample MR analysis with a Bonferroni-corrected P threshold (P < 2.5e-06) was conducted. The primary endpoint was the causal effect calculated by random-effect inverse variance weighted (IVW) method. Sensitivity analysis, volcano plots, scatter plots, and regional plots were also performed and visualized.

Results

After multiple MR tests between 19942 eQTLs and urolithiasis phenotype from both cohorts, 30 common eQTLs with consistent effect size direction were found to be causally associated with urolithiasis risk. Finally only one gene (LMAN2) was simultaneously identified among all top significant eQTLs from both FinnGen Biobank (beta = 0.6758, se = 0.0327, P = 6.775e-95) and UK Biobank (beta = 0.0044, se = 0.0009, P = 2.417e-06). We also found that LMAN2 was with the largest beta effect size on urolithiasis phenotype from the two cohorts.

Conclusion

We for the first time implemented genome-wide MR analysis to investigate the genetic susceptibility of urolithiasis in general population of European ancestry. Our results provided novel insights into common genetic variants of urinary stone disease, which was of great help to subsequent researches.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We express our thanks to those people who have contributed to the IEU GWAS database project and the MRC Integrative Epidemiology Unit (IEU) at the University of Bristol. Sincere thanks also go to the many GWAS consortia who have made the GWAS data that they generated publicly available, and many members of the IEU who have contributed to curating these data. In addition, we want to acknowledge the participants and investigators of the eQTLGen consortium and FinnGen study.

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Author notes

  1. Lede Lin, Yucheng Ma and Zhen Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology and Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Lede Lin, Yucheng Ma, Linhu Liu, Qibo Hu & Liang Zhou

  2. Department of Urology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China

    Zhen Li

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  1. Lede Lin
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Contributions

Conception and design of study: L L, Y M, and Z L. Acquisition of data: L L, Y M, Z L, L L, and Q H. Data analysis and/or interpretation: L L, Y M, and Z L. Drafting of manuscript and/or critical revision: L L and Y M. Approval of final version of manuscript: L L, Y M, Z L, L L, Q H, and L Z.

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Correspondence to Liang Zhou.

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Lin, L., Ma, Y., Li, Z. et al. Genetic susceptibility of urolithiasis: comprehensive results from genome-wide analysis. World J Urol 42, 230 (2024). https://doi.org/10.1007/s00345-024-04937-y

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