Identification of potential pathogenic genes for urolithiasis through multi-omics Mendelian randomization analysis

Area of Science:

• Genetics
• Urology
• Bioinformatics

Background:

• Urolithiasis affects 10% globally with high recurrence, but its genetic basis is unclear.
• Understanding genetic factors is crucial for developing effective treatments and prevention strategies for kidney stones.

Purpose of the Study:

• To identify pathogenic genes associated with urolithiasis using a multi-omics Mendelian randomization approach.
• To investigate the causal relationships between gene expression and urolithiasis risk.

Main Methods:

• Integrated genome-wide association studies (GWAS), eQTL, mQTL, and pQTL data.
• Employed Summary Data-Based Mendelian Randomization (SMR) and Bayesian colocalization analyses.
• Utilized external validation and multivariable Mendelian randomization (MR) to control for confounders like BMI and smoking.

Main Results:

• Identified seven genes associated with urolithiasis, highlighting LMAN2, NUCKS1, and L3MBTL3.
• LMAN2 expression positively correlates with urolithiasis risk, while NUCKS1 and L3MBTL3 expression show protective effects.
• Confirmed these genetic associations are independent of major lifestyle and metabolic factors.

Conclusions:

• LMAN2, NUCKS1, and L3MBTL3 are significant genetic contributors to urolithiasis.
• These genes represent potential biomarkers and therapeutic targets for personalized urolithiasis treatment.
• The findings advance our understanding of the genetic underpinnings of kidney stone formation.