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Systematic mediation and interaction analyses of kidney function genetic loci in a general population study
Dariush Ghasemi-Semeskandeh1,2,3, David Emmert2, Eva König2
1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Plos One
|June 24, 2025
Summary
This study reveals that specific genetic variations influence kidney function more strongly in certain populations. Thyroid function significantly modifies these genetic effects, highlighting the importance of individual population studies for understanding kidney disease genetics.
Area of Science:
- Genetics
- Nephrology
- Endocrinology
Background:
- Chronic kidney disease (CKD) affects over 10% of the global population, with significant environmental influences.
- Genome-wide association study meta-analyses (GWAMAs) have identified numerous genetic loci for CKD traits.
- Single population studies may offer unique insights into specific genetic mechanisms beyond aggregated analyses.
Purpose of the Study:
- To evaluate if a specific population study can enhance knowledge of kidney function genetics.
- To assess 147 kidney function-associated loci in the Cooperative Health Research In South Tyrol (CHRIS) study cohort.
- To investigate the role of thyroid function as a potential modifier of genetic associations with kidney function.
Main Methods:
- Association analysis of 147 kidney function loci with estimated glomerular filtration rate from serum creatinine (eGFRcrea) in 10,146 CHRIS participants.
- Systematic mediation analysis using 70 quantitative traits to identify intermediate factors.
- SNP-by-thyroid stimulating hormone (TSH) interaction analyses to explore thyroid hormone effects.
Main Results:
- Significant associations with eGFRcrea were found at 11 loci, with effect sizes up to 5.4 times larger than in GWAMAs.
- Serum magnesium and activated partial thromboplastin time were identified as partial mediators for eGFRcrea associations at SHROOM3 and SLC34A1.
- Thyroid hormones (free triiodothyronine and thyroxine) acted as effect modifiers across all loci, with significant SNP-TSH interactions observed at STC1.
Conclusions:
- Individual population studies, like the CHRIS study, are valuable for characterizing genetic associations with kidney function.
- The identified genetic associations at SHROOM3 and SLC34A1, and the modifying role of thyroid function, warrant further investigation.
- Understanding genetic influences in specific populations can reveal novel therapeutic targets and mechanisms in kidney disease.
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