Systematic mediation and interaction analyses of kidney function genetic loci in a general population study

Chronic kidney disease (CKD) is a complex disease affecting >10% of the global population, with large between- and within-continent variability reflecting major environmental determinants. To identify molecular targets for treatment and prevention, genome-wide association study meta-analyses (GWA...

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Published in:PloS one Vol. 20; no. 6; p. e0323057
Main Authors: Ghasemi-Semeskandeh, Dariush, Emmert, David, König, Eva, Foco, Luisa, Gögele, Martin, Sarhan, Mohamed S., Barin, Laura, Fujii, Ryosuke, Fuchsberger, Christian, Peters, Dorien J. M., Pramstaller, Peter P., Pattaro, Cristian
Format: Journal Article
Language:English
Published: United States Public Library of Science 24.06.2025
Public Library of Science (PLoS)
Subjects:
Adult
Aged
Alpine regions
Analysis
Anthropometry
Autocrine signalling
Biology and Life Sciences
Chronic illnesses
Chronic kidney failure
Creatinine
Creatinine - blood
Datasets
Female
Gene frequency
Gene loci
Genetic aspects
Genetic Loci
Genetics
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genotype & phenotype
Glomerular filtration rate
Glomerular Filtration Rate - genetics
Humans
Kidney - physiology
Kidney - physiopathology
Kidney diseases
Kidney function tests
Kidneys
Magnesium
Male
Medicine and Health Sciences
Middle Aged
Mortality
Nucleotides
Paracrine signalling
Phenotypes
Physical Sciences
Polymorphism, Single Nucleotide
Population
Population genetics
Population studies
Renal Insufficiency, Chronic - genetics
Renal Insufficiency, Chronic - physiopathology
Risk factors
Single-nucleotide polymorphism
Stanniocalcin
Thromboplastin
Thyroid
Thyroid gland
Thyroid hormones
Thyroid-stimulating hormone
Thyroxine
Triiodothyronine
Italy
ISSN:1932-6203, 1932-6203
Online Access:Get full text
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Summary:Chronic kidney disease (CKD) is a complex disease affecting >10% of the global population, with large between- and within-continent variability reflecting major environmental determinants. To identify molecular targets for treatment and prevention, genome-wide association study meta-analyses (GWAMAs) of CKD-defining traits have identified hundreds of genetic loci in aggregated population samples. However, while GWAMAs estimate the average allelic effect across studies, single population studies may be relevant to unravel specific mechanisms. To assess whether a study sample from a specific population could extend existing knowledge on kidney function genetics, we selected 147 kidney function relevant loci identified by a large GWAMA, assessing their association with the glomerular filtration rate estimated from serum creatinine (eGFRcrea) in 10,146 participants to the Cooperative Health Research In South Tyrol (CHRIS) study, conducted in an Alpine region where thyroid dysfunction is common. We identified associations with single nucleotide polymorphisms (SNPs) at 11 loci, showing up-to-5.4 times larger effect sizes than in the corresponding GWAMA, not explainable by allele frequency differences. Systematic mediation analysis across 70 quantitative traits identified serum magnesium and the activated partial thromboplastin time as partial mediators of the eGFRcrea associations at SHROOM3 and SLC34A1 , respectively. Given that free triiodothyronine and thyroxine acted as effect modifiers across all loci, we conducted SNP-by-thyroid stimulating hormone (TSH) interaction analyses, identifying significant interactions at STC1 : SNPs had larger effects on eGFRcrea at higher TSH levels, possibly reflecting stanniocalcin-1 autocrine and paracrine role. Individual population studies can help characterize genetic associations. The interplay between phenotypes at SHROOM3 and SLC34A1 and the role of thyroid function as a genetic effect modifier warrant further investigations.
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Competing Interests: The authors have declared that no competing interests exist.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0323057