Systematic mediation and interaction analyses in an individual population study help characterize kidney function genetic loci

Chronic kidney disease (CKD) is a complex disease affecting >10% of the global population, with large between- and within-continent variability reflecting major environmental effects. To identify molecular targets for treatment, genome-wide association study meta-analyses (GWAMAs) of CKD-defining traits have identified hundreds of genetic loci in aggregated populations. However, while GWAMAs estimate the average allelic effect across studies, single population studies may be relevant to unravel specific mechanisms. To assess whether an individual study from a specific population could extend existing knowledge on kidney function genetics, we selected 147 kidney function relevant loci identified by a large European ancestry GWAMA, assessing their association with the glomerular filtration rate estimated from serum creatinine (eGFRcrea) in the Cooperative Health Research In South Tyrol (CHRIS) study (n=10,146), conducted in an Alpine region where thyroid dysfunction is common. We replicated 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 minor allele frequency differences. Systematic mediation analysis across 70 quantitative traits identified serum magnesium, the activated partial thromboplastin time, and serum urate as partial mediators of the eGFRcrea associations at SHROOM3, SLC34A1, and IGF1R, respectively. Given that free triiodothyronine and thyroxine were 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The CHRIS study was funded by the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol. This work was carried out within the TrainCKDis project, funded by the European Union Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement H2020-MSCA-ITN-2019 ID:860977 (TrainCKDis). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The CHRIS study was approved by the Ethical Committee of the Healthcare System of the Autonomous Province of Bozen/Bolzano, protocol no. 21/2011 (19 Apr 2011). All participants provided written informed consent. All the methods were performed in strict accordance with the approved protocol. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used for the current study and the results are stored in a controlled storage at the Eurac Research Institute for Biomedicine. The data are not openly available due to reasons of sensitivity and can be requested with an application to access.request.biomedicine@eurac.edu.