The association between hypertension and the incidence of colorectal cancer remains controversial. This study aimed to clarify this relationship in a Japanese population using two large-scale cohort datasets. We conducted a population-based retrospective cohort study using the Shizuoka Kokuho Database, which contains insurance claims from the Shizuoka region and medical checkup data collected between 2012 and 2022. Propensity score matching was used to compare colorectal cancer incidence between normotensive and hypertensive groups, and cumulative incidence was analyzed using Gray's test, with death treated as a competing risk. Among individuals not taking antihypertensive medications, the normotensive and hypertensive group included 113,724 and 85,399 individuals, respectively. During the follow-up period (median, 4.38 years), colorectal cancer developed in 1130 individuals in the normotensive group and 850 in the hypertensive group. After propensity score matching, colorectal cancer incidence was significantly higher in the hypertensive group, with a hazard ratio of 1.15 (95% confidence interval, 1.02-1.30). This association was observed in men. Among individuals taking antihypertensive medications, an increased risk of colorectal cancer was observed in women. To evaluate whether genetically determined susceptibility to hypertension influences colorectal cancer incidence, we additionally analyzed polygenic risk score for blood pressure using a separate Japanese prospective cohort (Japan Multi-Institutional Collaborative Cohort). No positive association between polygenic risk score for blood pressure and colorectal cancer incidence was identified. This discordance between epidemiological findings and genetic analysis warrants careful interpretation, including, but not limited to, the possibility of previously unrecognized environmental factors shared by colorectal cancer and hypertension.

Background:Chronic kidney disease (CKD) is a significant global health concern. While diet is crucial to CKD prevention and management, the interaction between diet and genetic predisposition to CKD is underexplored. We conducted an exploratory investigation of the interplay between a polygenic score (PGS) for kidney function and dietary exposures in relation to glomerular filtration rate estimated based on serum creatinine (eGFRcrea) on 5717 generally healthy adult participants of the Cooperative Health Research In South Tyrol study. Methods:Dietary intake was assessed using the GA2LEN food frequency questionnaire, from which we derived dietary quality indices including the Mediterranean, Alternative Healthy Eating Index and Dietary Approaches to Stop Hypertension diets, and nutrients relevant to kidney function (proteins, potassium and phosphorus). Genetic predisposition to lower kidney function was quantified using a PGS derived from 131 single nucleotide polymorphisms whose risk alleles were associated with lower eGFRcrea and higher blood urea nitrogen. We fitted multivariable generalized additive models incorporating diet-by-PGS interaction terms to model nonlinear associations with eGFRcrea. Results:The PGS was linearly associated with eGFRcrea (estimated degrees of freedom, df = 1.00, P < .0001), regardless of dietary exposures. All nutrients showed significant linear negative associations with eGFRcrea, a pattern not observed for dietary indices. Nominally significant nonlinear interactions were observed between the PGS and both protein (df = 4.93, P = .0298) and phosphorus intake (df = 5.37, P = .0283). Conclusions:The association of dietary protein and phosphorus intake with eGFRcrea may vary by genetic predisposition to low eGFRcrea levels, with stronger dietary effects in those with a high genetic predisposition.

Epigenetic aging biomarkers are promising novel biological age indicators derived from algorithms based on DNA methylation patterns. Since epigenetic age was first described over a decade ago, it has been used as an exposure or an outcome in biomedical research to address the fundamental question of “aging”. Yet, a critical question remains unresolved: how epigenetic age mediates the effects of exposures on health outcomes. Mediation analysis provides a rigorous statistical framework for decomposing total effects into direct and indirect pathways, thereby testing the extent to which epigenetic age deviation explains exposure-outcome relationships. Meanwhile, the reporting quality using mediation analysis varied across studies. This scoping review provides a methodological primer on causal mediation analysis and a literature review using epigenetic age as a mediator with quality assessment. We conducted an initial literature search through four online databases (PubMed, Embase, MEDLINE, and CINAHL) at the beginning of September 2025. We identified 22 studies (published since 2022) examining epigenetic aging as a mediator between environmental/lifestyle exposures and health outcomes. Most studies used blood-based DNA methylation and applied causal mediation frameworks. GrimAge, PhenoAge, and DunedinPACE were more frequently used. Outcomes primarily included mortality and cardiovascular disease, while exposures covered smoking, diet, socioeconomic factors, clinical biomarkers, and environmental pollutants. Although causal mediation analysis suggested that epigenetic aging could be a possible mechanistic mediator linking exposures to disease risk, many studies lacked methodological rigor. To enhance epigenetic evaluation in broad settings, further work should apply causal mediation analysis to epigenetic aging markers with a rigorous methodology.

Abstract Background Chronic kidney disease (CKD) is a growing public health concern, closely linked to aging and chronic conditions such as diabetes, cardiovascular disease, and hypertension. Diet is a modifiable risk factor for kidney function, but evidence on how specific dietary patterns (DPs) relate to kidney health in healthy populations remains limited. To address this, we evaluated associations between DPs and kidney function, considering sex and menstrual status. DPs were derived using both an a priori approach (DASH) and a hybrid method (RRR), capturing established dietary recommendations as well as population-specific behaviours relevant to kidney health. Methods We analysed cross-sectional data from 6133 healthy adult participants of the Cooperative Health Research In South Tyrol (CHRIS) study. Participants self-reporting previous diagnoses of any kidney disease, hypertension, or diabetes were excluded. Using self-reported food frequency questionnaire data, we derived the DASH-score and two RRR-based sex-specific DP-scores based on nine cardio-renal-metabolic parameters. We applied sex-stratified linear and non-linear models to examine associations with creatinine-based eGFR, including interaction and stratified analyses by menstrual status in females. Results In males, a DP reflecting high intake of cereals, whole grains, sugar, fruits, and legumes, and low intake of beer, red and processed meat was associated with higher eGFR levels (β = 0.75, p = 0.0001). Similarly, higher adherence to the DASH diet was also positively associated with eGFR (β = 0.64, p = 0.0029). In females, the associations varied by menstrual status. Among those with ceased menstruation, a DP reflecting low intake of meat, spirits, and refined grains, and high intake of whole grains and dairy products was associated with higher eGFR (β = 1.11, p = 0.0049). In females still experiencing regular menstruation, a DP reflecting high intake of beef, nuts, beer, and legumes, and low intake of refined grains was associated with lower eGFR (β = −0.43, p = 0.0326). No association was observed with the DASH score in females. Conclusions The DASH-style diet is associated with better kidney function in males, but not in females. Identifying sex-specific kidney function-oriented DPs using RRR provides new insights into the diet-eGFR relationship, suggesting potential effect modification by menstrual status.

Background: Cardiovascular disease (CVD) remains a leading cause of death in Japan. Although several CVD risk scores tailored for Japanese individuals have been developed, no tools are available to estimate these scores at the population level. We developed the “Jcvrisk” R package, which integrates four major Japanese CVD risk models recommended by the clinical guideline from the Japanese Circulation Society (JCS). As a showcase, we applied the Jcvrisk package to longitudinal population-based study to evaluate trends in estimated different risk scores. Methods: We used longitudinal data from the Yakumo Study, an annual health checkup for residents in Yakumo, Hokkaido. This package includes four risk models with 14 risk scores from representative cardiovascular cohort studies, including three Evidence for Cardiovascular Prevention From Observational Cohorts scores, one Hisayama score, two Suita scores, and eight Japan Atherosclerosis Longitudinal Study scores. For temporal comparisons of CVD risk scores, we summarized scores from 2000 to 2020 every 5 years. Results: The mean age of participants throughout all study years was around 60 years. Most risk factors did not change remarkably over the 20 years, with only a decrease in smoking prevalence and an increase in high density lipoprotein cholesterol. However, all CVD risk scores consistently indicated an upward trend in 10-year CVD risk. Conclusion: Jcvrisk package includes functions to calculate CVD risk scores for Japanese adults. The package serves as a valuable tool for researchers and policymakers aiming to assess and monitor cardiovascular risk at both individual and the population level in Japan.

Objectives: Mitochondrial dysfunction has been implicated in neurodegenerative diseases, but evidence regarding its association with cognitive performance in the general population remains limited. This study aimed to examine the association between peripheral blood mitochondrial DNA copy number (mtDNA-CN) and cognitive function in the general Japanese population. Methods: We conducted a cross-sectional analysis of 282 participants (134 men and 148 women) from the Yakumo Study, a population-based health examination in Hokkaido, Japan. Peripheral blood mtDNA-CN was measured by quantitative real-time PCR and categorized into tertiles. Cognitive function was assessed using the short version of the Mini-Mental State Examination (SMMSE), the Logical Memory Test (LMT), and the Digit Cancellation Test (D-CAT). Logistic regression analyses were performed to evaluate the association between mtDNA-CN levels and cognitive performance, with adjustments for relevant demographic and clinical factors. Results: Lower mtDNA-CN was significantly associated with poorer SMMSE scores in women and with reduced D-CAT3 performance—reflecting attention and executive function—in men. No significant associations were observed for LMT scores in either sex. These domain- and sex-specific associations remained consistent after adjustment for potential confounders. Conclusions: Lower mtDNA-CN was associated with poorer cognitive performance in the general Japanese population, in a cognitive domain- and sex-specific manner. mtDNA-CN thus has potential as a non-invasive biomarker for the early identification of individuals at increased risk of cognitive decline. Longitudinal studies are necessary to evaluate its predictive utility and potential application in dementia prevention strategies.

The present study aimed to clarify associations between coffee intake and kidney function with consideration of the effect modifications from coffee intake-related genetic polymorphisms. This cross-sectional study included 7,468 Japanese participants 35–69 years old (3,953 women: 52.9

BACKGROUND:Although serum carotene may contribute to dementia prevention, there is a lack of longitudinal evidence for early cognitive decline before dementia symptoms. The aim of this study was to examine whether serum carotene levels were associated with annually evaluated cognitive trajectories among the Japanese general population. METHODS:Among 581 baseline participants, 199 individuals (83 males; mean age [min, max], 62.7 [39, 90] years) who underwent cognitive assessments more than twice after baseline were analyzed. "Attention" levels were assessed using one- and three-target Digit Cancellation Tests (D-CAT1 and D-CAT3). "General cognitive ability" was assessed by the short version of Mini-Mental State Examination (SMMSE). Serum carotenes (α-carotene, β-carotene and lycopene) were measured by high-performance liquid chromatography. After the measurements, we calculated total carotene levels by summing up the levels of all measured carotene. Carotene levels were categorized into three groups for analysis (low: 0%-25%, middle: 25%-75%, and high: 75%-100%). A linear mixed model was used to estimate the slope of the D-CAT score trajectory and to compare it between three categories. RESULTS:Compared with the middle carotene group, decline of attention was faster in the D-CAT1 for low β-carotene (β = -3.48, p = 0.035), lycopene (β = -3.10, p = 0.062), and total carotene (β = -4.75, p = 0.003), but not for α-carotene (β = -2.60, p = 0.111). For the D-CAT3, decline of attention was faster in the group of low lycopene (β = -3.17, p = 0.002) and total carotene (β = -2.17, p = 0.037) compared with the middle carotene group, while no clear association for α-carotene (β = -0.67, p = 0.521) and β-carotene (β = -0.64, p = 0.639). There were no clear associations between serum carotene and the SMMSE score. CONCLUSIONS:These findings suggest low levels of serum lycopene are associated with a decline of attention in the setting of the general population.

BACKGROUND:Although body roundness index (BRI) is gaining attention as an indicator of abdominal obesity, evidence on this indicator is still sparse. OBJECTIVES:We aimed to summarize basic information about BRI in a Japanese population and to examine associations of BRI with all-cause and cardiovascular disease (CVD) mortality with a preliminary meta-analysis. METHODS:This population-based cohort study included participants [mean age of 58.4 y (min, max: 40, 89), 37.8% men] in health check-up programs between 2004 and 2018, and we followed up until 31 December, 2023. BRI was calculated by a conventional formula for height (cm) and waist circumference (cm). CVD mortality was defined as mortality with International Classification of Diseases, 10th Revision codes of I00-I99. Hazard ratios (HRs) were estimated for all-cause and CVD mortality using Cox proportional hazards regression models. RESULTS:During the follow-up period (median: 13.3 y), 206 individuals died, and 47 individuals died from CVD. Women had a wider distribution of BRI [median: 3.72; interquartile range (IQR): 2.84-4.88] compared with men (median: 3.54; IQR: 2.88-4.19). BRI increased from the 40-49 age group (median: 3.24; IQR: 2.42-4.08) to those over 70 y old (median: 4.22; IQR: 3.20-5.32). Compared with Q1, HRs [95% confidence interval (CI)] in Q3 were lower for both all-cause mortality (HR: 0.64; 95% CI: 0.43, 0.96) and CVD mortality (HR: 0.27; 95% CI: 0.09, 0.78). Preliminary meta-analysis also supported a similar U-shaped association of BRI with mortality with a HR in Q3 of 0.85 (95% CI: 0.75, 0.95) compared with Q1. CONCLUSIONS:BRI varies across age groups and between sexes in a Japanese population. Both our results and this meta-analysis suggest that BRI has U-shaped associations with all-cause and CVD mortality. The trial was registered at PROSPERO as 1149845.

Supplementary Figure S2 shows a density plot of AHRR DNAm levels by passive smoking among never smokers.

Chronic kidney disease (CKD) affects 10% of the worldwide population. While diet plays a key role in CKD prevention and management, interaction between diet and CKD genetic predisposition is largely unexplored. We investigated the interplay between a polygenic score (PGS) and dietary patterns in determining the CKD-defining trait, the estimated glomerular filtration rate (eGFR), in the Cooperative Health Research In South Tyrol (CHRIS) study. We derived eGFR for 5,717 individuals without CKD and related morbidities (median age: 40 years; 53% females; median eGFR: 101.7 ml/min/1.73 m2). Using data from the GA2LEN food frequency questionnaire, we estimated the CKD-relevant nutrients protein, potassium, and phosphorus, and the overall diet quality as the Dietary Approach to Stop Hypertension (DASH) index. We derived the eGFR PGS using 131 high-quality imputed variants, with effect sizes derived from a large genome-wide association study meta-analysis (n = 1,046,070), and where variants were selected for kidney function relevance and identified using an additive genetic model. We fitted multiply adjusted generalized additive models incorporating tensor product smooths and diet-PGS interaction terms to model non-linear associations with eGFR. The PGS explained 1.5% of the eGFR variance. Among dietary exposures, the DASH score explained the largest proportion (2.2%), followed by potassium (1.9%), proteins (1.8%), and phosphorus (0.2%). In all models, the PGS was linearly associated with eGFR (P < 0.0001), regardless of dietary exposures. All nutrients showed statistically significant linear associations with eGFR, while the association with the DASH score was not significant. Proteins and phosphorus showed significant non-linear interactions with the PGS (protein:PGS P = 0.0298; phosphorus:PGS P = 0.0283), indicating that higher intake of these nutrients was associated with lower eGFR levels in individuals with a high PGS but not in those with a low PGS. The PGS explained a modest proportion of eGFR variance and interacted significantly with dietary proteins and phosphorus. These findings suggest genetic predisposition to potentially modify the association between protein and phosphorus intake, and kidney function.

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.

Background Although utility of composite trait‐specific polygenic risk score (multi‐trait PRS) has been examined among European ancestries, few studies investigated among East Asians and incorporated modifiable risk factors. We examined the associations of multi‐trait PRS for cardiometabolic factors with cardiovascular disease mortality by integrating nongenetic determinants. Methods A total of 14 086 Japanese participants (mean age, 55±9; 55.8% women) of the J‐MICC (Japan Multi‐Institutional Collaborative Cohort) study were analyzed in this study. We calculated 6 PRSs for cardiometabolic traits (systolic blood pressure, body mass index, triglycerides, low‐density lipoprotein cholesterol, estimated glomerular filtration rate, and hemoglobin A1c). Based on these PRSs, we developed multi‐trait PRS and considered as a primary exposure. Three nongenetic factors (smoking, alcohol drinking, and educational attainment) from the self‐reported questionnaire were also examined. Results During a median 12.1‐year follow‐up period, a total of 472 all‐cause and 79 cardiovascular disease mortality cases were documented. Compared with 0% to 90% of multi‐trait PRSs, an adjusted hazard ratio (HR) among the top 10% of multi‐trait PRSs was 1.32 (95% CI, 1.00–1.73) for all‐cause death and 2.63 (95% CI, 1.48–4.67) for cardiovascular disease death. Incorporation of educational attainment with multi‐trait PRSs showed null associations in those who went beyond high school (HR, 2.07 [95% CI, 0.44–9.66]) even in the top 10% of multi‐trait PRS. Conclusions Our analysis combining both genetic and nongenetic determinants highlighted that lifestyle factors and educational attainment can slightly reduce an individual's composite genetic risk for cardiovascular disease death.

BACKGROUND:Among the more than 300 mycotoxins that are known to have toxic effects on animals and humans, Fusarium toxins deoxynivalenol (DON), T-2 and HT-2 toxins (T2/HT2), and zearalenone (ZEN) are frequently detected in domestic agricultural products. This study aimed to assess DON, T2/HT2, and ZEN exposure in Japanese adults by measuring urinary mycotoxins, observing their distributions, and making comparisons with data from other countries. METHODS:A total of 201 individuals participated in the study. Twenty-four-hour urine samples were collected from young adults (34 men and 35 women) in the Tokai region (urban area) and spot urine samples were collected from middle-aged and elderly adults (64 men and 68 women) in the Donan area of Hokkaido Prefecture (rural area). Urinary DON, T2/HT2, and ZEN levels were measured using a validated liquid chromatography-tandem mass spectrometry method. RESULTS:For DON, T2/HT2, and ZEN, the detection frequencies above the limit of detection (LOD) level (0.15, 0.13, and 0.01 µg/L, respectively) in all the samples were 53%, 26%, and 71%, respectively. The median concentrations (95th percentile) of urinary DON, HT2, and ZEN were 0.19 (3.93), <LOD (0.55), and 0.02 (0.12) µg/L, respectively. Although at least one of the investigated mycotoxins was detected in the urine of 86% of study participants, the concentrations were similar to or lower than those found in other countries (from 19 reports within the past decade). Moreover, the probable daily intake (PDI) values in the present study were lower than the provisional maximum tolerable daily intake levels. The urinary mycotoxin levels did not significantly differ with respect to sex, age, or occupation. CONCLUSIONS:This study represents the first comprehensive exposure assessment for DON, T2/HT2, and ZEN in Japanese adults using human biomonitoring methods. These data provide valuable information for a better understanding of mycotoxin exposure in Japan.

ABSTRACT Aims/Introduction Previous observational studies have suggested an increased risk of type 2 diabetes associated with both short and long sleep duration. However, there remains uncertainty, particularly regarding the adverse effects of long sleep duration. We investigated the association between self‐reported questionnaire‐based and objectively measured accelerometer‐derived sleep duration and the risk of type 2 diabetes using data from the UK Biobank. Materials and Methods First, we performed conventional Cox regression analysis with restricted cubic splines to illustrate the potentially non‐linear association between sleep duration and the risk of type 2 diabetes. Second, we performed non‐linear Mendelian randomization (MR) analysis using the doubly‐ranked method with 85 and 20 genetic variants associated with questionnaire‐based and accelerometer‐based sleep duration, respectively. Third, we performed two‐sample MR analysis. Results The results of conventional analysis of accelerometer‐derived sleep duration did not suggest a strong association between longer sleep duration and type 2 diabetes risk (hazard ratio [HR] of ≥10 h compared with 7–8 h, 1.08; 95% confidence interval [CI], 0.92–1.27). The results of non‐linear MR showed no strong evidence for an increased risk of type 2 diabetes associated with questionnaire‐based longer sleep duration (HR of 9 h compared with 7 h, 0.77; 95% CI, 0.52–1.15). This finding was consistent with non‐linear MR of accelerometer‐derived sleep duration (HR of 9 h compared with 7 h, 0.78; 95% CI, 0.29–2.06). Conclusions Our findings suggest that longer sleep duration does not play a major role in the development of type 2 diabetes.

Supplementary Figure S4 shows a scatter plot of CPD versus AHRR DNAm levels and HRs for each cause of mortality, stratified by CPD and AHRR DNAm.

Summary Genome-wide association studies (GWAS) generated thousands of loci associated with complex traits and diseases. However, to characterize of the pleiotropic, molecular and population genetic bounds of uncovered loci, investigations are conducted, that remain conceptually and practically separated. Also in the best case, such investigations proceed by one locus at a time. To address these limitations, we introduce an efficient and reproducible Snakemake pipeline for executing haplotype-based association analysis on GWAS-identified genetic loci, which is especially helpful in samples enriched with molecular omics data. Haplomics takes as input the genetic coordinates of each locus along with all available clinical and molecular phenotypes, the necessary covariates, and VCF genotype files, to reconstruct haplotypes and test them for associations with the phenotypes. The reconstructed haplotypes, the annotation of included variants, and association results are graphically displayed in an HTML report. We tested Haplomics in population-based study sample encompassing 391 traits, including 72 clinical markers, 171 serum metabolites, 148 plasma protein concentrations, and whole-exome sequencing (WES) imputed genotypes. We estimated WES-based haplotypes at 11 kidney function genetic loci from a GWAS and conducted association analyses throughout, identifying 19 significant associations after multiple testing correction. Haplomics is a scalable, easy-to-use and fast haplotype reconstruction and association pipeline that makes it possible to jointly conduct molecular and population-genetic characterization of multiple GWAS loci in unified analysis framework. Availability and implementation Haplomics is freely available on GitHub https://github.com/dariushghasemi/haplomics. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The CHRIS study was funded by the Autonomous Province of Bolzano/Bozen - South Tyrol -Department of Innovation, Research, University and Museums and supported by the European Regional Development Fund (FESR1157). 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 Ethics Committee of the Healthcare System of the Autonomous Province of Bolzano-South Tyrol approved the CHRIS baseline protocol on 19 April 2011 (21-2011). The study conforms to the Declaration of Helsinki, and with national and institutional legal and ethical requirements. The CHRIS Access Committee at Eurac Research Institute for Biomedicine in Bolzano, Italy, gave approval for this work to publish. 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 in the current study can be requested with an application to: biomedicine{at}eurac.edu at the Eurac Research Institute for Biomedicine.

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.

Supplementary Figure S1 shows a density plot of AHRR DNAm levels by smoking habits.