Quantifying variations associated with dental caries reveals disparity in effect allele frequencies across diverse populations.

BACKGROUND: Dental caries (DC) is a multifaceted oral condition influenced by genetic and environmental factors. Recent advancements in genotyping and sequencing technologies, such as Genome-Wide Association Studies (GWAS) have helped researchers to identify numerous genetic variants associated with DC, but their prevalence and significance across diverse global populations remain poorly understood as most of the studies were conducted in European populations, and very few were conducted in Asians specifically in Indians. AIM: This study aimed to evaluate the genetic affinity of effect alleles associated with DC to understand the genetic relationship between global populations with respect to the Indian context. METHODOLOGY: This present study used an empirical approach in which variants associated with DC susceptibility were selected. These variants were identified and annotated using the GWAS summary. The genetic affinity was evaluated using Fst. RESULTS: The effect of allele frequencies among different populations was examined, revealing variations in allele distribution. African populations exhibited higher frequencies of specific risk alleles, whereas East Asian and European populations displayed distinct profiles. South Asian populations showed a unique genetic cluster. CONCLUSION: Our study emphasises the complex genetic landscape of DC and highlights the need for population-specific research as well as validation of GWAS-identified markers in Indians before defining them as established candidate genes.

The Genesis of Schizophrenia: An Origin Story.

Schizophrenia is routinely referred to as a neurodevelopmental disorder, but the role of brain development in a disorder typically diagnosed during early adult life is enigmatic. The authors revisit the neurodevelopmental model of schizophrenia with genomic insights from the most recent schizophrenia clinical genetic association studies, transcriptomic and epigenomic analyses from human postmortem brain studies, and analyses from cellular models that recapitulate neurodevelopment. Emerging insights into schizophrenia genetic risk continue to converge on brain development, particularly stages of early brain development, that may be perturbed to deviate from a typical, normative course, resulting in schizophrenia clinical symptomatology. As the authors explicate, schizophrenia genetic risk is likely dynamic and context dependent, with effects of genetic risk varying spatiotemporally, across the neurodevelopmental continuum. Optimizing therapeutic strategies for the heterogeneous collective of individuals with schizophrenia may likely be guided by leveraging markers of genetic risk and derivative functional insights, well before the emergence of psychosis. Ultimately, rather than a focus on therapeutic intervention during adolescence or adulthood, principles of prediction and prophylaxis in the pre- and perinatal and neonatal stages may best comport with the biology of schizophrenia to address the early-stage perturbations that alter the normative neurodevelopmental trajectory.

Circulating interleukin-27 is associated with the risk of chronic periodontitis and allergic rhinitis: A Mendelian randomization analysis.

BACKGROUND: Chronic periodontitis (CP) and allergic rhinitis (AR) have attracted wide attention as global public health problems with high incidence. Recent studies have shown that circulating interleukin-27 (IL-27) is associated with the risk of CP and AR. The aim of this study is to analyze the causal effect between them using Mendelian randomization (MR). METHODS: Bidirectional MR analyses were performed with the use of publicly available genome-wide association study (GWAS) data. Summary data on circulating IL-27, CP, and AR published in genome-wide association studies were collected. Instrumental variables (IV) were extracted using assumptions of correlation, independence and exclusivity as criteria. Inverse variance weighting (IVW) was used as the main method, combined with weighted median method (WM) and MR-Egger and other MR Analysis methods for causal inference of exposure and outcome. Cochran's Q and MR-Egger intercept were used for sensitivity analysis. RESULTS: The IVW study showed a causal effect between increased circulating IL-27 levels and increased risk of CP (OR = 1.14, 95%CI = 1.02-1.26, p = .020). Similarly, the increase of circulating IL-27 level had a causal effect on the decreased risk of AR (OR = 0.88, 95%CI = 0.80-0.97, p = .012). In addition, IVW study found that there was a causal between the increased risk of CP and circulating IL-27 level (OR = 1.05, 95%CI = 1.01-1.10, p = .016). However, there was no significant causal relationship between the risk of AR and circulating IL-27 levels (OR = 0.97, 95%CI = 0.91-1.02, p = .209). no significant heterogeneity or horizontal pleiotropy was found in sensitivity analysis. CONCLUSIONS: There is a causal effect between circulating IL-27 level and CP, AR, which will help to find new ideas and methods for the diagnosis and treatment of CP and AR.

Prospective of Mitochondrial DNA Variations in Cancer on Genomic Medicine.

Mitochondrial DNA (mtDNA) has emerged as a pivotal component in understanding the etiology and susceptibility of cancer. A recent study by Chen and colleagues delineated the germline genetic effect of mtDNA single-nucleotide polymorphisms (SNP) and haplogroups across pan-cancer risk. They identified a subset of mtSNPs and the corresponding risk score, as well as haplogroups A and M7 alongside their genetic interactions, conferring a protective effect against various cancers. These findings underscored the value of mtDNA variations as biomarkers for cancer etiology and as tools for cancer risk stratification. Future investigations are encouraged to integrate comprehensive omics data of genomics, transcriptomics, proteomics, and metabolomics, etc., from nuclear DNA with mtDNA variations, alongside single-cell and spatial technologies, to unravel the tumor mechanism and identify the drug targets. Moreover, the incorporation of polygenic risk score, that included mtDNA variations with both rare and common frequencies, and liquid biopsy-based biomarkers would enhance the predictive performance of cancer risk assessment and refine the risk stratification of population-based cancer screening. This commentary advocates for the validation across diverse populations to harness the full potential of mitochondrial genomics, and ultimately paves the prospective way for advancements in personalized cancer therapeutics and prevention strategies. See related article by Chen and colleagues, Cancer Epidemiol Biomarkers Prev 2024;33:381-8.

Understanding the Impact of the Sirtuin 1 (SIRT1) Gene on Age-related Macular Degeneration: A Comprehensive Study.

Age-related macular degeneration (AMD) is a prevalent and incurable condition affecting the central retina and posing a significant risk to vision, particularly in individuals over the age of 60. As the global population ages, the prevalence of AMD is expected to rise, leading to substantial socioeconomic impacts and increased healthcare costs. The disease manifests primarily in two forms, neovascular and non-neovascular, with genetic, environmental and lifestyle factors playing a pivotal role in disease susceptibility and progression. This review article involved conducting an extensive search across various databases, including Google Scholar, PubMed, Web of Science, ScienceDirect, Scopus and EMBASE, to compile relevant case-control studies and literature reviews from online published articles extracted using search terms related to the work. SIRT1, a key member of the sirtuin family, influences cellular processes such as ageing, metabolism, DNA repair and stress response. Its dysregulation is linked to retinal ageing and ocular conditions like AMD. This review discusses the role of SIRT1 in AMD pathology, its association with genetic variants and its potential as a biomarker, paving the way for targeted interventions and personalised treatment strategies. In addition, it highlights the findings of case-control studies investigating the relationship between SIRT1 gene polymorphisms and AMD risk. These studies collectively revealed a significant association between certain SIRT1 gene variants and AMD risk. Further studies with larger sample sizes are required to validate these findings. As the prevalence of AMD grows, understanding the role of SIRT1 and other biomarkers becomes increasingly vital for improving diagnosis, treatment and, ultimately, patient outcomes.

Generalized genetic liability to substance use disorders.

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.

Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus.

Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.

Mendelian randomization evidence based on European ancestry for the causal effects of leukocyte telomere length on prostate cancer.

BACKGROUND: Several lines of evidence suggest that leukocyte telomere length (LTL) can affect the development of prostate cancer (PC). METHODS: Here, we employed single nucleoside polymorphisms (SNPs) as instrumental variables (IVs) for LTL (n = 472,174) and conducted Mendelian randomization analysis to estimate their causal impact on PCs (79,148 patients/61,106 controls and 6311 patients/88,902 controls). RESULTS: Every 1-s.d extension of LTL increased the risk of PCs by 34%. Additionally, the analysis of candidate mediators between LTL and PCs via two-step Mendelian randomization revealed that among the 23 candidates, Alzheimer's disease, liver iron content, sex hormone binding global levels, naive CD4-CD8-T cell% T cell, and circulating leptin levels played substantial mediating roles. There is no robust evidence to support the reverse causal relationship between LTL and the selected mediators of PCs. Adjusting for the former four mediators, rather than adjusting for circulating leptin levels, decreased the impact of LTL on PCs. CONCLUSION: This study provides potential intervention measures for preventing LTL-induced PCs.

Shared genetic aetiology of respiratory diseases: a genome-wide multitraits association analysis.

OBJECTIVE: This study aims to explore the common genetic basis between respiratory diseases and to identify shared molecular and biological mechanisms. METHODS: This genome-wide pleiotropic association study uses multiple statistical methods to systematically analyse the shared genetic basis between five respiratory diseases (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, lung cancer and snoring) using the largest publicly available genome wide association studies summary statistics. The missions of this study are to evaluate global and local genetic correlations, to identify pleiotropic loci, to elucidate biological pathways at the multiomics level and to explore causal relationships between respiratory diseases. Data were collected from 27 November 2022 to 30 March 2023 and analysed from 14 April 2023 to 13 July 2023. MAIN OUTCOMES AND MEASURES: The primary outcomes are shared genetic loci, pleiotropic genes, biological pathways and estimates of genetic correlations and causal effects. RESULTS: Significant genetic correlations were found for 10 paired traits in 5 respiratory diseases. Cross-Phenotype Association identified 12 400 significant potential pleiotropic single-nucleotide polymorphism at 156 independent pleiotropic loci. In addition, multitrait colocalisation analysis identified 15 colocalised loci and a subset of colocalised traits. Gene-based analyses identified 432 potential pleiotropic genes and were further validated at the transcriptome and protein levels. Both pathway enrichment and single-cell enrichment analyses supported the role of the immune system in respiratory diseases. Additionally, five pairs of respiratory diseases have a causal relationship. CONCLUSIONS AND RELEVANCE: This study reveals the common genetic basis and pleiotropic genes among respiratory diseases. It provides strong evidence for further therapeutic strategies and risk prediction for the phenomenon of respiratory disease comorbidity.

Genetic counseling and genetic testing for pathogenic germline mutations among high-risk patients previously diagnosed with breast cancer: a traceback approach.

Genetic counseling and testing are more accessible than ever due to reduced costs, expanding indications and public awareness. Nonetheless, many patients missed the opportunity of genetic counseling and testing due to barriers that existed at that time of their cancer diagnoses. Given the identified implications of pathogenic mutations on patients' treatment and familial outcomes, an opportunity exists to utilize a 'traceback' approach to retrospectively examine their genetic makeup and provide consequent insights to their disease and treatment. In this study, we identified living patients diagnosed with breast cancer (BC) between July 2007 and January 2022 who would have been eligible for testing, but not tested. Overall, 422 patients met the eligibility criteria, 282 were reached and invited to participate, and germline testing was performed for 238, accounting for 84.4% of those invited. The median age (range) was 39.5 (24-64) years at BC diagnosis and 49 (31-75) years at the date of testing. Genetic testing revealed that 25 (10.5%) patients had pathogenic/likely pathogenic (P/LP) variants; mostly in BRCA2 and BRCA1. We concluded that long overdue genetic referral through a traceback approach is feasible and effective to diagnose P/LP variants in patients with history of BC who had missed the opportunity of genetic testing, with potential clinical implications for patients and their relatives.

Risk of diabetes mellitus based on the interactive association between G6PD rs72554664 polymorphism and sex in Taiwan Biobank individuals.

The presence of glucose-6-phosphate dehydrogenase (G6PD) deficiency may increase the risk of type 2 diabetes mellitus (T2DM), with differing prevalence between males and females. Although G6PD deficiency is an X-linked genetic condition, its interaction with sex regarding T2DM risk among the Taiwanese population has not been fully explored. This study aimed to investigate the association between G6PD deficiency and T2DM risk in the Taiwanese population, focusing on the potential influence of sex. Data were obtained from the Taiwan Biobank (TWB) database, involving 85,334 participants aged 30 to 70 years. We used multiple logistic regression analysis to assess the interaction between G6PD rs72554664 and sex in relation to T2DM risk. The T2DM cohort comprised 55.35% females and 44.65% males (p < 0.001). The TC + TT genotype of rs72554664 was associated with an increased risk of T2DM, with an odds ratio (OR) of 1.95 (95% CI: 1.39-2.75), and males showed an OR of 1.31 (95% CI: 1.19-1.44). Notably, the G6PD rs72554664-T allelic variant in hemizygous males significantly elevated the T2DM risk (OR), 4.57; p < 0.001) compared to females with the CC genotype. Our findings suggest that the G6PD rs72554664 variant, in conjunction with sex, significantly affects T2DM risk, particularly increasing susceptibility in males. The association of the G6PD rs72554664-T allelic variant with a higher risk of T2DM highlights the importance of sex-specific mechanisms in the interplay between G6PD deficiency and T2DM.

EMCMDA: predicting miRNA-disease associations via efficient matrix completion.

Abundant researches have consistently illustrated the crucial role of microRNAs (miRNAs) in a wide array of essential biological processes. Furthermore, miRNAs have been validated as promising therapeutic targets for addressing complex diseases. Given the costly and time-consuming nature of traditional biological experimental validation methods, it is imperative to develop computational methods. In the work, we developed a novel approach named efficient matrix completion (EMCMDA) for predicting miRNA-disease associations. First, we calculated the similarities across multiple sources for miRNA/disease pairs and combined this information to create a holistic miRNA/disease similarity measure. Second, we utilized this biological information to create a heterogeneous network and established a target matrix derived from this network. Lastly, we framed the miRNA-disease association prediction issue as a low-rank matrix-complete issue that was addressed via minimizing matrix truncated schatten p-norm. Notably, we improved the conventional singular value contraction algorithm through using a weighted singular value contraction technique. This technique dynamically adjusts the degree of contraction based on the significance of each singular value, ensuring that the physical meaning of these singular values is fully considered. We evaluated the performance of EMCMDA by applying two distinct cross-validation experiments on two diverse databases, and the outcomes were statistically significant. In addition, we executed comprehensive case studies on two prevalent human diseases, namely lung cancer and breast cancer. Following prediction and multiple validations, it was evident that EMCMDA proficiently forecasts previously undisclosed disease-related miRNAs. These results underscore the robustness and efficacy of EMCMDA in miRNA-disease association prediction.

Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for lung cancer.

BACKGROUND: Drug repurposing provides a cost-effective approach to address the need for lung cancer prevention and therapeutics. We aimed to identify actionable druggable targets using Mendelian randomization (MR). METHODS: Summary-level data of gene expression quantitative trait loci (eQTLs) were sourced from the eQTLGen resource. We procured genetic associations with lung cancer and its subtypes from the TRICL, ILCCO studies (discovery) and the FinnGen study (replication). We implemented Summary-data-based Mendelian Randomization analysis to identify potential therapeutic targets for lung cancer. Colocalization analysis was further conducted to assess whether the identified signal pairs shared a causal genetic variant. FINDINGS: In the main analysis dataset, we identified 55 genes that demonstrate a causal relationship with lung cancer and its subtypes. However, in the replication cohort, only three genes were found to have such a causal association with lung cancer and its subtypes, and of these, HYKK (also known as AGPHD1) was consistently present in both the primary analysis dataset and the replication cohort. Following HEIDI tests and colocalization analyses, it was revealed that HYKK (AGPHD1) is associated with an increased risk of squamous cell carcinoma of the lung, with an odds ratio and confidence interval of OR = 1.28,95%CI = 1.24 to 1.33. INTERPRETATION: We have found that the HYKK (AGPHD1) gene is associated with an increased risk of squamous cell carcinoma of the lung, suggesting that this gene may represent a potential therapeutic target for both the prevention and treatment of lung squamous cell carcinoma.

Single-cell and genome-wide Mendelian randomization identifies causative genes for gout.

BACKGROUND: Gout is a prevalent manifestation of metabolic osteoarthritis induced by elevated blood uric acid levels. The purpose of this study was to investigate the mechanisms of gene expression regulation in gout disease and elucidate its pathogenesis. METHODS: The study integrated gout genome-wide association study (GWAS) data, single-cell transcriptomics (scRNA-seq), expression quantitative trait loci (eQTL), and methylation quantitative trait loci (mQTL) data for analysis, and utilized two-sample Mendelian randomization study to comprehend the causal relationship between proteins and gout. RESULTS: We identified 17 association signals for gout at unique genetic loci, including four genes related by protein-protein interaction network (PPI) analysis: TRIM46, THBS3, MTX1, and KRTCAP2. Additionally, we discerned 22 methylation sites in relation to gout. The study also found that genes such as TRIM46, MAP3K11, KRTCAP2, and TM7SF2 could potentially elevate the risk of gout. Through a Mendelian randomization (MR) analysis, we identified three proteins causally associated with gout: ADH1B, BMP1, and HIST1H3A. CONCLUSION: According to our findings, gout is linked with the expression and function of particular genes and proteins. These genes and proteins have the potential to function as novel diagnostic and therapeutic targets for gout. These discoveries shed new light on the pathological mechanisms of gout and clear the way for future research on this condition.

Serum 25-hydroxyvitamin D levels and dermatomyositis: A 2-sample mendelian randomization study.

BACKGROUND: Previous studies have reported low serum 25-hydroxyvitamin D [25(OH)D] levels in dermatomyositis (DM) patients, but the exact causal relationship between them remains elusive. Our aim is to confirm the causal relationship between 25(OH)D and DM risk through a Mendelian randomization study. METHODS: Retrieve genome-wide association study (GWAS) data on 25(OH)D (n = 441 291) and DM (n cases = 201, n controls = 172 834) from the GWAS database (https://gwas.mrcieu.ac.uk/). Select single-nucleotide polymorphisms (SNPs) strongly correlated with 25(OH)D as instrumental variables (IVs). The primary analytical approach involves the use of the inverse-variance weighted method (IVW), supplemented by MR-Egger regression and weighted median methods to enhance the reliability of the results. Heterogeneity and sensitivity analyses were conducted using Cochran's Q and leave-one-out approaches, respectively. RESULTS: The IVW analysis confirmed a positive causal relationship between genetic variation in 25(OH)D levels and DM (OR = 2.36, 95% CI = 1.01-5.52, p = .048). Although not statistically significant (all p > .05), the other methods also suggested a protective effect of 25(OH)D on DM. Based on MR-Egger intercepts and Cochran's Q analysis, the selected SNPs showed no horizontal pleiotropy and heterogeneity. Sensitivity analysis demonstrated the robustness of the results against individual SNPs. CONCLUSION: We provide the first evidence of a causal relationship between 25(OH)D levels and DM. Our findings support the importance of measuring serum 25(OH)D levels and considering vitamin D supplementation in clinical practice for patients with DM.

The causal associations of inflammatory cytokines with obesity and systemic lupus erythematosus: A Mendelian randomization study.

OBJECTIVE: Previous studies have partly discussed the roles of inflammatory cytokines in obesity and systemic lupus erythematosus (SLE), but the causal relationship among inflammatory cytokines, obesity, and SLE is unclear. It is challenging to comprehensively evaluate the causal relationship between these variables. This study aimed to investigate the role of cytokines as intermediates between obesity and SLE. METHODS: The inverse-variance weighted method (IVW) of mendelian randomization (MR) is mainly used to explore the causal relationship between exposure and outcome by using the genetic variation of the open large genome-wide association studies (GWAS), namely single-nucleotide polymorphisms (SNPs) related to obesity (more than 600 000 participants), inflammatory cytokines (8293 healthy participants) and SLE (7219 cases). Methods such as weighted median, MR-Egger are used to evaluate the reliability of causality. Reverse analysis is performed for each MR analysis to avoid reverse causality. Cochran's Q statistic and funnel chart are used to detect heterogeneity, MR-Egger intercept test and leave-one-out sensitivity analyses evaluated pleiotropy. RESULTS: Obesity was associated with 25 cytokines, and 3 cytokines were associated with SLE, including CTACK (OR = 1.19, 95% CI: 1.06, 1.33, p = .002), IL-18 (OR = 1.13, 95% CI: 1.01, 1.26, p = .027), SCGFb (OR = 0.89, 95% CI: 0.79, 0.99, p = .044). In the opposite direction, SLE was associated with 18 cytokines, and 2 cytokines were associated with obesity, including IP-10 (ßIVW = -.03, 95% CI: -0.05, -0.01, p = .002), MIP-1B (ßIVW = -.03, 95% CI: -0.05, -0.01, p = .004). CONCLUSION: Our MR study suggested that CTACK, IL-18 and SCGFb may play an intermediary role in obesity to SLE, while IP-10 and MIP-1B may play an intermediary role in SLE to obesity.

Genetic, epigenetic and environmental factors in diverticular disease: systematic review.

BACKGROUND: Diverticulosis is a normal anatomical variant of the colon present in more than 70% of the westernized population over the age of 80. Approximately 3% will develop diverticulitis in their lifetime. Many patients present emergently, suffer high morbidity rates and require substantial healthcare resources. Diverticulosis is the most common finding at colonoscopy and has the potential for causing a significant morbidity rate and burden on healthcare. There is a need to better understand the aetiology and pathogenesis of diverticular disease. Research suggests a genetic susceptibility of 40-50% in the formation of diverticular disease. The aim of this review is to present the hypothesized functional effects of the identified gene loci and environmental factors. METHODS: A systematic literature review was performed using PubMed, MEDLINE and Embase. Medical subject headings terms used were: 'diverticular disease, diverticulosis, diverticulitis, genomics, genetics and epigenetics'. A review of grey literature identified environmental factors. RESULTS: Of 995 articles identified, 59 articles met the inclusion criteria. Age, obesity and smoking are strongly associated environmental risk factors. Intrinsic factors of the colonic wall are associated with the presence of diverticula. Genetic pathways of interest and environmental risk factors were identified. The COLQ, FAM155A, PHGR1, ARHGAP15, S100A10, and TNFSF15 genes are the strongest candidates for further research. CONCLUSION: There is increasing evidence to support the role of genomics in the spectrum of diverticular disease. Genomic, epigenetic and omic research with demographic context will help improve the understanding and management of this complex disease.

Genetic association between celiac disease and chronic kidney disease: a two-sample Mendelian randomization study.

OBJECTIVE: A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal impact of celiac disease on the risk of chronic kidney disease (CKD). METHODS: The study comprised data from three genome-wide association studies involving individuals of European ancestry. The study groups included participants with celiac disease (n = 24,269), CKD (n = 117,165), and estimated glomerular filtration rate levels based on serum creatinine (eGFRcrea, n = 133,413). We employed four widely recognized causal inference algorithms: MR-Egger, inverse variance weighted (IVW), weighted median, and weighted mode. To address potential issues related to pleiotropy and overall effects, MR-Egger regression and the MR-PRESSO global test were performed. Heterogeneity was assessed using Cochran's Q test. RESULTS: We identified 14 genetic variants with genome-wide significance. The MR analysis provided consistent evidence across the various methodologies, supporting a causal relationship between celiac disease and an elevated risk of CKD (odds ratio (OR)IVW = 1.027, p = 0.025; ORweighted median = 1.028, P = 0.049; ORweighted mode = 1.030, p = 0.044). Furthermore, we observed a causal link between celiac disease and a decreased eGFRcrea (ORIVW = 0.997, P = 2.94E-06; ORweighted median = 0.996, P = 1.68E-05; ORweighted mode = 0.996, P = 3.11E-04; ORMR Egger = 0.996, P = 5.00E-03). We found no significant evidence of horizontal pleiotropy, heterogeneity, or bias based on MR-Egger regression, MR-PRESSO, and Cochran's Q test. CONCLUSION: The results of this study indicate a causal relationship between celiac disease and an increased risk of CKD.