Search Results (96)

Objectives: Thyroid dysfunction, particularly hypothyroidism, has been associated with endometrial cancer in observational studies; however, these findings may be confounded by obesity, an endometrial cancer risk factor. To clarify these associations, we performed Mendelian randomisation analysis, a genetic approach that mitigates confounding and reverse causation analyses. Methods: We accessed European-ancestry GWAS summary statistics for endometrial cancer (12,270 cases; 46,126 controls), endometrioid (8758 cases), and non-endometrioid (1230 cases) subtypes. Thyroid dysfunction phenotype and BMI GWAS data were predominantly from individuals of European descent. We used these datasets to conduct univariable and multivariable Mendelian randomisation analyses incorporating body mass index (BMI). Results: Our main finding was a causal association between hypothyroidism and decreased risk of endometrial cancer (OR = 0.93; 95% CI 0.89–0.97; p = 3.96 × 10⁻⁴). Subtype analysis revealed a decreased risk of the most common histological subtype, endometrioid endometrial cancer, and a similar protective association for Hashimoto’s thyroiditis, an autoimmune disease and common cause of hypothyroidism. Sensitivity analyses confirmed the robustness of the associations. Further analyses revealed that while BMI was causally associated with hypothyroidism risk, both BMI and hypothyroidism independently influenced endometrial cancer risk. Conclusions: Our study has identified hypothyroidism as a protective factor for endometrial cancer, challenging previous observational associations and highlighting potential confounding by obesity. Further investigation into immune mechanisms, particularly those linked to Hashimoto’s thyroiditis, may provide insights into the biological pathways underlying endometrial cancer development. Full article

Background/Objectives: Epilepsy and sleep disturbances frequently co-occur, yet the causal nature of this relationship remains uncertain, particularly in relation to epilepsy subtypes and status epilepticus. We investigated potential bidirectional causal associations between sleep-related traits and epilepsy, including subtypes and status epilepticus, using Mendelian randomization (MR). Methods: We conducted two-sample MR using genome-wide association study (GWAS) summary statistics from European ancestry cohorts. Epilepsy, its subtypes, and status epilepticus were analyzed using data from the International League Against Epilepsy Consortium on Complex Epilepsies (ILAE) and the FinnGen study. Nine self-reported sleep-related traits were derived from the UK Biobank-based GWAS. Causal estimates were primarily obtained using inverse variance weighted models with additional MR analysis methods. Pleiotropy and heterogeneity were assessed to enhance the robustness of the finding. Results: Several subtype-specific associations were identified, with direction and statistical significance varying across cohorts and subtypes. After correction for multiple testing and filtering for tests with ≥10 instrumental variables to ensure robust and reliable MR estimates, several consistent and potentially mutually reinforcing associations emerged. In the ILAE cohort, focal epilepsy with hippocampal sclerosis was associated with an increased risk of insomnia, and juvenile myoclonic epilepsy with reduced sleep duration. In the FinnGen cohort, overall epilepsy was associated with increased risk of both insomnia and daytime sleepiness. In reverse MR, daytime sleepiness and napping were associated with increased risk of epilepsy, while daytime napping and frequent insomnia symptoms were linked to elevated risk of status epilepticus. Conclusions: Our findings reveal subtype-specific and bidirectional causal links between epilepsy and sleep-related traits. These results highlight the biological interplay between epileptic networks and sleep regulation and underscore the need for further clinical and mechanistic studies. Full article

Background/Objectives: The anti-Müllerian hormone (AMH) is a key biomarker of the ovarian reserve, correlating with ovarian follicle count, fertility outcomes, and menopause timing. Understanding its genetic determinants has broad implications for female reproductive health. However, prior genome-wide association studies (GWASs) have focused exclusively on women of European ancestry, limiting insights into diverse populations. Methods: We conducted a GWAS to identify genetic loci associated with circulating AMH levels in a sample of 1185 Samoan women from two independently recruited samples. Using a Cox mixed-effects model we accounted for AMH levels below detectable limits and meta-analysed the summary statistics using a fixed-effect model. To prioritize variants and genes, we used FUMA and performed colocalization and transcriptome-wide association analysis (TWAS). We also assessed whether any previously reported loci were replicated in our GWAS. Results: We identified eleven genome-wide suggestive loci, with the strongest signal at ARID3A (19-946163-G-C; p = 2.32 × 10⁻⁷) and replicated rs10093345 near EIF4EBP1. The gene-based testing revealed ARID3A and R3HDM4 as significant genes. Integrating GWAS results with expression quantitative trait loci via TWAS, we detected seven transcriptome-wide significant genes. The lead variant in ARID3A is in high linkage disequilibrium (r² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausible candidate gene that encodes the kisspeptin receptor, a regulator of ovarian follicle development linked to AMH levels. Conclusions: This study expands our understandings of AMH genetics by focusing on Samoan women. While these findings may be particularly relevant to Pacific Islanders, they hold broader implications for reproductive phenotypes such as the ovarian reserve, menopause timing, and polycystic ovary syndrome. Full article

Background: Population differences in gut microbiota composition and related metabolites may influence their potential causal relationship with chronic kidney disease (CKD); however, this relationship remains poorly understood in the Chinese population. Materials and Methods: We conducted a two-sample Mendelian randomization (MR) study using summary statistics of 500 gut microbial features (9 phyla, 3 classes, 14 orders, 32 families, 95 genera, 248 species, and 99 gut metabolic modules (GMMs)) from the 4D-SZ (from Shenzhen, China) discovery cohort (n = 1539). CKD summary statistics were obtained from the China Kadoorie Biobank (CKB) (489 cases and 75,531 controls). Associations between gut microbiota and CKD were evaluated via inverse variance weighted, MR-Egger, weighted median, and MR-PRESSO. To validate our findings, we replicated the analyses in two independent East Asian CKD GWAS datasets: the Biobank of Japan (BBJ) dataset (2117 cases and 174,345 controls) and the J-Kidney-Biobank (JKB) dataset (382 cases and 3471 controls). We further validated the results via a meta-GWAS of BUN and eGFR in Biobank Japan (BBJ) and the Taiwan Biobank (TWB). Additionally, we analyzed 304 serum proteins from the Guangzhou Nutrition and Health Study (GNHS) and conducted mediation MR analyses to explore potential mediators. Result: At the locus-wide significance threshold, we identified 18 gut microbiome features associated with CKD onset in the China Kadoorie Biobank (CKB). Genus Alistipes (OR 1.02, 95% CI 1.00–1.03, p = 0.03) was associated with incident CKD risk in the JKB cohort. Species Bifidobacterium catenulatum–Bifidobacterium pseudocatenulatum complex (OR 1.0074, 95% CI 1.0070–1.0142, p = 0.01) was associated with incident CKD risk in a meta-GWAS of BUN. Sensitivity analyses, including Cochran’s Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots, yielded consistent results. Mediation analysis revealed that 26.7% (95% CI: 0.006–0.6700, p = 0.04) of the effect of Alistipes on CKD risk was mediated through the serum protein FBLN1. Conclusions: Our study provides Mendelian randomization-based evidence supporting a potential causal relationship between gut microbiota and CKD, highlighting the potential mediating role of FBLN1 in the association between genus Alistipes and CKD. Further studies are needed to explore whether and how genus Alistipes and FBLN1 contribute to CKD development. Full article

Background: Although clinical studies have indicated a possible association between dyslipidemia and osteoporosis, the underlying genetic basis and mechanistic pathways remain insufficiently defined. Most prior research has concentrated on conventional lipid markers, which are prone to confounding and limit causal inference. Exploring lipidomic profiles offers a more comprehensive view of lipid metabolism and may reveal novel genetic links beyond traditional lipid traits. Additionally, alterations in immune cell function, often triggered by metabolic disturbances, may contribute to osteoporosis development; however, the potential mediating role of immune cells in the lipid–bone axis has not been systematically investigated. Methods: A total of 179 lipid species across 13 lipid classes were analyzed in 7174 Finnish individuals from the GeneRISK cohort. Genome-Wide Association Study (GWAS) summary statistics for osteoporosis and 731 immune cell immunophenotypes were sourced from the GWAS Catalog. A two-step, two-sample Mendelian randomization analysis, using inverse variance weighting (IVW), was conducted to explore the potential causal effects of lipids on osteoporosis and the mediating role of immune cells in the relationship between lipids and osteoporosis. Results: Mendelian randomization analysis indicated that triacylglycerol levels of 48:0 were possibly associated with an increased risk of osteoporosis (IVW: odds ratio [OR] 1.1320, 95% CI 1.0401–1.2321; p = 0.004), while triacylglycerol levels of 48:3 appeared to be associated with a reduced risk of osteoporosis (IVW: OR 0.9053, 95% CI 0.8364–0.9800; p = 0.014). Two statistically significant mediating effects were identified: First, IgD− CD38dim %B cells appeared to partially negatively mediate the association between triacylglycerol levels of 48:3 and osteoporosis, with a negative mediating effect of −0.00669 (95% CI: −0.0214, 0.00805), which accounted for 6.73% of the total effect. That is, the protective effect of triacylglycerol levels of 48:3 against osteoporosis was attenuated by IgD− CD38dim %B cells. Second, HLA DR++ monocytes% leukocytes also partially negatively mediated this relationship, with a mediating effect of −0.023 (95% CI: −0.0434, −0.00266), accounting for 23.2% of the total effect. This indicates that other immune cells, HLA DR++ monocytes %leukocytes, resisted the protective effect of triacylglycerol levels of 48:3 against osteoporosis, with a weakening effect stronger than that of IgD− CD38dim %B cells. Conclusions: Our findings contribute to the growing understanding of the potential causal relationships and shared pathogenic mechanisms between dyslipidemia and osteoporosis. The results suggest that the potential genetic effects of plasma lipid metabolites on osteoporosis may be partially down-regulated by specific kinds of immune cells. Full article

Background/Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted and diverse disorder with an ambiguous etiology. Recent evidence indicates that immune system impairment and inflammatory mechanisms are pivotal to the initiation and advancement of ME/CFS. Nonetheless, the causal relationships among these factors remain inadequately comprehended. Methods: This study investigated the causative contributions of immunological dysfunction and inflammatory variables in ME/CFS utilizing genome-wide association study (GWAS) data. We employed Mendelian randomization (MR) to investigate associations between 91 inflammatory cytokines, 731 immune cell characteristics, and the risk of ME/CFS. Summary statistics for immune cell traits and inflammatory cytokines were sourced from European GWAS cohorts (n = 3757 and n = 14,824, respectively), while ME/CFS data were obtained from the UK Biobank (n = 462,933, including 2076 cases). We predominantly employed the inverse variance weighted (IVW) approach, complemented by MR-Egger, weighted median, BWMR, and MR-RAPS tests to guarantee robust and precise outcomes. Results: The study revealed significant causal links between various inflammatory factors, immune cell characteristics, and the risk of ME/CFS. Increased CXCL5 and CCL20 levels were significantly linked to a higher risk of ME/CFS, while elevated TNF levels were inversely related to ME/CFS risk. Furthermore, 13 immune cell characteristics were identified as having substantial causal associations with the likelihood of ME/CFS. These data are supportive of the causality that immune system dysfunction and inflammatory variables play a pivotal role in the development of ME/CFS. Conclusions: This study provides new insights into the causal role of immune system dysfunction in the development of ME/CFS, contributing to a deeper understanding of its underlying mechanisms. These results offer a foundation for identifying diagnostic biomarkers and developing targeted therapeutic strategies. Future research should validate these findings using multi-center cohort studies and further investigate the mechanisms behind key factors to enable the development of personalized treatment approaches. Full article

Sjögren’s disease (SjD) is a systemic autoimmune disorder primarily causing dry eyes and mouth. It frequently overlaps with other autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic basis of SjD remains underexplored, limiting our understanding of its connections to other immune-mediated conditions. In this study, we aimed to identify gene networks associated with SjD through the integration of genetic, transcriptomic, and epigenomic data. We further compared the genetic factors of SjD with other immune-mediated diseases. We analyzed genome-wide association studies (GWAS) summary statistics, DNA methylation, and transcriptomic data using our in-house network-based methods, dmGWAS and EW_dmGWAS, to identify key gene modules associated with SjD. In dmGWAS analysis, discovery and evaluation datasets were used to identify consensus results. We conducted gene-set, cell-type, and disease-enrichment analyses on significant gene modules and explored potential drug targets. Genetic correlations and Mendelian randomization were applied to assess SjD’s link with 17 other AIDs and 16 cancer types. dmGWAS identified 207 and 211 gene modules in the discovery and evaluation phases, respectively, while EW_dmGWAS detected 886 modules. Key modules highlighted 55 genes (discovery), 52 genes (evaluation), and 59 genes (EW_dmGWAS), with at least 50 genes from each analysis linked to AIDs and cancer. Enrichment analyses confirmed their relevance to immune and oncogenic pathways. We pinpointed four candidate drug targets associated with AIDs. We developed a novel integrative omics approach to identify potential genetic markers of SjD and compared them with AIDs and cancers. Our approach can be similarly applied to other disease studies. Full article

Background: At present, there are still limitations and challenges in the treatment of hyperuricemia (HUA). Mendelian randomization (MR) has been widely used to identify new therapeutic targets. Therefore, we conducted a systematic druggable genome-wide MR to explore potential therapeutic targets and drugs for HUA. Methods: We integrated druggable genome data; blood, kidney, and intestinal expression quantitative trait loci (eQTLs); and HUA-associated genome-wide association study (GWAS) data to analyze the potential causal relationships between drug target genes and HUA using the MR method. Summary-data-based MR (SMR) analysis and Bayesian colocalization were used to assess causality. In addition, we conducted phenome-wide association studies, protein network construction, and enrichment analysis of significant targets to evaluate their biological functions and potential side effects. Finally, we performed drug prediction and molecular docking to identify potential drugs targeting these genes for HUA treatment. Results: Overall, we identified 22 druggable genes significantly associated with HUA through MR, SMR, and colocalization analyses. Among them, two prior druggable genes (ADORA2B and NDUFC2) reached statistically significant levels in at least two tissues in the blood, kidney, and intestine. Further results from phenome-wide studies revealed that there were no potential side effects of ADORA2B or NDUFC2. Moreover, we screened 15 potential drugs targeting the 22 druggable genes that could serve as candidates for HUA drug development. Conclusions: This study provides genetic evidence supporting the potential benefits of targeting 22 druggable genes for HUA treatment, offering new insights into the development of targeted drugs for HUA. Full article

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by substantial heritability and a high mortality rate among psychiatric disorders. While cerebrospinal fluid (CSF) metabolomics has emerged as a novel approach to investigating central nervous system pathologies, its specific causal relationship with anorexia nervosa remains to be fully elucidated. Using genome-wide association study (GWAS) summary statistics for human CSF metabolites and AN information from publicly available datasets, we performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method as the primary approach, complemented by sensitivity analyses. Through a comprehensive analysis of 338 CSF metabolites, we identified six metabolites with significant causal relationships with AN risk. 1-stearoyl-2-linoleoyl-gpc (18:0/18:2) (OR = 1.09, 95% CI 1.00–1.18) and alpha-tocopherol (OR = 1.36, 95% CI 1.00–1.83) showed positive associations, increasing AN risk. Conversely, sphingomyelin (d18:1/20:0, d16:1/22:0) (OR = 0.86, 95% CI 0.77–0.95), 2,3-dihydroxy-2-methylbutyrate (OR = 0.92, 95% CI 0.86–0.98), N-acetylhistidine (OR = 0.92, 95% CI 0.86–0.98), and oxalate (ethanedioate) (OR = 0.83, 95% CI 0.73–0.94) had protective effects, reducing AN risk. Sensitivity analyses showed no evidence of horizontal pleiotropy or heterogeneity in the MR results. An MR directionality test and a Steiger filtering test confirmed the absence of reverse causality, thereby substantiating the robustness of our findings. These findings suggest that these CSF metabolites could serve as potential biomarkers for early AN detection and highlight novel therapeutic targets, potentially improving diagnosis and intervention strategies for this challenging disorder. Full article

Background: The gut microbiome (GM) has been reported to play a role in traumatic brain injury (TBI). To investigate the causal relationship between GMs, inflammatory mediators, and TBI, a comprehensive Mendelian randomization (MR) analysis was conducted. Methods: We utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM and TBI. To assess the potential causal associations between GM and TBI, we employed the inverse-variance-weighted, MR-Egger, and weighted median methods. Mediation analysis was used to assess the possible mediating factors. Several sensitivity analyses methods were implemented to verify the stability of the results. Additionally, we utilized FUMA GWAS to map single-nucleotide polymorphisms to genes and conduct transcriptomic MR analysis. Results: We identified potential causal relationships between nine bacterial taxa and TBI. Notably, class Methanobacteria, family Methanobacteriaceae, and order Methanobacteriales (p = 0.0003) maintained a robust positive correlation with TBI. This causal association passed false discovery rate (FDR) correction (FDR < 0.05). Genetically determined 1 inflammatory protein, 30 immune cells and 3 inflammatory factors were significantly causally related to TBI. None of them mediated the relationship between GMs and TBI. The outcome of the sensitivity analysis corroborated the findings. Regarding the mapped genes of significant GMs, genes such as CLK4, MTRF1, NAA16, SH3BP5, and ZNF354A in class Methanobacteria showed a significant causal correlation with TBI. Conclusions: Our study reveals the potential causal effects of nine GMs, especially Methanogens on TBI, and there was no link between TBI and GM through inflammatory protein, immune cells, and inflammatory factors, which may offer fresh insights into TBI biomarkers and therapeutic targets through specific GMs. Full article

Genetic variants increase the risk of neurocognitive disorders in later life, including vascular dementia (VaD) and Alzheimer’s disease (AD), but the precise relationships between genetic risk factors and underlying disease etiologies are not well understood. Transcriptome-wide association studies (TWASs) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWASs on VaD and AD have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European ancestry (EA) and African ancestry (AA) samples to identify genes associated with general cognitive function, white matter hyperintensity (WMH), and AD. Regions were fine-mapped using Fine-mapping Of CaUsal gene Sets (FOCUS). We identified 266, 23, 69, and 2 genes associated with general cognitive function, WMH, AD (using EA GWAS summary statistics), and AD (using AA GWAS), respectively (Bonferroni-corrected alpha = p < 2.9 × 10⁻⁶), some of which had been previously identified. Enrichment analysis showed that many of the identified genes were in pathways related to innate immunity, vascular dysfunction, and neuroinflammation. Further, the downregulation of ICA1L was associated with a higher WMH and with AD, indicating its potential contribution to overlapping AD and VaD neuropathology. To our knowledge, our study is the first TWAS on cognitive function and neurocognitive disorders that used expression mapping studies for multiple ancestries. This work may expand the benefits of TWASs beyond a single ancestry group and help to identify gene targets for pharmaceuticals or preventative treatments for dementia. Full article

Background/Objectives: Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships of vascular calcification—coronary artery calcification (CAC) and abdominal aortic calcification (AAC)—with Alzheimer’s disease (AD), and five cognitive traits. Methods: We analyse large-scale genome-wide association studies (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), and gene-based association analysis. Results: Our findings reveal a nominally significant positive genome-wide genetic correlation between CAC and AD, which becomes non-significant after excluding the APOE region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. MR found no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline-significant association between AAC and fluid intelligence scores. Pairwise-GWAS analysis identifies no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, with gene association analyses revealing significant genes in shared regions, including APOE, TOMM40, NECTIN2, and APOC1. Moreover, we identify suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, implicating pleiotropic genes, including NAV1, IPO9, PHACTR1, UFL1, FHL5, and FOCAD. Conclusions: Current findings reveal limited genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci, particularly at the APOE region, highlight the complex interplay between vascular calcification and neurodegenerative processes. Given APOE’s roles in lipid metabolism, neuroinflammation, and vascular integrity, its involvement may link vascular and neurodegenerative disorders, pointing to potential targets for further investigation. Full article

The genome-wide association studies (GWAS) of lung disease and lung function indices suffer from challenges to be transformed into clinical interventions, due to a lack of knowledge on the molecular mechanism underlying the GWAS associations. A proteome-wide association study (PWAS) was first performed to identify candidate proteins by integrating two independent largest protein quantitative trait loci datasets of plasma proteins and four large-scale GWAS summary statistics of lung function indices (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and peak expiratory flow (PEF)), followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, with a discovery dataset, we conducted Mendelian randomization (MR) and Bayesian colocalization analyses to select potentially causal proteins, followed by a replicated MR analysis with an independent dataset. Mediation analysis was also performed to explore the possible mediating role of these indices on the association between proteins and two common lung diseases (chronic obstructive pulmonary disease, COPD and Asthma). We finally prioritized the potential drug targets. A total of 210 protein–lung function index associations were identified by PWAS, and were significantly enriched in the pulmonary fibrosis and lung tissue repair. Subsequent MR and colocalization analysis identified 59 causal protein-index pairs, among which 42 pairs were replicated. Further mediation analysis identified 3 potential pathways from proteins to COPD or asthma mediated by FEV1/FVC. The mediated proportion ranges from 68.4% to 82.7%. Notably, 24 proteins were reported as druggable targets in Drug Gene Interaction Database, among which 8 were reported to interact with drugs, including FKBP4, GM2A, COL6A3, MAPK3, SERPING1, XPNPEP1, DNER, and FER. Our study identified the crucial plasma proteins causally associated with lung functions and highlighted potential mediating mechanism underlying the effect of proteins on common lung diseases. These findings may have an important insight into pathogenesis and possible future therapies of lung disorders. Full article

Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by the destruction of alveolar structures, the abnormal accumulation of extracellular matrix (ECM), and ultimately respiratory failure. Although previous studies have shown that plasma proteins play an important role in the onset and progression of PF, there is currently a lack of systematic studies on causal relationships. To address the identified gap, the study employs the MR method to identify potential drug targets associated with PF. Plasma protein data (pQTL, exposure) were sourced from Ferkingstad et al. (n = 35,559), and PF-related summary statistics were obtained from the GWAS database (n = 469,126). The study integrates enrichment analysis, protein–protein interaction (PPI) networks, drug prediction, molecular docking, and single-cell sequencing to further evaluate the biological functions and pharmacological potential of the identified targets. In the MR analysis, 64 genetic loci were significantly associated with the occurrence of PF. Further reverse Mendelian analysis revealed a positive causal relationship between PF and genes such as NPTX1, IL31, and CTSE, suggesting that these proteins may play a promotive role in the onset and progression of pulmonary fibrosis. The PPI network analysis identified core genes such as CDH1, CRP, VTN, COL1A1, and MAPK8, which are involved in the key pathological processes of PF, including cell signaling, ECM remodeling, and immune responses. The drug prediction analysis identified potential drugs such as sorafenib, vitamin C, and vitamin E, and the molecular docking analysis showed good binding between the drugs and the proteins. The single-cell sequencing results showed that core genes were highly expressed in fibroblasts and alveolar type II cells, confirming their potential role in the pathogenesis of PF. This study successfully identifies 64 potential drug targets for PF, with 10 core targets considered particularly promising for clinical trials. These findings offer valuable insights into the molecular mechanisms underlying PF and open new avenues for the development of targeted therapies. This research may accelerate the development of effective PF treatments and reduce drug development costs by providing more precise and personalized approaches to managing the disease. Full article

DNA damage repair (DDR) plays a key role in maintaining genomic stability and developing inflammatory bowel disease (IBD). However, no report about the causal association between DDR and IBD exists. Whether DDR-related genes are the precise causal association to IBD in etiology remains unclear. Herein, we employed a multi-omics summary data-based Mendelian randomization (SMR) approach to ascertain the potential causal effects of DDR-related genes in IBD. Methods: Summary statistics from expression quantitative trait loci (eQTL), DNA methylation QTL (mQTL), and protein QTL (pQTL) on European descent were included. The GWAS summarized data for IBD and its two subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), were acquired from the FinnGen study. We elected from genetic variants located within or near 2000 DDR-related genes in cis, which are closely associated with DDR-related gene changes. Variants were selected as instrumental variables (IVs) and assessed for causality with IBD and its subtypes using both SMR and two-sample MR (TSMR) approaches. Colocalization analysis was employed to evaluate whether a single genetic variant simultaneously influences two traits, thereby validating the pleiotropy hypothesis. Results: We identified seven DDR-related genes (Arid5b, Cox5a, Erbb2, Ube2l3, Gpx1, H2bcl2, and Mapk3), 33 DNA methylation genes, and two DDR-related proteins (CD274 and FCGR2A) which were all causally associated with IBD and its subtypes. Beyond causality, we integrated the multi-omics data between mQTL-eQTL and conducted druggability values. We found that DNA methylation of Erbb2 and Gpx1 significantly impacted their gene expression levels offering insights into the potential regulatory mechanisms of risk variants on IBD. Meanwhile, CD247 and FCGR2A could serve as targets for potential pharmacological interventions in IBD. Conclusions: Our study demonstrates the causal role of DDR in IBD based on the data-driven MR. Moreover, we found potential regulatory mechanisms of risk variants on IBD and potential pharmacological targets. Full article