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PubMed1990

Psychosocial effects on immune function: neuroendocrine pathways.

Psychoneuroimmunology represents the newest interdisciplinary endeavor relevant to psychosomatic medicine. Work in this area is particularly exciting because it promises to reveal a more unified view of the individual and the complex interactions between social, psychological, neural, endocrinological, immunological, and genetic factors that contribute to disease. This article reviews the major biological pathways implicated in the psychosocial modulation of immune function and disease resistance.

Autonomic Nervous System↗

PubMed2001

Caspase mRNA expression in a rat model of focal cerebral ischemia.

Proteins of the caspase family are involved in the signalling pathway that ultimately leads to programmed cell death (apoptosis), which has been reported to occur in some experimental models of stroke. In a previous paper we used quantitative reverse transcription and polymerase chain reaction (RT-PCR) to characterise changes in the mRNA expression of one member of this family, caspase-3, in a rat model of permanent focal ischemia. Here we have used this technique to study the expression of a further three caspases which are involved in different aspects of caspase signalling. Caspase-8, involved in Fas-mediated apoptosis, was upregulated in the cortex of ischemic rats. Caspase-11, which leads to the synthesis of the functional form of the cytokine interleukin-1 beta, also showed increased expression, but with a different temporal profile from caspase-8. In contrast, caspase-9, which forms part of the pathway signalling through the mitochondria, showed a decrease in expression. The expression of a further four caspases (1, 2, 6 and 7) has also been characterised in a simpler experiment. These caspases all showed distinctive patterns of expression following the induction of ischemia. These data lead us to conclude that caspase expression as a whole is under very strict transcriptional control in this model. Certain elements of caspase signalling, such as the Fas-induced pathway and the events upstream of IL-1 beta processing, are upregulated, while others are not. This may be due to some form of genetic program activated in response to ischemia in the brain and may highlight which biological pathways are modulated.

Animals↗

PubMed2026

Multiregion profiling of genomic and transcriptional heterogeneity in head and neck squamous-cell carcinoma.

BACKGROUND: Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. PATIENTS AND METHODS: In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. RESULTS: Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. CONCLUSIONS: This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

head and neck squamous-cell carcinoma (HNSCC)↗

PubMed2026

Ultra-processed Foods, Cancer, and Early-onset Cancer: A Comprehensive Review.

The classification of foods according to their degree of processing, and particularly the concept of ultra-processed foods, is relatively new. Consumption of ultra-processed foods has increased markedly worldwide in recent decades. Their growing consumption has coincided with a rising global burden of cancer, including marked increases in several cancers diagnosed before age 50 years. In this comprehensive review, we summarize trends in ultra-processed food consumption and the sociodemographic, psychological, and behavioral characteristics associated with higher intake. We further review the epidemiological evidence linking ultra-processed foods with cancer incidence and mortality, with particular attention to the limited but emerging evidence relevant to early-onset cancer. Potential mechanisms linking ultra-processed foods to cancer include unfavorable nutrient displacement, changes in body composition and fat deposition, and increased exposure to additives, processing by-products, and other chemicals. These influences may converge on a range of biological pathways, including metabolic dysfunction, chronic inflammation, immune dysregulation, gut microbiome disruption, DNA damage and genomic instability, and epigenetic alterations. Substantial uncertainties remain, including heterogeneous exposure definitions and classification practices, limitations in dietary assessment and temporal exposure capture, residual confounding, and the complexity of putative biological mechanisms. We conclude by highlighting key research challenges and future directions, along with considerations related to policy, regulation, and industry practices.

Ultra-processed foods↗

PubMed2026

Genetic overlap between depression and C-reactive protein levels: Evidence from a cross-trait analysis.

Inflammation and depression have been consistently associated, with elevated C-reactive protein (CRP) levels observed in a significant subset of affected individuals. However, the genetic mechanisms underlying this association remain poorly understood. We integrated results from large-scale genome-wide association studies (GWAS) of depression and CRP levels in a cross-trait analysis specifically focusing on identifying horizontally pleiotropic loci. Identified variants were stratified as concordant versus discordant based on their direction of effects on the two traits and followed up using functional annotation, gene set enrichment, and colocalization analyses. We also explored causal relationships using Mendelian Randomization (MR) analysis with extensive sensitivity analyses, including adjustment for body mass index (BMI). We identified 9 novel loci. Functional analyses revealed that concordant loci were enriched in genes linked to immune and inflammatory processes, while discordant loci mostly mapped to metabolic pathways, including lipid regulation. MR provided strong evidence for body mass index driving a causal relationship between the genetic liability of depression on CRP levels. Our findings suggest that the association between depression and CRP levels is partly driven by shared genetic influences, pointing to different biological pathways depending on whether genetic effects are concordant or discordant. These results underscore the importance of considering effect direction when assessing the genetic overlap between depression and inflammatory processes. In addition, they highlight BMI as a key factor in the causal relationship between depression and systemic inflammation.

C-Reactive Protein↗

PubMed1977

Ribonucleotide reduction and the possible role of cobalamin in evolution.

The biological pathways of ribonucleotide reduction are briefly reviewed. The hypothesis is presented that reduction of ribonucleoside triphosphates to their deoxynucleotide analogs through the mediation of vitamin B12 or a similar corrinoid preceded and was necessary for the subsequent development of a DNA-type genome. There are two known biological systems for ribonucleotide reduction: (1) The ribonucleoside diphosphate reduction system which utilizes a nonheme iron ribonucleotide reductase enzyme, thioredoxin and its reductase, and NADPH. This enzyme complex is found in most bacteria, some higher organisms, and in all animals. (2) The ribonucleoside triphosphate reduction system which utilizes adenosyl cobalamin, ribonucleotide reductase and either thioredoxin or a disulfhydryl compound. The cobalamin-dependent reductase is restricted to a few species of bacteria and blue-gree algae. This system is considered more primitive than the iron reductase one based on their differences in distribution, components, and products.

Bacteria↗

PubMed1997

Qualitative modeling of normal blood coagulation and its pathological states using stochastic activity networks.

We have developed a method for representing biological pathways and simulating their behavior based on the use of stochastic activity networks (SANs). SANs, an extension of the original Petri net, have been used traditionally to model flow systems including data-communications networks and manufacturing processes. We apply the methodology to the blood coagulation cascade, a biological flow system, and present the representation method as well as results of simulation studies based on published experimental data. In addition to describing the dynamic model, we also present the results of its utilization to perform simulations of clinical states including hemophilia's A and B as well as sensitivity analysis of individual factors and their impact on thrombin production.

Blood Coagulation↗

PubMed2026

HeteroGeNETics: Neuroendocrine tumor genetics reflect their heterogeneous complex diversity.

Neuroendocrine neoplasms (NENs) comprise a diverse group of malignancies arising across multiple anatomical sites and displaying remarkable biological and clinical heterogeneity. While advances in sequencing have identified recurrent genetic alterations in several NEN subtypes, these tumors remain largely characterized by a relatively low mutational burden and lack of dominant oncogenic drivers. Consequently, emerging evidence suggests that the molecular basis of neuroendocrine tumorigenesis extends beyond individual mutations and involves broader processes such as chromatin remodeling, telomere maintenance, epigenetic dysregulation and cellular plasticity. This review aims to summarize the current molecular landscape of pulmonary, gastro-enteropancreatic and thymic NENs, focusing on the biological pathways and cellular programs disrupted by recurrent genetic alterations unrelated to syndromes. We discuss how multi-omic studies have refined molecular classification and revealed common principles underlying neuroendocrine tumor development. Collectively, recent literature supports a shift from mutation-centered models toward a more integrated understanding of the complex biology and evolution of NENs.

genomics↗

PubMed2000

Nitric oxide reactivity and mechanisms involved in its biological effects.

Nitric oxide (NO) is implicated in many different biological functions. This is due to its widespread distribution in tissue and to its ability to react with a range of molecules in the organism, of which haemoglobin (Hb), soluble guanylyl cyclase (GC), and superoxide anion are of particular note. In this review we describe the biological pathways of NO and their involvement in its physiological effects and toxicity. This endothelial factor rapidly diffuses into the vascular compartment, and the reaction with the Hb haem group is the main metabolic pathway for endogenous NO. Hb is, therefore, a scavenger for this mediator, which prevents it from reaching the tissue components. NO also reacts with the GC haem group, and this combination is fundamental to its acute vasorelaxing effect. Although molecular oxygen plays a very small part in the oxidization process of NO in biological systems, NO reacts with the superoxide anion to generate peroxynitrite at a rate that is limited only by its diffusion coefficient. This reaction is important in pathological conditions because the peroxynitrite thus formed is a selective oxidant and nitrating agent that interacts with numerous biological molecules, thereby damaging them. In addition, of particular note are the interactions of NO with thiol groups, which may mediate several relevant effects in the organism. NO may also activate endogenous ribosyltransferases, which facilitate the transfer of adenosine diphosphate-ribose groups from nicotine adenine dinucleotide to the G protein amino acid residues. These last two processes may also be involved in the control of arterial tone and more precisely so when chronic NO production takes place.

Animals↗

PubMed2026

Tumor Loss of the Y Chromosome Defines a Biological Phenotype Associated with Resistance to Radiotherapy Across Cancer Types.

PURPOSE: Sex-linked determinants of radiotherapy response remain poorly understood. We investigated whether tumor loss of the Y chromosome (LOY) is associated with biological and clinical features of radiotherapy resistance across cancer types. MATERIALS AND METHODS: We integrated publicly available cancer cell-line experimental datasets and clinical data to evaluate the impact of LOY on radiotherapy response. The radiosensitivity of 125 cancer cell lines, stratified by Y chromosome status, was analyzed. Gene expression analyses were performed to identify biological pathways associated with LOY. Clinical associations were examined in 537 male patients treated with radiotherapy across multiple tumor types in The Cancer Genome Atlas. RESULTS: LOY was associated with increased post-radiotherapy survival in cancer cell lines (p < 0.001). Transcriptomic analyses demonstrated LOY-associated alterations in DNA damage response, senescence, longevity, and proliferation pathways. In TCGA tumors, LOY was associated with remodeling of the tumor microenvironment, including altered immune and stromal signatures. Clinically, LOY was associated with inferior survival in common-support overlap-weighted analyses adjusted for age, tumor stage, and TCGA-defined tumor type. CONCLUSION: These findings suggest that tumor LOY is associated with a distinct biological profile characterized by features of radioresistance and adverse clinical outcomes following radiotherapy. Further studies are warranted to determine whether LOY represents a clinically relevant sex-linked determinant of radiotherapy response.

loss of Y chromosome↗

PubMed2001

A novel pathway of cellular phosphatidylinositol(3,4,5)-trisphosphate synthesis is regulated by oxidative stress.

BACKGROUND: Phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] is a key second messenger found ubiquitously in higher eukaryotic cells. The activation of Class I phosphoinositide 3-kinases and the subsequent production of PtdIns(3,4,5)P(3) is an important cell signaling event that has been causally linked to the activation of a variety of downstream cellular processes, such as cell migration and proliferation. Although numerous proteins regulating a variety of biological pathways have been shown to bind PtdIns(3,4,5)P(3), there are no data to demonstrate multiple mechanisms for PtdIns(3,4,5)P(3) synthesis in vivo. RESULTS: In this study, we demonstrate an alternative pathway for the in vivo production of PtdIns(3,4,5)P(3) mediated by the action of murine Type Ialpha phosphatidylinositol 4-phosphate 5-kinase (Type Ialpha PIPkinase), an enzyme best characterized as regulating cellular PtdIns(4,5)P(2) levels. Analysis of this novel pathway of PtdIns(3,4,5)P(3) synthesis in cellular membranes leads us to conclude that in vivo, Type Ialpha PIPkinase also acts as a PtdIns(3,4)P(2) 5-kinase. We demonstrate for the first time that cells actually contain an endogenous PtdIns(3,4)P(2) 5-kinase, and that during oxidative stress, this enzyme is responsible for PtdIns(3,4,5)P(3) synthesis. Furthermore, we demonstrate that by upregulating the H(2)O(2)-induced PtdIns(3,4,5)P(3) levels using overexpression studies, the endogenous PtdIns(3,4)P(2) 5-kinase is likely to be Type Ialpha PIPkinase. CONCLUSIONS: We describe for the first time a novel in vivo activity for Type Ialpha PIPkinase, and a novel pathway for the in vivo synthesis of functional PtdIns(3,4,5)P(3), a key lipid second messenger regulating a number of diverse cellular processes.

Animals↗

PubMed2000

Tibetan and Andean patterns of adaptation to high-altitude hypoxia.

Understanding the workings of the evolutionary process in contemporary humans requires linking the evolutionary history of traits with their current genetics and biology. Unusual environments provide natural experimental settings to investigate evolution and adaptation. The example of high-altitude hypoxia illustrates some of the progress and many of the remaining challenges for studies of evolution in contemporary populations. Current studies exemplify the frequently encountered problem of determining whether large, consistent population differences in mean values of a trait reflect genetic differences. In this review I describe 4 quantitative traits that provide evidence that indigenous populations of the Tibetan and Andean plateaus differ in their phenotypic adaptive responses to high-altitude hypoxia. These 4 traits are resting ventilation, hypoxic ventilatory response, oxygen saturation, and hemoglobin concentration. The Tibetan means of the first 2 traits were more than 0.5 standard deviation higher than the Aymara means, whereas the Tibetan means were more than 1 standard deviation lower than the Aymara means for the last 2 traits. Quantitative genetic analyses of within-population variance revealed significant genetic variance in all 4 traits in the Tibetan population but only in hypoxic ventilatory response and hemoglobin concentration in the Aymara population. A major gene for oxygen saturation was detected among the Tibetans. These findings are interpreted as indirect evidence of population genetic differences. It appears that the biological characteristics of sea-level humans did not constrain high-altitude colonists of the 2 plateaus to a single adaptive response. Instead, microevolutionary processes may have operated differently in the geographically separated Tibetan and Andean populations exposed to the same environmental stress. Knowledge of the genetic bases of these traits will be necessary to evaluate these inferences. Future research will likely be directed toward determining whether the population means reflect differences identified at the chromosomal level. Future research will also likely consider the biological pathways and environmental influences linking genotypes to phenotypes, the costs and benefits of the Tibetan and Andean patterns of adaptation, and the question of whether the observed phenotypes are indeed adaptations that enhance Darwinian fitness.

Adaptation, Physiological↗

PubMed2001

PIES, a protein interaction extraction system.

We consider the problem of extracting, manipulating, and managing biological pathways, especially protein-protein interaction pathways. We discuss here the Protein Interaction Extraction System (PIES). PIES is contructed on top of three main technologies: Kleisli, BioNLP, and Graphviz. Kleisli is a broad-scale data integration system that we use for downloading Medline abstracts and for general manipulation and management of pathway/interaction databases. BioNLP is a natural language-based information extraction module that we use for analysing Medline abstracts and to extract precise protein-protein and other interaction information. Graphviz is a graphical layout package developed for directed graphs that we use for visualization of the extracted pathways. PIES can be augmented with various means for extracting protein interaction information from sequence databases, for example, by using Kleisli's power to integrate sequence comparison tools to detect gene fusion events in sequence databases.

Abstracting and Indexing↗

PubMed1994

Does wild-type p53 play a role in normal cell differentiation?

Inactivation of the p53 tumor suppressor gene plays a major role in malignant transformation. The central question in this issue is concerned with the understanding of the function of p53 in normal cells and its deregulation in cancer cells. Several in vitro and in vivo experimental models have indicated that induction of cells to undergo differentiation involve up-regulation in the expression of the p53. In the case of B cell differentiation, p53 was found to be involved in several steps of the differentiation pathway. The conclusion that p53 plays a role in normal development and differentiation in vivo is substantiated by the observation that p53 is expressed during embryonic development and is detected at low levels in a number of organs of adult mice. Accentuated levels of p53 in testes of adult mice, suggests that p53 plays a role in the meiotic process of spermatogenesis. B cell differentiation and spermatogenesis are biological pathways which normally involve DNA reshuffling and rearrangements. In accordance with the notion that p53 is associated with DNA repair it is tempting to speculate that at least in these physiological pathways p53 functions as a master gene that controls genome integrity.

Animals↗

PubMed1997

Switching of gene expression: analysis of the factors that spatially and temporally regulate plant gene expression.

In this chapter, we have reviewed the present research and understanding of several families of transcription factors in plants. From this information, it appears there is good conservation between the types of transcription factors in plants and animals. However, there are several types of factors which have been isolated in plants that remain to be documented in animals (e.g., HD-Zip and GT). These as well as the presence of two types of TATA-binding proteins (TBPs) in plants suggest that although transcription in eukaryotes is highly conserved, fundamental differences may exist. Despite the differences, the modes of regulating transcription are well conserved. Figure 3 summarizes these modes of regulation. In recent years, the role of chromatin structure as well as subcellular localization have been the focus of a vast amount of research in mammals, Drosophila and yeast. However, very little research in these areas has been done in plants. Isolation of genes such as Curly leaf suggest a conservation of genes that influence the formation of heterochromatin-like structures. Whether or not this gene influences chromatin/heterochromatin structure in plants, however, remains to be tested. The study of nuclear localization of factors such as COP1 and KN1 is now leading to models for regulating nuclear transport as well as intercellular transport of transcription factors. Further study of the inter- and intracellular movement of these and other transcription factors may provide information on new modes of regulating transcription. In addition to understanding the role chromatin structure and subcellular localization of transcription factors may have on transcription initiation, the biological role of many plant transcription factors remains to be identified. Several approaches may be taken to understand the mechanisms by which transcription factors influence biochemical and physiological processes in the plant. These steps include 1) identification of the DNA-binding sites of the factors as well as the promoter regions which contain these sites. Presently, this approach is limiting in that not many non-coding regions have been sequenced and characterized in detail. Furthermore, the presence of a putative binding site within a promoter does not necessarily indicate that the factor will bind to the site in vivo. 2) Analysis of the binding affinity for a particular factor to a binding site in comparison to other related factors, via in vitro competition assays and quantitative titrations. This will provide information on how strongly these factors are binding to the sites, but without knowledge of all the factors present in a single cell it is difficult to recreate the in vivo conditions. 3) Generation of transgenic plants or microinjection of DNA/RNA to express a particular factor ectopically, reduce expression of the factor via antisense expression, and creation of dominant negative mutants by overexpression of key dimerization domains may provide information concerning what biological pathways these factors influence. 4) Isolation of mutations in particular transcription factors has been extremely informative in floral development. However, this approach usually entails isolation of a mutant due to a phenotype and eventual mutated locus. The cloning of the locus may or may not involve a transcription factor. 5) Many plant transcription factors have been isolated via sequence similarity to other previously identified and/or characterized transcription factors. However, the biological role of may of these factors is not known. In addition to ectopic expression of these factors by creating transgenic plants, isolation of a loss-of-function mutation may provide valuable information concerning the role of this factor in vivo. Many loss-of-function mutations in MADS box genes have led to a better understanding of how the MADS domain proteins interact with one another as well as how they influence floral development. (ABSTRACT TRUNCATED)

Cell Compartmentation↗

PubMed2025

Longitudinal Multi-Organ Transcriptomic Atlas of Salt-Induced Hypertension.

BACKGROUND: Salt-sensitive hypertension is a prevalent and clinically significant subtype of hypertension, where increased dietary salt intake elevates blood pressure and causes injury to multiple organ systems. Despite extensive research, dynamic molecular changes and conserved versus organ-specific transcriptional programs in hypertensive multi-organ damage remain poorly understood. Defining complex molecular pathways both in a temporal sequence and in an organ-specific manner is essential for developing targeted, precision therapies to mitigate hypertensive disease burden. METHODS: We generated a longitudinal multi-organ transcriptomic atlas of salt-sensitive hypertension using RNA sequencing of kidney cortex, kidney medulla, heart, and liver from Dahl salt-sensitive rats across four disease stages. A comprehensive bioinformatic analysis mapped dynamic transcriptional programs, evaluated 50 biological pathways, and defined upstream regulators. Histological and biochemical assays complemented transcriptomic analysis, while integration with human genome-wide association studies (GWAS) and compound-transcriptome analysis provided translational insights and identified candidate therapeutics. RESULTS: Salt-induced hypertension elicited both shared and tissue-specific transcriptional programs that evolved with disease progression. The kidney medulla showed robust early immune activation with metabolic suppression, while the cortex exhibited transient metabolic activation before declining and initiating immune activation. The liver and heart showed time-dependent metabolic and inflammatory remodeling. Cross-organ comparisons revealed a shared early proliferative response that converged on proinflammatory and fibrotic signatures. Upstream regulator analysis identified 79 time- and tissue-specific transcription factors associated with gene expression dynamics. GWAS integration analysis revealed endocrine signaling, ion transport, lipid metabolism, and detoxification as conserved pathways across species, underscoring the translational relevance of the model and study. Predictive compound-transcriptome analyses identified kinase inhibitors targeting phosphoinositide 3-kinase, mechanistic target of rapamycin and cyclin-dependent kinases as top candidates to counteract maladaptive transcriptional programs. CONCLUSIONS: This study defines temporal and tissue-specific transcriptomic remodeling in salt-sensitive hypertension and highlights the need for precision interventions to prevent progressive organ damage.

Journal Article↗

PubMed2001

Transcriptional regulation and function during the human cell cycle.

We report here the transcriptional profiling of the cell cycle on a genome-wide scale in human fibroblasts. We identified approximately 700 genes that display transcriptional fluctuation with a periodicity consistent with that of the cell cycle. Systematic analysis of these genes revealed functional organization within groups of coregulated transcripts. A diverse set of cytoskeletal reorganization genes exhibit cell-cycle-dependent regulation, indicating that biological pathways are redirected for the execution of cell division. Many genes involved in cell motility and remodeling of the extracellular matrix are expressed predominantly in M phase, indicating a mechanism for balancing proliferative and invasive cellular behavior. Transcripts upregulated during S phase displayed extensive overlap with genes induced by DNA damage; cell-cycle-regulated transcripts may therefore constitute coherent programs used in response to external stimuli. Our data also provide clues to biological function for hundreds of previously uncharacterized human genes.

Apoptosis↗

PubMed2026

Multilevel genomic, transcriptomic, and epidemiologic evidence linking diabetic retinopathy to Alzheimer disease.

BACKGROUND: Diabetic retinopathy (DR) and Alzheimer disease (AD) share metabolic and vascular dysfunctions, but the extent to which they reflect overlapping genetic susceptibility and neurovascular-metabolic regulatory pathways remains unclear. We combined multi-omics analyses with population-based data to examine the genetic convergence, cellular pathways, and longitudinal association between DR and AD. METHODS: We performed a two-sample Mendelian randomisation (MR) to estimate the association between genetically predicted DR liability and AD risk. We used Bayesian colocalisation analysis to identify shared genomic loci, and summary-data-based MR (SMR) to detect expression-mediated genes jointly associated with DR and AD. We analysed single-cell RNA sequencing data to characterise shared cellular features and related biological pathways. We also conducted an MR-based mediation analysis to explore whether lipid-related, metabolic, or inflammatory traits mediated the observed DR-AD association, and a longitudinal analysis of the UK Biobank cohort to assess the association between DR and incident AD. RESULTS: With the MR analysis, we found that genetically predicted liability to DR was associated with a modest increase in AD risk. Colocalisation analysis supported a shared genetic signal. We identified three genes with shared expression-mediated associations across DR and AD through SMR. Functional enrichment analyses revealed partially overlapping neurovascular and metabolic pathways. Using MR-based mediation analysis, we found no significant intermediary traits linking DR and AD. Findings from the UK Biobank cohort were directionally consistent with the genetic analyses. CONCLUSIONS: Genetic liability to DR is associated with an increased risk of AD and is accompanied by shared expression-mediated effects and convergent neurovascular-metabolic pathways. These findings support the possibility that DR may serve as a clinically accessible indicator of increased neurodegenerative vulnerability.

Humans↗