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PubMed2005

Chemical genetics and orphan genetic diseases.

Many orphan diseases have been identified that individually affect small numbers of patients but cumulatively affect approximately 6%-10% of the European and United States populations. Human genetics has become increasingly effective at identifying genetic defects underlying such orphan genetic diseases, but little progress has been made toward understanding the causal molecular pathologies and creating targeted therapies. Chemical genetics, positioned at the interface of chemistry and genetics, can be used for elucidation of molecular mechanisms underlying diseases and for drug discovery. This review discusses recent advances in chemical genetics and how small-molecule tools can be used to study and ultimately treat orphan genetic diseases. We focus here on a case study involving spinal muscular atrophy, a pediatric neurodegenerative disease caused by homozygous deletion of the SMN1 (survival of motor neuron 1) gene.

Drug Design↗

PubMed2025

Cross-Phenotype Genome-Wide Association Study on the Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis.

OBJECTIVE: An increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype genome-wide association study (GWAS) meta-analysis. METHODS: We performed cross-phenotype GWAS meta-analysis and Bayesian colocalization analysis for patients with SSc and patients with PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, Bayesian colocalization analyses with expression quantitative trait loci and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies. Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci. RESULTS: We detected a strong genetic correlation between SSc and PBC (global genetic correlation = 0.84, P = 1.7 × 10-6). In the cross-phenotype GWAS meta-analysis, we identified 44 nonhuman leukocyte antigens loci that reached genome-wide significance (P < 5 × 10-8). Evidence of shared causal variants between patients with SSc and patients with PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3, and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function. CONCLUSION: Our study supports a strong shared genetic susceptibility between SSc and PBC. Using cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders.

Humans↗

PubMed2026

Causal effect of chloride intracellular channel protein 5 on chronic periodontitis: A Mendelian randomization study.

This study aimed to evaluate the potential causal effect of chloride intracellular channel protein 5 (CLIC5) on the risk of chronic periodontitis (CP) using a Mendelian randomization (MR) approach. MR analysis was conducted utilizing publicly available summary statistics from genome-wide association studies summary statistics for CLIC5 and CP. Multiple MR methods, including inverse variance weighted, MR Egger, weighted median and weighted mode, were employed to estimate the causal effects. Sensitivity analyses, comprising leave-one-out and heterogeneity assessments were performed to evaluate the robustness of our findings. This MR analysis consistently revealed a negative association between CLIC5 and CP, with statistical significance achieved using the inverse variance weighted and weighted median methods. The concordant effect estimates obtained from all methodological approaches collectively indicated a potential protective effect of CLIC5 against CP. The sensitivity analyses further confirmed the robustness of these findings. This study provides genetic evidence suggesting a potential causal association between increased CLIC5 levels and decreased risk of CP. These findings augment the existing literature implicating chloride channel proteins in modulating the inflammatory processes pertinent to periodontal health. Further investigation is warranted to decipher the underlying biological mechanisms and to explore the potential of CLIC5 as a therapeutic target for CP.

Chloride Channels↗

PubMed2024

Role of myeloid cells in mediating the effects of lipids on ulcerative colitis.

OBJECTIVE: To evaluate the causal relationship between lipids and ulcerative colitis (UC) through Mendelian Randomization (MR), and to further investigate the involvement of immune cells in mediating this process. METHODS: Utilizing summary statistics from genome-wide association studies (GWAS) of individuals with European ancestry, we analyzed the causal link between 179 lipid types and UC (2,569 UC cases and 453,779 controls) through Two-sample Mendelian randomization (2SMR) and Bayesian-weighted MR (BWMR). Based on this, a mediation screening of 731 immune cell phenotypes was conducted to identify exposure and mediator factors. Lastly, the role and proportion of immune cells in mediating the causal effects of lipids on UC were assessed via reverse MR (RMR) and two-step MR. RESULTS: The results of MR showed that there was a causal relationship between the six genetically predicted lipid types and UC (P <0.05), and the four immune cell phenotypes were identified as mediators of the association between lipids and UC. Notably, Phosphatidylcholine (PC) (16:0_0:0) served as the exposure factor, and myeloid cells CD11b on CD33+ HLA DR+ CD14dim acted as the mediator. Mediation analysis showed that CD11b on CD33+ HLA DR+ CD14dim had a mediation effect of -0.0205 between PC (16:0_0:0) and UC, with the mediation effect ratio at 15.38%. CONCLUSION: Our findings elucidate the causal effect of lipids on UC and identify the significant mediating role of myeloid cells CD11b on CD33+ HLA DR+ CD14dim in regulating UC through PC (16:0_0:0), offering new pathways and strategies for UC clinical treatment.

Humans↗

PubMed2026

Causal Relationship of Polyunsaturated Fatty Acids With Mental Disorders: A Systematic Review and Meta-analysis.

CONTEXT: Mental disorders (MDs) pose a important global health challenge, with a complex pathogenesis complicating treatment development. Nutritional interventions, particularly polyunsaturated fatty acids (PUFAs), have gained attention as potential therapeutic options. OBJECTIVE: This Mendelian randomization (MR) meta-analysis aimed to evaluate the potential causal relationship between PUFAs and MDs. DATA SOURCES: Genome-wide association study data were utilized to analyze the association between PUFAs (including omega-3, omega-3 percentage [omega-3%], omega-6, omega-6 percentage [omega-6%], and omega-6 to omega-3 ratio) and 12 major MDs. DATA EXTRACTION: Two-sample MR technology was used to assess the role of PUFAs in MDs. DATA ANALYSIS: The MR analysis revealed that genetically predicted omega-3 was causally linked to MDs, such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% exhibited protective effects against emotional personality disorder. Conversely, omega-6 was inversely correlated with attention-deficit/hyperactivity disorder risk, while a high omega-6 to omega-3 ratio was associated with an increased risk of depression and other mood disorders. CONCLUSION: High omega-3 levels and omega-3% may reduce the risk of MDs, whereas a high omega-6:omega-3 ratio may elevate the risk. These findings highlight the potential of PUFAs, particularly omega-3, in MD prevention and treatment, while underscoring the need for further research into the complex interactions between omega-3 and omega-6. The study provides a scientific foundation for future clinical trials and dietary intervention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no. CRD42024598472.

Humans↗

PubMed2003

Genes that determine flower color: the role of regulatory changes in the evolution of phenotypic adaptations.

A central goal of evolutionary genetics is to trace the causal pathway between mutations at particular genes and adaptation at the phenotypic level. The proximate objective is to identify adaptations through the analysis of molecular sequence data from specific candidate genes or their regulatory elements. In this paper, we consider the molecular evolution of floral color in the morning glory genus (Ipomoea) as a model for relating molecular and phenotypic evolution. To begin, flower color variation usually conforms to simple Mendelian transmission, thus facilitating genetic and molecular analyses. Population genetic studies of flower color polymorphisms in the common morning glory (Ipomoea purpurea) have shown that some morphs are subject to complex patterns of selection. Striking differences in floral color and morphology are also associated with speciation in the genus Ipomoea. The molecular bases for these adaptive shifts can be dissected because the biosynthetic pathways that determine floral pigmentation are well understood and many of the genes of flavonoid biosynthesis have been isolated and extensively studied. We present a comparative analysis of the level of gene expression in Ipomoea for several key genes in flavonoid biosynthesis. Specifically we ask: how frequently are adaptive shifts in flower color phenotypes associated with changes in regulation of gene expression versus mutations in structural genes? The results of this study show that most species differences in this crucial phenotype are associated with changes in the regulation of gene expression.

Adaptation, Physiological↗

PubMed2026

Modelling time-varying genetic effects on binary disease risk via functional Mendelian randomization.

MOTIVATION: Genome-wide association studies have identified thousands of genetic variants associated with complex traits, establishing Mendelian randomization (MR) as a powerful framework for causal inference using variants as natural experiments. However, existing MR methods treat causal effects as static, relying on cross-sectional exposure measurements and ignoring how genetic predispositions to disease operate dynamically across the life course. Recovering age-specific causal effect functions from longitudinal data requires combining functional data representations of exposure trajectories with instrumental variable estimation strategies suitable for binary disease endpoints, a methodological gap that has remained unaddressed. RESULTS: We develop a functional MR framework for binary outcomes that integrates functional principal component analysis with two-stage residual inclusion (2SRI), ensuring consistent estimation under the nonlinear logistic link function that renders standard instrumental variable estimators inconsistent. Simulations across different causal effect trajectory shapes, varying measurement densities, and varying instrument strengths demonstrate accurate recovery of time-varying genetically predicted effects with minimal bias. Applied to UK Biobank data, the framework identifies an age-specific causal effect of genetically predicted body mass index on type 2 diabetes risk concentrated in early mid-adulthood and progressively attenuating thereafter. Concordance between the proposed 2SRI estimator applied to type 2 diabetes and the established continuous-outcome functional MR estimator applied to the paired glycated haemoglobin marker in the same cohort provides indirect empirical support for the validity of the proposed approach. AVAILABILITY AND IMPLEMENTATION: The method is implemented in the R package mvfmr, with a full tutorial vignette.

Mendelian Randomization Analysis↗

PubMed2025

New evidence for the protective effect of gut microbiota regulation of ferroptosis-related proteins against osteoporosis.

Osteoporosis (OP), characterized by bone degradation and increased fracture susceptibility, constitutes a significant global health burden. Recent findings implicate gut microbiota and ferroptosis in the regulation of bone metabolism; however, causal evidence for the gut microbiota's influence on OP specifically via ferroptosis regulation remains to be established. This study employed two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics to investigate these causal relationships and delineate mediating pathways.We assessed causal links between gut microbiota, ferroptosis-related proteins, and OP risk. Associations for gut microbiota abundance and ferroptosis-related proteins were derived from GWAS data and Icelandic blood-derived protein quantitative trait loci, respectively. Outcome data for OP were obtained from the FinnGen Release R12. The primary analysis utilized the inverse variance weighted (IVW) method, supplemented by sensitivity analyses to evaluate heterogeneity and horizontal pleiotropy.  MR analysis identified 33 gut microbial taxa causally associated with OP risk: 13 protective and 20 detrimental. Similarly, 34 ferroptosis-related proteins were categorized as protective (18) or detrimental (16) for OP. Mediation analysis revealed that the protective effect of Terrisporobacter othiniensis on OP is partially mediated by the ferroptosis regulator MDM4 (indirect effect β = -0.020, 95% CI: -0.068 to 0.029), accounting for 6.8% of the total effect. Sensitivity analyses showed no significant evidence of heterogeneity or horizontal pleiotropy. This study provides the first genetically validated evidence supporting a causal relationship between specific gut microbiota, ferroptosis-associated proteins, and OP susceptibility. Specifically, Terrisporobacter othiniensis demonstrates a novel protective mechanism, modulating OP risk partly through the ferroptosis regulator MDM4. These findings broaden understanding of the "gut-bone axis" and highlight the gut microbiota-ferroptosis pathway, particularly the MDM4/p53 axis, as a promising target for novel OP prevention and therapeutic strategies.

Ferroptosis↗

PubMed1999

CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans.

Mutations in the clk-1 gene of the nematode Caenorhabditis elegans result in an average slowing of a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging. In yeast, a CLK-1 homologue is absolutely required for ubiquinone biosynthesis and thus respiration. Here we show that CLK-1 is fully active when fused to green fluorescent protein and is found in the mitochondria of all somatic cells. The activity of mutant mitochondria, however, is only very slightly impaired, as measured in vivo by a dye-uptake assay, and in vitro by the activity of succinate cytochrome c reductase. Overexpression of CLK-1 activity in wild-type worms can increase mitochondrial activity, accelerate behavioral rates during aging and shorten life span, indicating that clk-1 regulates and controls these processes. These observations also provide strong genetic evidence that mitochondria are causally involved in aging. Furthermore, the reduced respiration of the long-lived clk-1 mutants suggests that longevity is promoted by the age-dependent decrease in mitochondrial function that is observed in most species.

Aging↗

PubMed2025

Genomic structural equation modeling elucidates the shared genetic architecture of allergic disorders.

BACKGROUND: The intricate shared genetic architecture underlying allergic disorders-including allergic asthma, atopic dermatitis, contact dermatitis, allergic rhinitis, allergic conjunctivitis, allergic urticaria, anaphylaxis, and eosinophilic esophagitis-remains incompletely characterized. METHODS: Our study employed genomic structural equation modeling (Genomic SEM) to define the common factor representing the shared genetic architecture of allergic disorders. Coupled with diverse post-GWAS analytical methods, we aimed to discover susceptible loci and investigate genetic associations with external traits. Furthermore, we explored enriched genetic pathways, cellular layers, and genomic elements, and investigated putative plasma protein biomarkers. Polygenic risk score (PRS) analyses, leveraging our integrated GWAS data, were conducted to assess chromosomal-level risk associations for allergic disorders. RESULTS: A well-fitted genomic SEM integrated GWAS data, revealing the shared genetic architecture of allergic disorders. We identified a total of 2038 genome-wide significant SNP loci (p < 5e-8), including 31 previously unreported loci. Fine-mapping of variants and gene sets pinpointed 2 causal variants and 31 candidate susceptible genes. Genetic correlation analyses further illuminated the shared genetic architecture underlying multiple traits, notably psychiatric disorders. Preliminary findings identified four putative causal plasma protein biomarkers. CONCLUSION: Notably, this study presents the first comprehensive genetic characterization of allergic disorders through a GWAS analysis of an unmeasured composite phenotype, providing novel insights into shared etiological pathways across these conditions.

Humans↗

PubMed2026

Shared genetic architecture and neurobiological pathways of problematic alcohol use and anxiety disorders.

Problematic alcohol use (PAU) and anxiety disorders (ANX) frequently co-occur, implying shared genetic and neurobiological foundations. However, the directionality of potential causal relationships and the specific mechanisms underlying the overlap remain unclear. Thus, we investigated the shared genetic architecture and neurobiological pathways between PAU and ANX using a multimethod genomic approach. We analyzed summary statistics from genome-wide association studies (GWAS) of PAU and ANX using Mendelian Randomization to assess causal associations between ANX and PAU. We used MiXeR to assess the overall shared genomic architecture, Local Analysis of (co)Variant Association to estimate regional genetic correlations, and conjunctional false discovery rate (conjFDR) to identify individual overlapping loci. We used FUMA to map single-nucleotide polymorphisms (SNPs) to independent loci, conduct differential gene expression analyses across 30 general and 54 specific tissue types, and perform cell-type specificity analyses using a human brain cell atlas. Druggability of identified targets was also evaluated. Mendelian Randomization analyses indicated bidirectional causal associations between ANX and PAU. MiXeR identified moderate polygenic overlap (52.5%) and genetic correlation (rg = 0.44) between the traits, with high effect direction concordance among shared estimated causal variants (86.4%). ConjFDR identified 97 shared lead SNPs, of which 89 had concordant and 8 discordant effects on PAU and ANX. These loci mapped to 97 genes, including DRD2 and PDE4B, genes linked to dopaminergic and cAMP signaling pathways, respectively. Concordant gene expression was enriched in brain, nerve, adrenal gland, esophagus, stomach, and colon, with enriched expression specifically in the prefrontal cortex, anterior cingulate cortex, hippocampus, hypothalamus, substantia nigra and amygdala. FUMA cell-type enrichment analysis identified associations predominantly in neurons from the cerebral cortex, hippocampus, and thalamus. We found substantial genetic and neurobiological overlap between PAU and ANX, highlighting reciprocal, causal relationships between the traits, with differentially expressed genes enriched in addiction- and anxiety-relevant brain regions. These findings support shared genetic and neurobiological mechanisms linking PAU and ANX, while acknowledging that some signals may reflect broader internalizing or psychiatric liability.

Journal Article↗

PubMed1998

Fetal origin of maturity-onset diabetes mellitus: genetic or environmental cause?

Low birthweight is a risk factor for a number of diseases of adult life including non-insulin-dependent diabetes mellitus (NIDDM). This implies that either genetic constitution or factors operating during intrauterine development have a causal role in NIDDM. One reason for rejecting a genetic cause, however, is that there is a rapidly changing prevalence of NIDDM with the onset and establishment of affluence, which does not fit with conventional models of multifactorial genetic disease. But in this article a new model of genetic disease based on the concept of redundancy is explored. The idea is that mutant genes interact synergistically in highly redundant systems to degrade performance and increase the risk of disease. The mutational load is in turn determined by the pre-conceptual environment. This model can explain a rapidly changing prevalence of NIDDM.

Age of Onset↗

PubMed2004

Febrile seizures and mechanisms of epileptogenesis: insights from an animal model.

Temporal lobe epilepsy (TLE) is the most prevalent type of human epilepsy, yet the causes for its development, and the processes involved, are not known. Most individuals with TLE do not have a family history, suggesting that this limbic epilepsy is a consequence of acquired rather than genetic causes. Among suspected etiologies, febrile seizures have frequently been cited. This is due to the fact that retrospective analyses of adults with TLE have demonstrated a high prevalence (20-->60%) of a history of prolonged febrile seizures during early childhood, suggesting an etiological role for these seizures in the development of TLE. Specifically, neuronal damage induced by febrile seizures has been suggested as a mechanism for the development of mesial temporal sclerosis, the pathological hallmark of TLE. However, the statistical correlation between febrile seizures and TLE does not necessarily indicate a causal relationship. For example, preexisting (genetic or acquired) 'causes' that result independently in febrile seizures and in TLE would also result in tight statistical correlation. For obvious reasons, complex febrile seizures cannot be induced in the human, and studies of their mechanisms and of their consequences on brain molecules and circuits are severely limited. Therefore, an animal model was designed to study these seizures. The model reproduces the fundamental key elements of the human condition: the age specificity, the physiological temperatures seen in fevers of children, the length of the seizures and their lack of immediate morbidity. Neuroanatomical, molecular and functional methods have been used in this model to determine the consequences of prolonged febrile seizures on the survival and integrity of neurons, and on hyperexcitability in the hippocampal-limbic network. Experimental prolonged febrile seizures did not lead to death of any of the seizure-vulnerable populations in hippocampus, and the rate of neurogenesis was also unchanged. Neuronal function was altered sufficiently to promote synaptic reorganization of granule cells, and transient and long-term alterations in the expression of specific genes were observed. The contribution of these consequences of febrile seizures to the epileptogenic process is discussed.

Animals↗

PubMed2025

Dissecting the shared genetic architecture of schizophrenia with ventricular subregion volumes.

Schizophrenia is characterized by cerebral ventricular enlargement as an early and consistent structural anomaly. While genetic factors significantly influence both schizophrenia and cerebral ventricular enlargement, the shared genetic etiology between them requires further investigation. Using summary statistics from recent large genome-wide association studies on schizophrenia and 9 ventricular subregion volumes phenotypes. Gaussian causal mixture modeling was applied to characterize the genetic architecture and overlap between schizophrenia and ventricular subregion volumes phenotypes. Local genetic correlation was investigated with Local Analysis of Variant Association. The conjunctional false discovery rate framework was used to identify the specific shared genetic loci, annotated with FUMA. Gaussian causal mixture modeling estimated schizophrenia to be more polygenic more polygenic (9574 trait-influencing variants) than ventricular subregion volumes phenotypes (157-1267 trait-influencing variants). Conjunctional false discovery rate analysis identified 42 shared genetic loci, 17 loci were identified as novel for both schizophrenia and the ventricular subregion volumes phenotypes. Local Analysis of Variant Association revealed that 11 distinct loci demonstrated significant differences, among which 4 loci were situated in the Major Histocompatibility Complex region. Annotated genes in shared loci were enriched in molecular signaling pathways involved in inflammation and the brain structure. The shared loci between them were annotated and enriched in Major Histocompatibility Complex and inflammation-related pathways, highlighting new opportunities for future investigation.

Schizophrenia↗

PubMed2000

Plasticity, evolvability, and modularity in RNA.

RNA folding from sequences into secondary structures is a simple yet powerful, biophysically grounded model of a genotype-phenotype map in which concepts like plasticity, evolvability, epistasis, and modularity can not only be precisely defined and statistically measured but also reveal simultaneous and profoundly non-independent effects of natural selection. Molecular plasticity is viewed here as the capacity of an RNA sequence to assume a variety of energetically favorable shapes by equilibrating among them at constant temperature. Through simulations based on experimental designs, we study the dynamics of a population of RNA molecules that evolve toward a predefined target shape in a constant environment. Each shape in the plastic repertoire of a sequence contributes to the overall fitness of the sequence in proportion to the time the sequence spends in that shape. Plasticity is costly, since the more shapes a sequence can assume, the less time it spends in any one of them. Unsurprisingly, selection leads to a reduction of plasticity (environmental canalization). The most striking observation, however, is the simultaneous slow-down and eventual halting of the evolutionary process. The reduction of plasticity entails genetic canalization, that is, a dramatic loss of variability (and hence a loss of evolvability) to the point of lock-in. The causal bridge between environmental canalization and genetic canalization is provided by a correlation between the set of shapes in the plastic repertoire of a sequence and the set of dominant (minimum free energy) shapes in its genetic neighborhood. This statistical property of the RNA genotype-phenotype map, which we call plastogenetic congruence, traps populations in regions where most genetic variation is phenotypically neutral. We call this phenomenon neutral confinement. Analytical models of neutral confinement, made tractable by the assumption of perfect plastogenetic congruence, formally connect mutation rate, the topography of phenotype space, and evolvability. These models identify three mutational regimes: that corresponding to neutral confinement, an exploration threshold corresponding to a breakdown of neutral confinement with the simultaneous persistence of the dominant phenotype, and a classic error threshold corresponding to the loss of the dominant phenotype. In a final step, we analyze the structural properties of canalized phenotypes. The reduction of plasticity leads to extreme modularity, which we analyze from several perspectives: thermophysical (melting--the RNA version of a norm of reaction), kinetic (folding pathways--the RNA version of development), and genetic (transposability--the insensitivity to genetic context). The model thereby suggests a possible evolutionary origin of modularity as a side effect of environmental canalization.

Evolution, Molecular↗

PubMedDate not supplied

Mating systems and sexual selection in male-pregnant pipefishes and seahorses: insights from microsatellite-based studies of maternity.

In pipefishes and seahorses (family Syngnathidae), the males provide all postzygotic care of offspring by brooding embryos on their ventral surfaces. In some species, this phenomenon of male "pregnancy" results in a reversal of the usual direction of sexual selection, such that females compete more than males for access to mates, and secondary sexual characteristics evolve in females. Thus the syngnathids can provide critical tests of theories related to the evolution of sex differences and sexual selection. Microsatellite-based studies of the genetic mating systems of several species of pipefishes and seahorses have provided insights into important aspects of the natural history and evolution of these fishes. First, males of species with completely enclosed pouches have complete confidence of paternity, as might be predicted from parental investment theory for species in which males invest so heavily in offspring. Second, a wide range of genetic mating systems have been documented in nature, including genetic monogamy in a seahorse, polygynandry in two species of pipefish, and polyandry in a third pipefish species. The genetic mating systems appear to be causally related to the intensity of sexual selection, with secondary sex characters evolving most often in females of the more polyandrous species. Third, genetic studies of captive-breeding pipefish suggest that the sexual selection gradient (or Bateman gradient) may be a substantially better method for characterizing the mating system than previously available techniques. Finally, these genetic studies of syngnathid mating systems have led to some general insights into the occurrence of clustered mutations at microsatellite loci, the utility of linked loci in studies of parentage, and the use of parentage data for direct estimation of adult population size.

Animals↗

PubMed1995

Genetic abnormalities during transition from Helicobacter-pylori-associated gastritis to low-grade MALToma.

The helicobacter-associated transition from chronic gastritis to MALToma (lymphoma of mucosa-associated lymphoid tissue) may require genetic change in the host. We have studied gastrectomy specimens from twelve cases of primary B-cell gastric lymphoma showing evidence of chronic gastritis and low-grade or high-grade MALToma to look for allele imbalance at microsatellites for six tumour-suppressor genes. We detected allelic imbalance at two of these loci (DCC in three, APC in two). In two DCC cases allele imbalance was seen in the transition from chronic gastritis to low-grade MALToma and in the third between low-grade and high-grade. Allele imbalance between chronic gastritis and low-grade MALToma is not necessarily causal in the transition. Rather, genetic change has occurred in the process of transformation.

Alleles↗

PubMed2026

The causal relationship between multiple cardiovascular diseases and glioblastoma: A Mendelian randomization study.

Observational studies suggest an association between glioblastoma (GBM) and cardiovascular diseases (CVDs), but a causal relationship remains unestablished. This study aimed to investigate the causal link between multiple CVDs and GBM risk. The inverse variance weighted method indicated that all 18 CVDs had significant causal associations with GBM (P < .05). Genetically predicted CVDs were uniformly associated with a lower risk of GBM (odds ratio < 1), identifying them as potential protective factors. Sensitivity analyses confirmed the absence of significant heterogeneity or horizontal pleiotropy, and the MR-Steiger test validated the correct causal direction. This Mendelian randomization (MR) study provides evidence that a range of CVDs are causally associated with a decreased risk of developing GBM. These findings suggest shared biological pathways and offer new insights for understanding GBM etiology. We conducted a 2-sample MR analysis using publicly available genome-wide association study data. GBM was the outcome, and 18 cardiovascular-related traits (including coronary artery disease, myocardial infarction, and venous thromboembolism) were exposures. Instrumental variables were single-nucleotide polymorphisms significantly associated with exposures (P < 5 × 10-8). The primary analysis used the inverse variance weighted method, supplemented with MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including Cochran Q test, MR-Egger intercept test, leave-one-out analysis, and MR-Steiger directionality test, were performed to ensure robustness.

Causality↗