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Results for “Genetic causality”

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At least 253 records · Page 14Linked to original sources
PubMed2026

Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.

BACKGROUND: Organ-specific autoimmune diseases, particularly Graves' disease (GD) and its extrathyroidal manifestation, Graves' orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum. METHODS: Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein-protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region. RESULTS: Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell-cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand-receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds - venetoclax, irinotecan, and dutasteride - with predicted favorable docking scores and stable binding poses in our simulations. CONCLUSIONS: These findings demonstrate that TSHR acts as a molecular hub mediating peripheral-central neuroimmune crosstalk in GD and GO. The results support a broader "disease-molecule axis" framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Receptors, Thyrotropin↗
PubMed1985

High incidence of Creutzfeldt-Jakob disease in North African immigrants to France.

During the 15-year period 1968-1982, 328 French residents died of Creutzfeldt-Jakob disease (CJD); 273 had been born in France (annual mortality rate of 0.38 per million inhabitants). Of the 55 foreign-born cases, 12 came from Tunisia and 11 from Algeria (mortality rates of 4.53 and 0.95 per million). Nearly all of the Tunisians were Jews, and six belonged to two families. These findings complement earlier observations on Libyan-born Israelis, but still do not discriminate between genetic or environmental causal factors, which will require epidemiologic investigation of CJD in North Africa.

Africa, Northern↗
PubMed2026

Aerobic Fitness and Health-Related Phenotypes: A Two-Stage Phenome-Wide Mendelian Randomization Study.

PURPOSE: We investigated potentially causal associations between genetically predicted aerobic fitness and multiple health phenotypes using a two-stage phenome-wide Mendelian randomization (MR) study. METHODS: Genetically determined aerobic fitness, as operationalized by Cai et al., served as the exposure instrument. We screened 712 health-related phenotypes as outcomes using publicly available European-ancestry genome-wide association studies (GWAS) summary statistics from OpenGWAS (Discovery GWAS n > 5000), prioritizing non-UK Biobank/non-FinnGen datasets for Discovery when available and selecting an independent GWAS for validation. Associations were estimated using the MR-Robust Adjusted Profile Score method, controlled for multiple testing (5% false discovery rate) and unaffected by violations of MR assumptions (directional concordance between discovery and validation; no evidence of horizontal pleiotropy across inverse-variance weighted, MR-Egger, weighted-median, and weighted-mode methods; negative control analysis on hair color). RESULTS: We identified 108 discovery associations, of which 34 remained valid and statistically significant after validation. Higher genetically determined aerobic fitness was associated with lower lacunar stroke risk, lower arterial stiffness, higher heart rate variability, lower diastolic blood pressure, more favorable anthropometric measures, lower use of antidiabetic drugs, lower asthma risk, lower C-reactive protein, higher bone mineral density, favorable liver function biomarkers, favorable platelet-related traits, multiple blood count-derived hematological cell indices and counts, as well as higher years of schooling. Adverse associations were confined to atrial fibrillation, valvular heart disease, and systolic blood pressure. CONCLUSIONS: Genetically determined aerobic fitness is linked to a broad pattern of favorable cardiometabolic, inflammatory, musculoskeletal, respiratory, hepatic, and hematological phenotypes, alongside a narrow set of potential cardiovascular hazards.

Humans↗
PubMed2026

Does Toxoplasma gondii infection have a causal impact on human psychopathology? A Mendelian randomization analysis.

Toxoplasma gondii (T. gondii) is a prevalent zoonotic parasite that has been implicated in influencing human psychiatric disorders and risk-taking behaviors. Using genome-wide association study (GWAS) data, we selected 25 and 76 single-nucleotide polymorphisms as instrumental variables for anti-T. gondii IgG seropositivity and anti-T. gondii IgG levels, respectively, and conducted two-sample Mendelian randomization (MR) analyses across 18 GWAS datasets to investigate potential causal effects on addiction, bipolar disorder, obsessive-compulsive disorder, schizophrenia, and risk-taking behavior in European populations. Contrary to previous epidemiological evidence, our MR analyses do not support a significant causal association between T. gondii infection and any of the studied psychiatric disorders or risk-taking behavior. Collectively, these results establish that any true causal effect of genetic liability to T. gondii infection is likely to be small (OR < 1.18 for schizophrenia,&#x2009;<&#x2009;1.29 for bipolar disorder) and below the effect sizes typically reported in observational seroepidemiological studies, although small or infection-phase-specific effects cannot be excluded.

Humans↗
PubMed1992

[New views on the therapy of beta-thalassemia].

The author describes the present situation as regards treatment of beta-thalassaemias. Most frequently the classical combination of transfusions and desferrioxamine is used. Other possibilities are total or partial splenectomy, as well as transplantation of the bone marrow. The mentions also perspective causal therapy by genetic engineering. Systematic and planned prevention still remains most successful.

Humans↗
PubMed1990

[Risk factors in the etiology of Crohn disease].

So far the aetiology of Crohn's disease remains unclear. Besides a genetic predisposition a causal role of environmental factors has been taken into consideration within the last time period. A number of case-control studies have consistently reported about an increased consumption of dietary sugar in patients with Crohn's disease as compared with controls. Furthermore cigarette smoking and the use of oral contraceptive drugs have been shown to increase disease risk. While the role of the former can be regarded as established the role of the latter still remains controversial.

Cohort Studies↗
PubMedDate not supplied

Environmental risk factors in inflammatory bowel disease.

Besides a genetic predisposition, a causal role of various environmental factors have been taken into consideration in the etiology of inflammatory bowel disease (IBD). The most consistent association of environmental factors so far identified is the association between non smoking and ulcerative colitis (UC) as well a between smoking and Crohn's disease (CD). Other factors such as oral contraceptives, refined sugar, perinatal events, childhood infections, microbial agents, and domestic hygiene have been found to be associated with ulcerative colitis and Crohn's disease but further evaluation is required to confirm the consistency and to define the strength of the association. Recent data also suggest that measles virus may persist in intestinal tissue and early exposure to the virus may be a risk factor for development of CD. The further investigation of environmental factors on IBD and the explanation of their role is expected to open new avenues for basic scientific research and may lead to the development of a more rational approach to the prevention and treatment of IBD. The available data suggest that UC and CD are heterogeneous disorders of multifactorial etiology in which hereditary and environmental factors interact to produce the disease.

Colitis, Ulcerative↗
PubMedDate not supplied

What relevance do advances in molecular biology and genetics have for epidemiology: high tech needle and thread to sew the web of causation.

Epidemiology has changed, during the past, from miasma versus germ theory to the studies of relationship between exposure and outcome. New definitions such as risk factors or multifactorial aetiology, and more recently web of causation, have been helpful to understand many diseases. Molecular biology and genetics advances in the past decade can be instruments that allow to investigate more deeply the web of causation. Molecular biomarkers are the new investigating mean. Examples of studies using these new techniques are presented, in many epidemiological fields: in non communicable disease with linkage and association studies, allowing experimental studies; in cancer, investigating susceptibility to the disease, early exposure to environmental carcinogens detection and specific mutational patterns in aetiological studies; in communicable disease, in particular with genetic subtyping of particular agents and causal mechanisms research. To mix up all the knowledge required to handle these techniques and epidemiology shall be profitable integrate multidisciplinary team of scientists, epidemiologists and molecular biologists together. This might be the way to approach the distribution and determinants of disease in deep but also with more clear and explicit explanation of the elaborate relationships.

Causality↗
PubMed1998

[Biology of non-conventional transmissible agents or prions].

Transmissible subacute spongiform encephalopathies (TSE) are a group of human and animal diseases which includes Creutzfeldt-Jakob disease, Gerstmann-Straüssler-Scheinker syndrome (GSS), Kuru, fatal familial insomnia (FFI), scrapie in sheep and goat, mink and feline transmissible encephalopathy, chronic wasting disease, and bovine spongiforme encephalopathy (BSE). TSE are transmissible among individuals of the same species and some of different species. These diseases stem from a specific category of agents that have biological and physiochemical characteristics unlike other micro-organisms; they are known as transmissible spongiform encephalopathy agent (TSA), prions, or virinos. So far, despite considerable progress made in the molecular biology toward the understanding of neurological injury, the nature of the TSA/prions remains unknown. TSE are characterised by the pathognomic accumulation, within the central nervous system of the infected individual, of a normal protein from the host organism, the PrP (prion protein). Differences between the PrP isolated from normal individuals (PrP-c) and PrP isolated from infected individuals (PrP-res) have been investigated. There are no differences in the sequence in amino acids, and the secondary structure seems identical, but since normal PrP is totally degraded by proteinase K pathological PrP resists to enzymatic digestion. One can therefore describe two PrP isoforms: a normal isoform, the PrP-c (c for cellular), sensitive to proteinase K and present in the normal individual and in the infected patients or animals: and a pathological isoform, the PrP-res, resistant to proteinase K and present in amount proportional to the infectivity in the brains of infected individuals. The presence of TSA/prions is detectable in the spleens of infected animals early after inoculation; it is then present in the CNS following a period not exceeding a half of the total length of the experimental disease. In the CNS, PrP-res is the origin of spongiosis and gliosis that are observed in infected individuals. A double causality, "infectious" and genetic, of these diseases can be derived from the various ideas currently accepted. Indeed the genetic basis of some familial forms has now been confirmed and transmissibility has been proven in natural situations such as the outbreak of CJD among children treated with extractive growth hormone and the recent surge of a new disease decimating British cattle, the bovine spongiform subacute encephalopathy, or mad cow disease. In TSE affected individuals, PrP has a key role in the incubation time and in the species barrier.

Animals↗
PubMed2006

MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability.

Spindle assembly checkpoint (SAC) ensures bipolar attachment of chromosomes to the mitotic spindle and is essential for faithful chromosome segregation, thereby preventing chromosome instability (CIN). Genetic evidence suggests a causal link between compromised SAC, CIN, and cancer. Bloom syndrome (BS) is a genetic disorder that predisposes affected individuals to cancer. BS cells exhibit elevated rates of sister chromatid exchange, chromosome breaks, and CIN. The BS gene product, BLM, is a member of the RecQ helicases that are required for maintenance of genome stability. The BLM helicase interacts with proteins involved in DNA replication, recombination, and repair and is required for the repair of stalled-replication forks and in the DNA damage response. Here we present biochemical evidence to suggest a role of BLM phosphorylation during mitosis in maintaining chromosome stability. BLM is associated with the SAC kinase MPS1 and is phosphorylated at S144 in a MPS1-dependent manner. Phosphorylated BLM interacts with polo-like kinase 1, a mitotic kinase that binds to phosphoserine/threonine through its polo-box domain (PBD). Furthermore, BS cells expressing BLM-S144A show normal levels of sister chromatid exchange but fail to maintain the mitotic arrest when SAC is activated and exhibit a broad distribution of chromosome numbers. We propose that MPS1-dependent BLM phosphorylation is important for ensuring accurate chromosome segregation, and its deregulation may contribute to cancer.

Adenosine Triphosphatases↗
PubMed2026

Integrative Genomic and Functional Investigation of the Multi-Layered Genetic Architecture Between Anorexia Nervosa and Bone Loss.

OBJECTIVE: Bone loss is a severe and often irreversible complication of anorexia nervosa (AN), yet the genetic mechanisms underlying this comorbidity remain underexplored. This study focuses on constructing a comprehensive genetic architecture between AN and estimated calcaneal bone mineral density (eBMD). METHOD: We applied an integrative framework incorporating genetic correlation, pleiotropic association, and causal inference across single-variant, multi-variant, and gene expression levels. Functional validation was conducted in&#xa0;vitro to investigate the biological role of the key candidate gene. RESULTS: Local genetic correlation analysis identified significant signals at 8p21.2 and 10q26.3, despite the lack of significant global correlation. Mendelian randomization analysis pointed to a suggestive negative causal effect of genetically predisposed AN on eBMD. Extensive pleiotropic signals were detected, particularly at 3p21.31 and 10q26.3, loci enriched with genes associated with both traits. Notably, we identified a novel pleiotropic signal near NCAM1 at 11q23.2, which was supported by multi-layered genetic evidence and confirmed through in&#xa0;vitro functional experiments. NCAM1, a well-established neural-associated gene, promoted osteoclastic differentiation and bone resorption when overexpressed in osteoclast precursor cells, indicating that NCAM1 possesses distinct functional roles in both neural and skeletal tissues. DISCUSSION: This study constructs a comprehensive genetic architecture underlying AN and eBMD and highlights NCAM1 as a key pleiotropic gene.

anorexia nervosa↗
PubMed2025

Genetic risk factors in rheumatoid arthritis: A Mendelian randomization study of chronic kidney disease in European populations.

Rheumatoid arthritis (RA) is a heritable autoimmune disease linked to chronic kidney disease (CKD) in observational studies. However, whether this association is causal and driven by shared genetic risk remains unclear, warranting genetic investigation. To investigate possible causal relationships between RA and different CKD subtypes, we used Mendelian randomization (MR) analyses with data from genome-wide association studies. The inverse variance weighted (IVW) methodology was the main method, and sensitivity analyses were added to improve the validity of the causal estimations. Our analysis predicted that RA significantly increases the risk of IgA nephropathy (IVW odds ratio [OR]&#x2005;=&#x2005;1.041, 95% confidence interval [CI]&#x2005;=&#x2005;1.018-1.065, P&#x2005;=&#x2005;4.286e-04), diabetic nephropathy (IVW OR&#x2005;=&#x2005;1.078, 95% CI&#x2005;=&#x2005;1.009-1.152, P&#x2005;=&#x2005;.027), nephrotic syndrome (IVW OR&#x2005;=&#x2005;1.164, 95% CI&#x2005;=&#x2005;1.078-1.257, P&#x2005;=&#x2005;1.012e-04), and chronic renal failure (IVW OR&#x2005;=&#x2005;1.046, 95% CI&#x2005;=&#x2005;1.018-1.075, P&#x2005;=&#x2005;1.000e-03). MR analyses confirmed RA's positive causal effect on these CKD subtypes (all P&#x2005;<&#x2005;.05). While heterogeneity was observed for IgA nephropathy and chronic renal failure, sensitivity analyses (MR-Egger intercept, all P&#x2005;>&#x2005;.05) revealed no evidence of horizontal pleiotropy, supporting the robustness of our findings. Our findings suggest that in European-ancestry populations, a genetic predisposition to RA is causally associated with a higher risk of specific types of CKD. While these results require validation in diverse ethnic groups, they highlight the potential importance of renal monitoring for genetically susceptible RA patients, which may help mitigate the public health burden of CKD.

Humans↗
PubMed1996

A comparison of the nucleotide sequence of the cerato-ulmin gene and the rDNA ITS between aggressive and non-aggressive isolates of Ophiostoma ulmi sensu lato, the causal agent of Dutch elm disease.

Little genetic information exists comparing aggressive and non-aggressive isolates of the causal agent of Dutch elm disease, Ophiostoma ulmi. Two genetic elements were compared between the subgroups. The ceratoulmin cu gene product has been associated with disease symptoms. Nucleotide-sequence analysis of cu and the internal transcribed spacer (ITS) region of the rDNA were made from three aggressive and three non-aggressive isolates of the pathogen. Our results suggested uniformity within, and unique differences between, subgroups. Differences were detected for cu in the promoter, coding, and transcription termination regions. Sequence data for the ITS clearly distinguish the subgroups.

Amino Acid Sequence↗
PubMed2002

Genetics, biology and multifactorial diseases.

The schematic concept of "levels of causal interaction" is applied to the relation between genetics and biology. The strength of classical formal genetics lies in its power to proceed directly from observations on an external phenotype, to inferences concerning the nature and properties of the fundamental genetic factors. Its weakness comes from the fact that by short-circuiting the causal chain leading from genotype to phenotype, it creates a divorce between genetics and biology. It is argued that in order to reestablish an articulation of genetics and the biology of whole organisms, it will be necessary to study in detail the entire causal chain leading from a difference in a genetic factor to a difference in a corresponding phenotypic character. This proposal is illustrated by a consideration of multifactorial diseases, which appear to be due to strong interactions between a moderate number of distinct loci; the frequency of "abnormal" alleles at any given locus may be surprisingly high.

Alleles↗
PubMed1995

Leukaemia and Sellafield: is there a heritable link?

The demonstration of a statistical association between paternal preconceptional irradiation and childhood leukaemia appeared to provide a satisfactory explanation for the excess of cases in the village of Seascale, close to the Sellafield nuclear installation, and became the basis of two legal claims for compensation. In the ensuing scientific debate the biological plausibility of a causal interpretation of this association focused on the heritability of leukaemia and a comparison of the genetic risks implied by this finding with current information on the induction of genetic damage by irradiation. After a wide ranging review of the mechanistic issues it is concluded that there is no genetic basis for a causal relationship and this, together with recent appraisals of epidemiological studies, suggests that the association between childhood leukaemia and paternal preconceptional irradiation exposure is most likely to be a chance finding.

England↗
PubMed1992

Parathyroid hormone and genetic hypertension.

Recent research provides evidence that parathyroid hormone is implicated in the pathogenesis of genetic hypertension. Abnormalities in calcium metabolism in genetic hypertension have been reported. These include hypercalciuria, depressed serum ionized calcium associated with enhanced serum parathyroid hormone levels. Calcium supplement resulted in normalization of calcium metabolism and reduction in blood pressure. In addition, removal of parathyroid glands attenuated the rise in blood pressure in genetic hypertensive rat. This review focuses on the links between calcium metabolism and calcium endocrine system abnormalities and the etiology of experimental genetic hypertension. The mechanisms by which dietary supplement and parathyroidectomy lower genetic hypertension are also discussed. Although the causality of raised parathyroid hormone in genetic hypertension is not yet fully understood, we conclude that this hormone may play a permissive effect in the development of hypertension.

Age Factors↗