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Results for “Genetic causality”

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At least 163 records · Page 9Linked to original sources
PubMed1991

[Empirical estimation of recurrence risks in multifactorial diseases with variable age-at-onset: conditional probability approach].

Conditional probability approach in estimation of recurrence risks considered in the report is naturally extended to the case of diseases with variable age-at-onset which are divided into many age-at-onset incompatible classes, the distribution of families for classes of affected and normal siblings being polynomial, modified with regard both for classes by age manifestation and for age of relatives at the moment of observation. This case is realised within the framework of the so called "life-table" approach of general use in demography. It is emphasized that the estimate of "accumulated morbidity" obtained within this framework--as a resulting estimate of "forthcoming risk" for individuals which are at premanifestational age--is the "a posteriori" probability for relatives to be affected by the disease. It is indicated that conditional probability approach, being free of any biological models of the disease origin, is not free of ascertainment models: different kinds of stratifications of the patients for the features related to their ascertainment as probands (age-at-onset, age by the time of observation, sex, birth order, etc.) can naturally generate inconsistency of the ascertainment probability pi both within and among the families, violating the independence of the ascertainment of patients as probands. In this connection, the maximum likelihood equations are given for estimation of the ascertainment probabilities of different incompatible groups of patients as probands and the necessity to account for possible differences in pi-s is pointed out.

Age Factors↗
PubMed1990

[Condition to produce oscillation after twitch shortening in the bullfrog geniohyoid muscle].

Two different types of elastic behaviors could be distinguished in the twitch contraction curve of the isolated frog geniohyoid muscle under changing of chemical conditions; one was negative oscillation that occurred after completion of the relaxation phase which was sequential to a typical cyclic pattern demonstrated in the contraction and relaxation period, and the other was oscillation which occurred in the phase of plateau formation during relaxation. The former will relate to the parallel elastic component (the effect of caffeine combined with a low Ca++ condition) and the latter will to the series one (collagenase and dantrolene). The causal or genetic relationship is not yet clarified.

Animals↗
PubMed2026

Identification and genetic validation of potential therapeutic targets for pulmonary hypertension through multi-omics causal inference.

Pulmonary hypertension (PH) underscores the urgent need for novel therapeutic targets. This study aimed to employ a proteome-wide Mendelian randomization (MR) approach to systematically identify circulating proteins causally associated with PH, thereby providing genetically validated candidate targets for drug development. We adopted a 2-sample MR design, integrating large-scale plasma proteomic quantitative trait loci (pQTL) data (encompassing 4148 proteins) and summary statistics from a large-scale PH genome-wide association study (2047 cases, 8301 controls). Candidate targets were screened through a multilayered analytical pipeline comprising proteomic MR, transcriptomic MR, and summary-data-based Mendelian randomization. The ultimately identified MR-Identified Causal Candidate Targets (MR-ICTs) underwent rigorous Bayesian colocalization analysis, followed by biological characterization through functional enrichment analysis, single-cell transcriptomics, and phenome-wide association studies. Through robust genetic causal inference, this study provides that circulating proteins such as LYZ, GREM2, NID1, and PF4V1 play causal roles in PH pathogenesis. These findings offer a set of rigorously genetically validated, high-priority therapeutic targets for developing novel PH treatments, specifically addressing key pathological mechanisms such as innate immunity, BMP signaling pathway dysregulation, and platelet activation. Our multi-dimensional analysis ultimately identified 6 MR-ICTs causally associated with PH. Notably, the causal associations for lysozyme C (LYZ), gremlin-2 (GREM2), nidogen-1 (NID1), and platelet factor 4 variant 1 (PF4V1) were stringently validated by Bayesian colocalization analysis (posterior probability for hypothesis 4 [PPH4], indicating a shared causal variant, > 0.99). Functional enrichment analysis revealed significant involvement of these targets in immune response and TGF-β signaling pathways. Single-cell analysis further elucidated their cell-type-specific expression, with LYZ predominantly expressed in monocytes and PF4V1 almost exclusively in platelets.

Hypertension, Pulmonary↗
PubMed2026

Integrative cross-tissue transcriptome-wide association and metabolomic analysis reveals novel genetic risk loci for aortic aneurysm.

BACKGROUND: Aortic aneurysm (AA) is a life-threatening cardiovascular condition with a strong genetic component, however, its molecular mechanisms remain poorly understood. Although genome-wide association studies (GWAS) have identified numerous risk loci, most prior studies have investigated genetic and metabolic factors separately, leaving the causal pathways from genetic variants to disease largely unexplored. METHODS: We established an integrative framework combining cross-tissue transcriptome-wide association studies (TWAS) with metabolomic mediation analysis. First, we integrated GWAS data from FinnGen R12 with multi-tissue expression quantitative trait loci (eQTL) data from Genotype-Tissue Expression Project (GTEx) V8, then performed cross-tissue TWAS using the Unified Test for MOlecular SignaTures (UTMOST) and single-tissue validation with the Functional Summary-based Imputation (FUSION) to prioritize susceptibility genes. Second, we applied Mendelian randomization (MR), colocalization, and Fine-mapping Of CaUsal gene Sets (FOCUS) to assess causality and identify high-confidence genes. Third, we performed metabolite mediation analysis to uncover metabolic pathways linking genetic variants to disease risk. Finally, we validated key findings in mouse models of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) and Western blotting. RESULTS: We identified multiple novel susceptibility genes for AA and its subtypes. Key genes included ADH family members (ADH1A, ADH1B, ADH4, ADH6) and ZNF827, which showed cross-subtype associations with strong colocalization evidence in vascular tissues. Metabolite mediation analysis revealed significant pathways involving N-acetylphenylalanine and methionine sulfoxide. Functional enrichment revealed distinct biological mechanisms: AA and AAA were primarily associated with metabolic pathways, whereas TAA-related genes were enriched in developmental and contractile processes. PheWAS indicated no significant off-target associations. Critically, experimental validation in mouse models confirmed significant upregulation of ZNF827 in TAA and ADH6 in AAA at both mRNA and protein levels, corroborating the genetic predictions. CONCLUSION: This integrated cross-omics analysis identifies novel genetic loci and, crucially, uncovers specific nutrient-related metabolic pathways that mediate genetic risk. These findings provide a mechanistic basis for future nutritional and metabolic intervention studies in AA and its subtypes.

MAGMA↗
PubMed2004

Genetic alterations and DNA repair in human carcinogenesis.

A causal association between genetic alterations and cancer is supported by extensive experimental and epidemiological data. Mutational inactivation of tumor suppressor genes and activation of oncogenes are associated with the development of a wide range of cancers. The link between mutagenesis and carcinogenesis is particularly evident for cancers induced by chemical exposures, which, in some cases, lead to characteristic patterns of mutations. These "genotoxic," direct-acting carcinogens form covalent adducts with DNA, which cause mutations during DNA replication. The link between mutagenesis and carcinogenesis is also supported by the observation that DNA repair defects are associated with an increased cancer risk. Normally, DNA repair mechanisms serve to suppress mutagenesis by correcting DNA damage before it can lead to heritable mutations. It has been postulated that mutagenesis plays a role in both the initiation phase and the progression phase of carcinogenesis, and that an essential step in the carcinogenic process is the development of a mutator state in which the normal cellular processes that suppress mutagenesis become compromised. Given the link between mutations and cancer, attempts have been made to use the mutational profile of cancer cells as an indicator of the causative agent. While this may be a valid approach in some cases, it is complicated by the role of endogenous processes in promoting mutagenesis. In addition, many important carcinogenic agents may enhance mutagenesis indirectly through suppression of DNA repair functions or stimulation of inappropriate cell proliferation. Epigenetic phenomena may also suppress gene expression without causing overt changes in DNA sequence.

Animals↗
PubMed1999

Genetic epidemiology of single-nucleotide polymorphisms.

On the causal hypothesis, most genetic determinants of disease are single-nucleotide polymorphisms (SNPs) that are likely to be selected as markers for positional cloning. On the proximity hypothesis, most disease determinants will not be included among markers but may be detected through linkage disequilibrium with other SNPs. In that event, allelic association among SNPs is an essential factor in positional cloning. Recent simulation based on monotonic population expansion suggests that useful association does not usually extend beyond 3 kb. This is contradicted by significant disequilibrium at much greater distances, with corresponding reduction in the number of SNPs required for a cost-effective genome scan. A plausible explanation is that cyclical expansions follow population bottlenecks that establish new disequilibria. Data on more than 1,000 locus pairs indicate that most disequilibria trace to the Neolithic, with no apparent difference between haplotypes that are random or selected through a major disease gene. Short duration may be characteristic of alleles contributing to disease susceptibility and haplotypes characteristic of particular ethnic groups. Alleles that are highly polymorphic in all ethnic groups may be older, neutral, or advantageous, in weak disequilibrium with nearby markers, and therefore less useful for positional cloning of disease genes. Significant disequilibrium at large distance makes the number of suitably chosen SNPs required for genome screening as small as 30,000, or 1 per 100 kb, with greater density (including less common SNPs) reserved for candidate regions.

Case-Control Studies↗
PubMed2004

Genetic and functional confirmation of the causality of the DGAT1 K232A quantitative trait nucleotide in affecting milk yield and composition.

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait nucleotide underlying a quantitative trait locus (QTL) affecting milk fat composition, previously mapped to the centromeric end of bovine chromosome 14. We herein generate genetic and functional data that confirm the causality of the DGAT1 K232A mutation. We have constructed a high-density single-nucleotide polymorphism map of the 3.8-centimorgan BULGE30-BULGE9 interval containing the QTL and show that the association with milk fat percentage maximizes at the DGAT1 gene. We provide evidence that the K allele has undergone a selective sweep. By using a baculovirus expression system, we have expressed both DGAT1 alleles in Sf9 cells and show that the K allele, causing an increase in milk fat percentage in the live animal, is characterized by a higher Vmax in producing triglycerides than the A allele.

Acyltransferases↗
PubMed2004

Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations.

Given the myriad of age-related changes and the many proposed mechanistic theories of ageing, a major problem in gerontology is distinguishing causes from effects. This review aims to identify and evaluate those mechanisms which have gathered experimental support in favour of seeing them as a cause rather than an effect of ageing. Recent results related to energy metabolism and ageing, the free radical and the DNA damage theories of ageing are reviewed and their predictions evaluated through a systems biology rationale. Crucial in this approach are genetic manipulations in animal models that enable researchers to discriminate causes from effects of ageing and focus on the causal structure of human ageing. Based on a system-level interpretation, the GH/IGF-1 axis appears the most likely explanation for caloric restriction and a possible causal mechanism of human ageing. Although much work remains to fully understand the human ageing process, there is little evidence that free radicals are a causal factor in mammalian ageing, though they may be involved in signalling pathways related to ageing. On the other hand, studying how the DNA machinery affects ageing appears a promising avenue for disclosing the human ageing process.

Aged↗
PubMed1986

Palatal width growth rates as the genetic determinant of cleft palate induced by vitamin A.

While many studies have demonstrated sexual dimorphism and racial variation (Mongoloid greater than Caucasian greater than Black) in the incidence of palatal clefting, only generalized statements have been made concerning the causal mechanism (eg, "genetic propensity"). The present study tests the hypothesis that the more rapid the growth rate of the width of the facial skeleton, the higher the incidence of palatal clefting, given a uniform environmental insult. Two strains of pregnant rats with differing rates of craniofacial development (Wistar-fast and Sprague-Dawley-slow) were injected prenatally with high doses of vitamin A (300,000 IU/kg) on days 10-13 gestation. Fetuses were examined at 20 d prenatally and the incidence of palatal clefting was recorded. A significantly higher (P less than .05) incidence of palatal clefting was noted in the more rapidly developing strain (66% vs 81%). These results support statements by Fraser and others who suggest that head width and palatal clefting are causally related. The "genetic propensity" in this case, then, is the rate of palatal width development.

Aging↗
PubMed2026

Genetic evidence links hypertension to accelerated brain aging.

Hypertension affects one-third of adults and is a major comorbidity of neurocognitive disorders. The causal relationship, shared genetic architecture, and upstream mechanisms linking hypertension to brain aging remain unclear. Hypertension GWAS datasets from MVP and FinnGen R12 were meta-analyzed as the exposure, and a European-ancestry brain age gap (BAG) GWAS derived from the UK Biobank and LIFE-Adult cohorts was used as the outcome. MR and GSMR assessed causality. LDSC, HDL, and S-LDSC estimated genetic correlation. Four TWAS methods (MAGMA, FUSION, JTI-PrediXcan, FOCUS) mapped associations to genes, followed by SMR for causal validation and PoPS for prioritization. GSMAP with spatial transcriptomics characterized regional and cell-type enrichment. Hypertension and brain aging were genetically correlated, and MR and GSMR analyses suggested a causal effect of hypertension on increased brain age gap. TWAS identified 15 shared Hypertension-BAG genes, 10 supported by SMR. PoPS prioritized TRIM47 as the core gene. Shared signals were enriched in meninges, fiber tracts, cortical layer 1, and CA1 stratum lacunosum/radiatum, with cell-type enrichment in meninges, smooth muscle cells, oligodendrocytes, and astrocyte subtypes. Hypertension is genetically correlated with, and shows evidence of a causal effect on, accelerated brain aging. TRIM47 is a core gene bridging hypertension and BAG. GSMAP-based spatial enrichment provides a hypothesis-generating framework for understanding vascular, meningeal, and myelin-related pathways linking hypertension to increased brain age gap.

Humans↗
PubMed2026

Shared genetic architecture and cellular convergence between female reproductive disorders and pulmonary function: a genome-wide cross-trait analysis.

Female reproductive disorders (FRDs), including polycystic ovary syndrome, endometriosis, uterine leiomyomata, and infertility, have been epidemiologically associated with impaired pulmonary function. However, it remains unclear whether this cross-organ link reflects shared genetic etiology and, if so, which cellular mechanisms mediate it. We performed a systematic genome-wide cross-trait analysis of three FRDs and lung function traits (FEV₁, FVC, FEV₁/FVC) using GWAS summary statistics from individuals of European ancestry, integrating genetic correlation, bidirectional causal inference, pleiotropy mapping, and single-cell enrichment analyses. We identified significant negative genetic correlations between FRDs and lung volume traits, most prominently for FVC (rg range: - 0.077 to - 0.178). Bidirectional causal analyses indicated that FRDs have a detrimental effect on lung volume, with higher FRD genetic liability associated with reduced lung volume. Cross-trait meta-analysis identified 17 pleiotropic variants across 11 loci, with the 19q13.2 (LTBP4) and 12q13.13 (HOXC6/HOXC9) loci showing strong evidence of shared causal variants. Critically, single-cell analyses revealed that shared genetic risk converged on mesenchymal lineages across organs, specifically alveolar adventitial fibroblasts in the lung and stromal/smooth muscle cells in the endometrium. Transcriptome-wide analyses further nominated the estrogen-responsive gene RERG as a convergent gene linking these conditions with lung function. Our study revealed a shared genetic architecture between female reproductive disorders and lung function traits, providing a basis for further mechanistic investigations and potential clinical evaluation. Furthermore, our findings suggest that shared fibroproliferative and hormone-responsive pathways may offer insights into the biological mechanisms underlying these conditions.

Female↗
PubMed2026

The causal effect of juvenile idiopathic arthritis on IgA nephropathy: A Mendelian randomization study.

IgA nephropathy (IgAN) has been documented in patients with various comorbidities. Previous observational studies showed an association between juvenile idiopathic arthritis (JIA) and IgAN. The aim of this study was to determine whether there is a causal effect of JIA on the risk of IgAN using a 2-sample Mendelian randomization (MR) approach. A 2-sample MR analysis was conducted to elucidate the potential causal relationship between JIA and IgAN. Summary-level data from genome-wide association studies in the European population were utilized, including IgAN (5556 cases and 21,178 controls) and JIA (3305 cases and 9196 controls). The inverse variance weighted method showed significant evidence of a positive causal relationship between genetically predicted JIA and IgAN. For each standard deviation increase in genetically predicted JIA, the risk of IgAN was found to be increased by 22% (odds ratio [OR] = 1.22, 95% CI: 1.10-1.29, P = 3.03 × 10-4). Similar associations were observed with the weighted median (OR: 1.16, 95% CI: 1.05-1.29) and weighted mode methods (OR: 1.16 95% CI: 1.02-1.33), but not with the simple median (OR: 1.22, 95% CI: 0.99-1.50) and MR Egger method (OR: 1.21, 95% CI: 0.93-1.57). Reverse MR analysis found no inverse causal relationship between these 2 diseases. This study provides genetic evidence supporting a causal link between JIA and an increased risk of IgAN. In JIA patients, periodic evaluation of kidney function and proteinuria is warranted.

Humans↗