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At least 55 records · Page 3Linked to original sources
PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

Aged↗
PubMed2026

Polygenic Risk Identifies Older Adults Who May Benefit From Aspirin for the Primary Prevention of Ischemic Stroke.

BACKGROUND: Low-dose aspirin is no longer recommended for routine primary prevention in older adults due to bleeding risks outweighing vascular benefits. We hypothesized that an integrative polygenic score (iPGS) could identify a subgroup of older individuals who derive net benefit from aspirin for the primary prevention of ischemic stroke. METHODS: We performed post hoc analysis of the ASPREE randomized, placebo-controlled trial (Aspirin in Reducing Events in the Elderly) of daily 100-mg aspirin, in 12 031 genotyped participants of European ancestry aged >70 years without prior cardiovascular disease. The iPGS was derived from >1.2 million variants and evaluated both continuously and by quintiles. Cox models assessed associations between polygenic risk, ischemic stroke, and major bleeding events, and tested the interaction between the iPGS and treatment allocation, with adjustment for baseline lifestyle and clinical covariates. RESULTS: The mean age of participants was 75.1 years, and 54.9% were women. Over a median of 4.6 years, 187 ischemic strokes and 373 major bleeds occurred, including 101 intracranial bleeds (46 hemorrhagic strokes). Each 1-SD increase in the iPGS was associated with higher incident ischemic stroke risk (hazard ratio, 1.39 [95% CI, 1.20-1.62]). An interaction between the continuous iPGS and aspirin allocation was observed for ischemic stroke (P=0.04) but not major bleeding. In the highest iPGS quintile, aspirin reduced ischemic stroke by 51% (hazard ratio, 0.49 [95% CI, 0.28-0.85]) without significantly increasing major bleeding (hazard ratio, 1.15 [95% CI, 0.71-1.88]). No benefit was observed in the overall cohort or in lower-risk quintiles. CONCLUSIONS: Among older adults, high polygenic risk identifies individuals who may experience substantial stroke reduction with aspirin, with no excess bleeding. These findings raise the possibility that genomic risk stratification may enable targeted aspirin use for the primary prevention of ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Humans↗
PubMed1985

Segregation analysis of dopamine-beta-hydroxylase (DBH) and catechol-O-methyltransferase (COMT): identification of major locus and polygenic components.

Enzymes of catecholamine metabolism, plasma dopamine-beta-hydroxylase (DBH), and erythrocyte catechol-O-methyltransferase (COMT) were each previously shown to be transmitted as single codominant loci in a sample of approximately 30 multigenerational families that were analyzed with the single major locus model. Here, both major locus and polygenic hypotheses are tested by applying the mixed model of analysis to the identical samples, after breaking the families into two-generation units. For plasma DBH, the most parsimonious model is a dominant major locus (ie, high values dominant to low values) accounting for 41% of the variance and a polygenic component accounting for 25% of the variance. For erythrocyte COMT, the most parsimonious model is a dominant major locus accounting for 56% of the variance and a polygenic component accounting for 27% of the variance. The major locus for COMT has been supported by previous biochemical studies. The major locus for DBH is supported by the finding from our previous study of possible linkage to the ABO locus. Further biochemical and molecular genetic investigations are needed to better define the genetic loci determining the activity of these enzymes.

Catechol O-Methyltransferase↗
PubMed1998

Complex traits and polygenic inheritance in the mouse.

Polygenic inheritance has recently become an increasingly active field of research due to the availability of techniques allowing in-depth screening of genetic markers across the entire genome. The mouse is being used both in its own right and as a model system for certain human traits. The advantages and disadvantages of the mouse for such studies are outlined and in this context, the adequacy of the mouse as a model for polygenic traits in humans is discussed. A detailed overview of the approaches and methods used in the analysis of polygenic inheritance in the mouse is presented.

Animals↗
PubMed1982

Evidence for distinct polygenic regulation of antibody responses to some unrelated antigens in lines of mice selected for high or low antibody responses to somatic antigen of Salmonella.

The effect of the selective breeding of mice for high or low antibody production to complex immunogens is largely "nonspecific", since it modifies the responsiveness of high (H) and low (L) lines to many antigens unrelated to the selection antigen. However, the nonspecific effect of the polygenic control operating in these lines is not a general feature. For example, the group of genes in selection IV, carried out for responsiveness to somatic antigen of Salmonella, does not modify the responses to sheep erythrocytes (SE). Despite equivalent responses in H and L mice of selection IV, a large variability was found in individual responses of F2 interline hybrids, which demonstrates the presence of alleles with high or low effect on responses to SE. A selective breeding (Selection IV-A) was therefore initiated from this F2 population for responsiveness to SE.A progressive interline divergence occurred during the first seven generations of selection; the interline separation was due to polygenic regulation (about four independent loci from a preliminary estimate). Equivalent responses to the s antigen of Salmonella are observed in the two lines. This constitutes additional evidence for distinct polygenic regulation of responses to SE and to somatic antigen. Moreover, the pattern of responses to several unrelated antigens (nonspecific effect) also differs between Selections IV and IV-A.

Animals↗
PubMed1993

Selective breeding, congenic strains, and other classical genetic approaches to the analysis of alcohol-related polygenic pleiotropisms.

Dimensions of behavioral sensitivities to alcohol in mice are under control of polygenic systems of relatively small size. The mode of inheritance of these phenotypes is frequently additive, with no evidence of dominance, epistasis, or sex linkage. The utility of classical breeding methodologies, such as selection, for assessment of genetic correlations is reviewed. A distinction is drawn between pleiotropisms in these polygenic systems, and the statistical concept of a genetic correlation. Development of congenic strains is argued to be a powerful alternative methodology, heretofore unused in alcohol pharmacogenetics. Using the phenotype of behavioral activation produced by a low dose of ethanol, we describe the production of an activated congenic strain on the non-activated background of the C57BL/6 mouse strain. Through five generations of repeated backcrossing, from a genetically heterogenous stock, "activational" alleles are being successfully transferred to the C57BL/6 background. Theoretical issues in the creation of congenic strains in potentially polygenic systems are covered, including number of effective loci and heritability.

Alcohol Drinking↗
PubMed2006

Tomato defense to the powdery mildew fungus: differences in expression of genes in susceptible, monogenic- and polygenic resistance responses are mainly in timing.

Oidium neolycopersici is a causal agent of tomato powdery mildew. In this paper, gene expression profiles were investigated of susceptible, monogenic- and polygenic resistant tomato genotypes in response to O. neolycopersici infection by using cDNA-AFLP. Around 30,000 TDFs (Transcript Derived Fragments), representing approximately 22% of the transcriptome based on in silico estimation, were identified and 887 TDFs were differentially expressed (DE-TDFs) upon inoculation with O. neolycopersici spores. Forty-two percent of the identified DE-TDFs were detected in both the compatible and incompatible interactions, a subset of these were studied for their temporal patterns. All of these common induced DE-TDFs displayed an expression peak at 7 days post incoluation in monogenic resistant response but sustained up-regulation in the susceptible and the polygenic resistant response. While more than half of these common DE-TDFs showed earlier timing in incompatible interactions compared to compatible interaction. Only 2% of the identified DE-TDFs were specific to either the monogenic or the polygenic resistant response. By annotation of the 230 sequenced DE-TDFs we found that 34% of the corresponding transcripts were known to be involved in plant defense, whereas the other transcripts played general roles in signal transduction (11%), regulation (24%), protein synthesis and degradation (11%), energy metabolism (12%) including photosynthesis, photorespiration and respiration.

Base Sequence↗
PubMed2026

Advancing genetic evaluation of milk yield and composition using a genomic-polygenic model in smallholder dairy cattle farms in Thailand.

Improving the accuracy of genetic evaluation in smallholder dairy systems is essential for sustainable productivity. However, traditional polygenic models (PM) are often constrained by incomplete pedigree, heterogeneous management, and limited genotyping resources. This study evaluated a genomic-polygenic model (GPM) relative to a PM using data from a multibreed dairy population raised under Thai tropical smallholder conditions. Phenotypic records for 305-day milk yield (MY), fat percentage (FP), protein percentage (PP), and somatic cell count (SCC) from 14,417 first-lactation cows across 1,321 farms were analyzed together with genotypes from 5,479 animals generated using GeneSeek Genomic Profiler (GGP) arrays ranging from 9 K to 150 K SNPs. Both models included herd-year-season of calving, age at first calving, and heterosis as fixed effects, and additive genetic and residual components treated as random. The GPM yielded higher additive genetic variances and heritability estimates and produced more biologically consistent antagonistic correlations among traits than the PM. Prediction accuracy was improved for all animal groups under the GPM, with the largest gain observed in genotyped young sires (18.36%). Pedigree connectedness analysis indicated that genotyping animals with low to moderate relationships enhances accuracy cost-effectively. Despite persistent challenges associated with heterogeneous management and limited pedigree depth, the results demonstrate the practical value of genomic-polygenic evaluation for smallholder multibreed dairy populations in tropical environments.

Animals↗
PubMed1982

The effects of probucol on plasma lipoproteins in polygenic and familial hypercholesterolaemia.

During treatment with probucol at the dose of 1 g per day, the mean reduction in low density lipoprotein (LDL) cholesterol concentration was 11.2% in polygenic hypercholesterolaemia (n = 9) and 9.4% in heterozygous familial hypercholesterolaemia (n = 6). However, there was marked heterogeneity of response: in seven of the patients with polygenic hypercholesterolaemia who had in common moderate elevation of LDL cholesterol (5.3-6.4 mmol/1), the reduction ranged from 13 to 40% (mean, 23%). In two of this group the change in LDL concentration was associated with a decrease in LDL apolipoprotein B synthetic rate. Of the patients with familial hypercholesterolaemia one showed a 33% reduction in LDL cholesterol, and one a 13% reduction. Total high density lipoprotein (HDL) cholesterol concentration tended to decrease during treatment. This reflected a reduction of the cholesterol concentration in the HDL3 subclass; HDL2 cholesterol remaining unchanged. Plasma triglyceride and very low density lipoprotein cholesterol were unaffected by probucol. The drug was well tolerated with only one patient complaining of severe diarrhoea, and two of mild and transient diarrhoea. No clinically significant changes occurred in serial resting electrocardiograms. Thus, probucol appears to be a useful drug for the treatment of most patients with polygenic hypercholesterolaemia, and of some patients with heterozygous familial hypercholesterolaemia.

Adolescent↗
PubMed1987

Simple test of the Multifactorial-Polygenic Model with sex dependent thresholds.

Under the Multifactorial-Polygenic Model, a sex difference in population incidence implies higher risk in relatives of low risk sex probands than in those of high risk sex probands. The relationship between sex ratio in population incidence and expected relative risk (RR) to first-degree relatives of probands of the low risk sex vs the high risk sex under the Multifactorial-Polygenic Model was examined. Five observations were made from this analysis: as the sex ratio increases, the expected RR increases for each combination of incidence and r, the liability correlation between relatives, RRs are higher for low risk sex relatives than for high risk sex relatives at each combination of incidence, r, and sex ratio, the expected RR increases as r increases at each incidence and sex ratio, and variation in population incidence has little effect on RR at a given sex ratio and r, and the expected RRs are small, rarely exceeding two-fold. The quantitative relationship between sex ratio and RR provides the basis for a simple test of the Multifactorial-Polygenic Model when two different sex or severity thresholds can be identified.

Epidemiologic Methods↗
PubMed2006

Palliating the impact of fixation of a major gene on the genetic variation of artificially selected polygenes.

Selective sweeps of variation caused by fixation of major genes may have a dramatic impact on the genetic gain from background polygenic variation, particularly in the genome regions closely linked to the major gene. The response to selection can be restrained because of the reduced selection intensity and the reduced effective population size caused by the increase in frequency of the major gene. In the context of a selected population where fixation of a known major gene is desired, the question arises as to which is the optimal path of increase in frequency of the gene so that the selective sweep of variation resulting from its fixation is minimized. Using basic theoretical arguments we propose a frequency path that maximizes simultaneously the effective population size applicable to the selected background and the selection intensity on the polygenic variation by minimizing the average squared selection intensity on the major gene over generations up to a given fixation time. We also propose the use of mating between carriers and non-carriers of the major gene, in order to promote the effective recombination between the major gene and its linked polygenic background. Using a locus-based computer simulation assuming different degrees of linkage, we show that the path proposed is more effective than a similar path recently published, and that the combination of the selection and mating methods provides an efficient way to palliate the negative effects of a selective sweep.

Computer Simulation↗
PubMed2026

Integrating biological pathway polygenic scores and trauma in psychosis: findings from the EU-GEI study.

Psychotic disorders are complex, multifactorial conditions influenced by both genetic liability and early environmental adversity. Polygenic risk scores (PRSs) derived from genome-wide association studies have shown utility in capturing genetic predisposition, but their biological interpretability remains limited. In this study, we evaluated whether biologically informed pathway-specific polygenic scores (pPGSs) for psychosis, restricted to neurotransmitter-related pathways, could help clarify gene-environment interplay. Using data from 1 192 individuals in the EU-GEI multi-site case-control study, we constructed pPGSs for dopamine, glutamate, GABA, and serotonin systems. We investigated associations between pPGSs and childhood trauma (rGE), their interactions on psychosis risk (GxE), and the influence of the genome-wide psychosis PRS on these relationships. Serotonin, dopamine, and glutamate pPGSs were positively associated with a composite trauma exposure (i.e., abuse and neglect), suggesting shared genetic factors contributing to both psychosis liability and early adversity. Significant negative GxE effects were observed for both dopamine and serotonin pPGSs, indicating that higher trauma exposure diminished the relative influence of genetic liability on psychosis risk. Adjustment for the genome-wide psychosis PRS attenuated most effects, but serotonergic and dopaminergic associations remained robust, supporting pathway-specific contributions beyond general polygenic risk. These findings provide proof-of-concept for the utility of pPGSs in psychiatric research, suggesting both genetic contributions to trauma exposure and GxE effects on psychosis risk. Further research incorporating epigenetic data and longitudinal designs may enhance mechanistic insight and translational potential.

Adult↗
PubMed2025

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities.

Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal ( https://public.cgr.astrazeneca.com/t2d-pgs/v1/ ).

Humans↗
PubMed1998

Polygenic inheritance and micro/minisatellites.

While it has often been stated that the identification of the genes involved in complex polygenic traits may be extremely difficult, the principles learned in the past century about single gene-single disease inheritance may not be relevant to polygenic inheritance. A new paradigm specific to complex disorders may be needed. It is proposed that micro- and minisatellite polymorphisms play a role in the expression of many genes. As a result, these genes exist in the population with many functional alleleomorphic variants. While each variant has only a modest effect on a given phenotype, because the variants are common, and most quantitative traits are controlled by a number of genes, there is a reasonable probability that an individual will inherit a threshold number of functional variants beyond which there is an appreciable effect on the phenotype. Twelve different aspects of such a new model for complex inheritance, some corollary implications, and three examples of its immediate application, are presented with the hope that the model may allow an acceleration of the identification of the genes involved in complex polygenic disorders.

DNA↗
PubMed1985

Detection of simple polygenic segregations in a natural population.

Penetrance frequencies were used to quantify segregating polygenic effects in a natural population of Drosophila melanogaster. When males from a series of 100 isofemale strains were crossed to females from a veinlet (ve) line that had been selected for shortened veins, gaps commonly appeared in the fifth longitudinal (L5) vein in the ve/+ heterozygotes. We were able to assign each strain to one of six significantly different clusters, based upon the pattern of polygenic modifiers of ve dominance segregating in each strain. We conclude that the extensive range of phenotypic variation in vein-forming ability is actually based upon a relatively simple underlying polygenic structure that is consistent with segregation of only a small number of alleles or allele combinations in the wild population.

Journal Article↗
PubMed2004

The maintenance (or not) of polygenic variation by soft selection in heterogeneous environments.

On the basis of single-locus models, spatial heterogeneity of the environment coupled with strong population regulation within each habitat (soft selection) is considered an important mechanism maintaining genetic variation. We studied the capacity of soft selection to maintain polygenic variation for a trait determined by several additive loci, selected in opposite directions in two habitats connected by dispersal. We found three main types of stable equilibria. Extreme equilibria are characterized by extreme specialization to one habitat and loss of polymorphism. They are analogous to monomorphic equilibria in singe-locus models and are favored by similar factors: high dispersal, weak selection, and low marginal average fitness of intermediate genotypes. At the remaining two types of equilibria the population mean is intermediate but variance is very different. At fully polymorphic equilibria all loci are polymorphic, whereas at low-variance equilibria at most one locus remains polymorphic. For most parameters only one type of equilibrium is stable; the transition between the domains of fully polymorphic and low-variance equilibria is typically sharp. Low-variance equilibria are favored by high marginal average fitness of intermediate genotypes, in contrast to single-locus models, in which marginal overdominance is particularly favorable for maintenance of polymorphism. The capacity of soft selection to maintain polygenic variation is thus more limited than extrapolation from single-locus models would suggest, in particular if dispersal is high and selection weak. This is because in a polygenic model, variance can evolve independently of the mean, whereas in the single-locus two-allele case, selection for an intermediate mean automatically leads to maintenance of polymorphism.

Animals↗
PubMed2026

PEStimate: predicting offspring disease risk after polygenic embryo screening.

MOTIVATION: Polygenic embryo screening (PES) is a new, controversial technology, whereby human in vitro fertilization embryos are screened for their genetic risk of complex, polygenic diseases. PES aims to reduce the disease burden in offspring by prioritizing the selection of low-risk embryos. However, given that polygenic diseases are usually late-onset, PES outcomes must be estimated by epidemiological modeling. The liability threshold model has been previously used to predict outcomes. However, predictions rely on complex sets of equations, some of which require numerical integration or simulation. Further, previous models failed to account for the possibility that the selected embryo will not be born. RESULTS: Here, we present PEStimate, a freely available online app for predicting PES outcomes when screening for a single disease. PEStimate predicts the offspring risk with and without PES, as well as generates plots of the risk reduction versus key parameters. Users can adjust the number of available embryos, the live birth rate, the disease prevalence, the accuracy of the genetic risk predictor, the embryo selection method, the genetic risk of parents, and the disease status of parents, siblings, uncles/aunts, and grandparents of the embryos. Our model includes, for the first time, the possibility of embryo implantation failure, showing that risk reductions have been previously overestimated. PEStimate provides geneticists, healthcare professionals, patients, and other stakeholders with a necessary tool for examining the impact of PES and weighing its potential benefits against possible personal and societal harms. AVAILABILITY AND IMPLEMENTATION: PEStimate: https://polygenicembryo.shinyapps.io/pestimate. Source code: https://github.com/Lirazk/PEStimate.

Humans↗
PubMed1991

Evidence for balanced linkage of X chromosome polygenes in a natural population of Drosophila.

Extensive levels of polygenic variation can be maintained in a population without creating a severe segregational load. One way to account for this is that the alleles are arranged on a chromosome so that different regions balance each other phenotypically. To test whether this occurs in a natural population, we isolated ten Drosophila melanogaster X chromosomes and mapped regions of polygenic activity affecting sternopleural bristle number. The chromosomes fell into a small number of groups based upon the similarity of their distributions of polygenic activity. The results are consistent with a model in which a large proportion of the variation can be attributed to a small number of segregating chromosome regions and in which the chromosomes show internal balance.

Animals↗