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PubMed2026

Comparison of Performance of Publicly Available Polygenic Risk Scores to Predict Clinically Actionable Coronary Artery Calcium Scores: The BioHEART-CT Cohort.

AIM: Coronary artery disease (CAD) remains the leading cause of morbidity and mortality globally. Polygenic Risk Scores (PRS) have been trained against major adverse cardiovascular outcomes (MACE) in large cohorts. Few studies have examined the effectiveness of these CAD MACE PRS tools in detecting individuals with subclinical coronary calcification. An association would provide an opportunity for clinical translation and targeting of CT imaging to new patients at risk for subclinical disease. METHODS: An analysis of 53 publicly available CAD PRS tools was completed in participants of the BioHEART-CT Discovery 1000 cohort presenting for clinically referred CT coronary angiography (CCTA). Associations between PRS and two binary CACS outcomes reflecting clinically significant coronary calcification were assessed: a) Absolute CACS (CACS ≥100 Agatston units [AU]; and b) Percentile CACS (CACS ≥75th age-/sex-adjusted percentile). Models were adjusted for genetic principal components, modifiable cardiovascular risk factors, and age/sex (in Absolute CACS). A subgroup analysis was performed using Framingham Risk Score (FRS) at baseline. RESULTS: Among 803 BioHEART-CT Discovery 1000 participants, 487 (60.6%) had any detectable coronary calcium. Most PRS tools demonstrated significant association with CACS outcomes, particularly evident when PRS was modelled as a continuous predictor. For Percentile CACS, 94.3% of PRS tools were significantly associated after full adjustment (median OR per PRS SD 1.41 (IQR 1.23-1.60). Quintile-based analysis revealed that individuals in the Top Quintile PRS had up to 7.99-fold increased odds of Percentile CACS ≥75th compared to those in the Bottom Quintile. Analysis by FRS group revealed positive performance, especially in individuals of Low FRS wherein incorporating a PRS increased pre-test probability from 14% to 26%. CONCLUSION: Whilst most CAD PRS tools have been developed against clinical events, we show their ability to predict clinically relevant coronary calcification. Utility appears strongest in individuals traditionally considered lower risk, presenting an opportunity for clinical translation for improved diagnosis in the primary prevention setting, with the potential to triage individuals into a CACS screening pathway.

coronary artery disease↗
PubMed2000

Bayesian mapping of quantitative trait loci for complex binary traits.

A complex binary trait is a character that has a dichotomous expression but with a polygenic genetic background. Mapping quantitative trait loci (QTL) for such traits is difficult because of the discrete nature and the reduced variation in the phenotypic distribution. Bayesian statistics are proved to be a powerful tool for solving complicated genetic problems, such as multiple QTL with nonadditive effects, and have been successfully applied to QTL mapping for continuous traits. In this study, we show that Bayesian statistics are particularly useful for mapping QTL for complex binary traits. We model the binary trait under the classical threshold model of quantitative genetics. The Bayesian mapping statistics are developed on the basis of the idea of data augmentation. This treatment allows an easy way to generate the value of a hypothetical underlying variable (called the liability) and a threshold, which in turn allow the use of existing Bayesian statistics. The reversible jump Markov chain Monte Carlo algorithm is used to simulate the posterior samples of all unknowns, including the number of QTL, the locations and effects of identified QTL, genotypes of each individual at both the QTL and markers, and eventually the liability of each individual. The Bayesian mapping ends with an estimation of the joint posterior distribution of the number of QTL and the locations and effects of the identified QTL. Utilities of the method are demonstrated using a simulated outbred full-sib family. A computer program written in FORTRAN language is freely available on request.

Algorithms↗
PubMed2003

Estimating polygenic effects using markers of the entire genome.

Molecular markers have been used to map quantitative trait loci. However, they are rarely used to evaluate effects of chromosome segments of the entire genome. The original interval-mapping approach and various modified versions of it may have limited use in evaluating the genetic effects of the entire genome because they require evaluation of multiple models and model selection. Here we present a Bayesian regression method to simultaneously estimate genetic effects associated with markers of the entire genome. With the Bayesian method, we were able to handle situations in which the number of effects is even larger than the number of observations. The key to the success is that we allow each marker effect to have its own variance parameter, which in turn has its own prior distribution so that the variance can be estimated from the data. Under this hierarchical model, we were able to handle a large number of markers and most of the markers may have negligible effects. As a result, it is possible to evaluate the distribution of the marker effects. Using data from the North American Barley Genome Mapping Project in double-haploid barley, we found that the distribution of gene effects follows closely an L-shaped Gamma distribution, which is in contrast to the bell-shaped Gamma distribution when the gene effects were estimated from interval mapping. In addition, we show that the Bayesian method serves as an alternative or even better QTL mapping method because it produces clearer signals for QTL. Similar results were found from simulated data sets of F(2) and backcross (BC) families.

Bayes Theorem↗
PubMed2004

Polygenic variation maintained by balancing selection: pleiotropy, sex-dependent allelic effects and G x E interactions.

We investigate three alternative selection-based scenarios proposed to maintain polygenic variation: pleiotropic balancing selection, G x E interactions (with spatial or temporal variation in allelic effects), and sex-dependent allelic effects. Each analysis assumes an additive polygenic trait with n diallelic loci under stabilizing selection. We allow loci to have different effects and consider equilibria at which the population mean departs from the stabilizing-selection optimum. Under weak selection, each model produces essentially identical, approximate allele-frequency dynamics. Variation is maintained under pleiotropic balancing selection only at loci for which the strength of balancing selection exceeds the effective strength of stabilizing selection. In addition, for all models, polymorphism requires that the population mean be close enough to the optimum that directional selection does not overwhelm balancing selection. This balance allows many simultaneously stable equilibria, and we explore their properties numerically. Both spatial and temporal G x E can maintain variation at loci for which the coefficient of variation (across environments) of the effect of a substitution exceeds a critical value greater than one. The critical value depends on the correlation between substitution effects at different loci. For large positive correlations (e.g., rho(ij)2>3/4), even extreme fluctuations in allelic effects cannot maintain variation. Surprisingly, this constraint on correlations implies that sex-dependent allelic effects cannot maintain polygenic variation. We present numerical results that support our analytical approximations and discuss our results in connection to relevant data and alternative variance-maintaining mechanisms.

Data Interpretation, Statistical↗
PubMed2002

Evidence for genetic mediation of executive control: a study of aging male twins.

The objective of this study was to investigate the genetic and environmental influences on indexes of executive control in elderly male twins (members of the National Heart, Lung, and Blood Institute Twin Study). Multivariate genetic modeling was applied to performance on four tests: Digit Symbol Substitution, color--word interference, Trail Making B, and verbal fluency. After exclusion of individuals with a positive stroke history, data were available for 80 monozygotic and 78 dizygotic twin pairs of ages 69--80 years. Performance on all measures was adjusted for age and education. Significant genetic and environmental influences to performance on each measure of executive control were identified (range of heritability = 34%--68%). Multivariate analyses revealed that a model with a latent executive control factor most adequately fit the observed covariances on test performance, chi(2)(58, N = 316) = 69.7, p =.14. The shared executive control factor had a heritability of 79% and accounted for 10%--56% of the genetic variance in performance on each of the four tests. Of the 4 tests examined in this analysis, Digit Symbol Substitution appeared to be the marker of executive control with the largest genetic component, whereas verbal fluency stood out as displaying a pattern of genetic and environmental influences distinct from the other 3 measures.

Aged↗
PubMed2001

A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27.

Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of North-Eastern Indian origin including 535 individuals. Families were ascertained through a proband with CHD before 52 years of age and additional sibs with myocardial infarction (MI) or T2DM. Model-free two-point and multipoint linkage analysis were performed using the Mapmarker-Sibs (MLS) and maximum-likelihood-binomial (MLB) programs for autosomal markers and the Aspex program for chromosome X markers. In a second step, additional markers were studied to increase the genetic map density in three regions on chromosomes 3, 8 and 16 where initial indication for linkage was found. Our data show suggestive linkage with CHD on chromosome 16p13-pter with the MLS statistics at 8.69 cM (LOD = 3.06, P = 0.00017) which partially overlaps with a high pressure (HBP) peak. At the same locus, a nominal indication for linkage with T2DM was found in 35 large T2DM Pondicherian families also having Indian origin. With respect to region 8q23, we found suggestive linkage with T2DM (LOD = 2.55, P = 0.00058) as well as with HBP. On 3q27, we replicated previous indication for linkage found in Caucasians (for the metabolic syndrome and for diabetes) according to the categorized trait for CHD and MI with the MLB statistics (LOD = 2.13, P = 0.0009). The genome scan also revealed nominal evidence of linkage with CHD on 10q23 (LOD = 2.06, P = 0.00188). Interestingly, we detected in the same region overlapping linkages with three QTLs: age of onset of CHD (LOD = 2.03), HDL cholesterol (LOD = 1.48) and LDL/HDL ratio (LOD = 1.34). Ordered-subset analysis based on family body mass index ranking replicated finding on 2q37 for T2DM (at Calpain 10 locus). These results show the first evidence for susceptibility loci that predispose to CHD, T2DM and HBP in the context of the metabolic syndrome.

Chromosome Mapping↗
PubMed2002

Anterior segment dysgenesis and the developmental glaucomas are complex traits.

Glaucoma refers to a heterogeneous group of disorders that involve retinal ganglion cell death, optic nerve damage, and loss of visual field. Glaucoma is a leading cause of vision loss worldwide, affecting an estimated 67 million people. Elevated intraocular pressure is a major risk factor for glaucoma. Individuals with malformations of structures of the anterior segment of the eye frequently develop elevated intraocular pressure and glaucoma. In this review, we focus on the developmental glaucomas, the subset of glaucomas associated with anterior segment dysgenesis. To minimize overlap with other reviews in this issue and elsewhere, we highlight the complex, multifactorial nature of these diseases and recent advances using mice.

Animals↗
PubMed2000

Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21.

The positional cloning of multifactorial disease genes is a major challenge in human genetics. We have therefore empirically tested the utility of the available polymorphic microsatellite map to locate the already identified type 1 diabetes locus IDDM1 (sibling risk/population prevalence ratio lambda(s)= 2.7) within a 14 Mb region of chromosome 6p21 linked to disease. In a two-stage approach to fine mapping, linkage was evaluated in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers. The whole 14 Mb showed strong linkage. Then, each marker was analysed for evidence of allelic association, revealing evidence of disease association at one marker located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 markers flanking this marker revealed a highly specific region of 570 kb associated with disease ( P = 7.5 x 10(-35)), which included the HLA class II genes, known to be the primary determinants of IDDM1. The peak of association was as close as 85 kb centromeric of the disease-predisposing class II gene HLA-DQB1. We investigated the importance of the underlying inter-marker linkage disequilibrium, marker informativity and recombination for fine mapping and demonstrate that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. We demonstrate that fine mapping of a multifactorial disease gene is possible with high accuracy even in a region with extraordinary linkage disequilibrium across distances of several Mb. The results will be applicable to association studies of disease loci with lambda(s)values <2.7 except that much larger data sets will be required.

Adolescent↗
PubMed2004

GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies.

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.

Amino Acid Substitution↗
PubMedDate not supplied

Affected sib-pair analysis in endometriosis.

This paper (i) reviews the current clinical and molecular genetic data which strongly suggest that endometriosis has a genetic basis; (ii) outlines the general principles of affected-sib pair analysis; and (iii) describes the Oxford Endometriosis Gene (OXEGENE) Study which aims, using a positional cloning approach, to identify susceptibility genes involved in the development of the disease.

Adult↗
PubMedDate not supplied

Mapping a cave fish genome: polygenic systems and regressive evolution.

We used random amplified polymorphic DNA (RAPD) fingerprinting to generate anonymous DNA markers in the fish Astyanax mexicanus, a species with both surface and cave populations. Surface individuals are eyed and pigmented; troglobitic forms are blind and depigmented. We hybridized surface fish and Pachon population cave fish and produced a RAPD genomic map 1064 cM in length (about half the total length of the genome) that was used to screen for quantitative trait loci (QTL) for troglomorphic traits. Three QTL for reduced eye size, two for decreased numbers of melanophores, two for condition factor, and the locus for the unifactorial trait, albinism, were mapped. These factors account for an average of 46% of the variance in these traits in the backcross. The results are the first direct demonstration that troglomorphic changes in this population are multifactorial. Two closely linked pairs of QTL were found. Each consisted of a regressive and a constructive trait QTL. These close linkages are unlikely to have occurred by chance (P <.05 for each) and suggest that troglomorphic evolution might be facilitated by pleiotropy or by genetic hitchhiking.

Animals↗
PubMed2026

Polygenic and monogenic adaptation drive evolutionary rescue at different magnitudes of environmental change.

Understanding the genetic basis of rapid adaptation is key to predicting species' evolutionary responses to environmental change. However, it is still debatable whether many small-effect mutations or a few large-effect mutations underlie rapid adaptation, and how this knowledge can predict population survival or extinction. To address this question, we performed a series of ecologically grounded forward-in-time genetic simulations to study rapid adaptation and extinction with increasing magnitudes of environmental change. These simulations were seeded with genomic variation of the plant Arabidopsis thaliana to have a realistic genomic structure, with one (monogenic) to 1,000 (polygenic) variants with varying heritabilities contributing to an environmental adaptive trait. Our results revealed two distinct scenarios of rapid adaptation and population rescue. Under small-to-moderate environmental shifts, high polygenic traits increased evolutionary rescue probability. Under extreme environmental shifts, high polygenic traits lead predictably to extinction, yet monogenic traits sometimes produce one-off winning adaptive genotypes. We interpret our rapid evolutionary rescue findings in terms of the fundamental theorem of natural selection, where trait polygenicity shapes the distribution of genetic variance in fitness across replicates and, in turn, the probability of population survival, with polygenic architectures producing more stable and predictable fitness variance and monogenic architectures generating highly skewed and variable outcomes. These results highlight the insights genomics gives us into the (un)predictability of species' evolutionary responses to global change, with management implications for assisted adaptation and conservation.

Arabidopsis↗
PubMed2025

Polygenic risk of coronary artery disease for long-term survivors of breast cancer.

BACKGROUND: Cardiovascular disease is a leading cause of death for long-term breast cancer survivors. We evaluated whether a polygenic risk score for coronary artery disease (CAD-PRS) was associated with the risk of incident CAD for survivors of unilateral or contralateral breast cancer. METHODS: The study included 1307 women with breast cancer first diagnosed at younger than 55&#x2009;years of age who participated in the Women's Environmental&#xa0;Cancer and Radiation Epidemiology Follow-up Study. The CAD-PRS was based on a PRS developed and validated in a separate population. We modeled the association between incident CAD and the CAD-PRS, adjusting for age, CAD risk factors, first (and second) breast cancer treatment, study recruitment phase, and genetic population stratification. We also explored whether the risk of CAD depended on interactions between the CAD-PRS and cardiotoxic cancer treatment. RESULTS: There were 66 incident CAD diagnoses reported at a median of 16&#x2009;years after breast cancer diagnosis. Participants with CAD-PRS&#x2009;at or above the median had a 2.48-times increased risk of CAD (95% confidence interval [CI]&#x2009;=&#x2009;1.44 to 4.29) relative to participants with CAD-PRS&#x2009;below the&#x2009;median. Anthracycline-based chemotherapy was associated with increased CAD risk (hazard ratio [HR]&#x2009;=&#x2009;2.04, 95% CI&#x2009;=&#x2009;1.04 to 3.98), and the association was not modified by the CAD-PRS. The association between incident CAD and left-sided radiation therapy (RT) was increased for those with CAD-PRS&#x2009;at or above the median (HR&#x2009;=&#x2009;2.90, 95% CI&#x2009;=&#x2009;1.26 to 6.68) but not for those with CAD-PRS&#x2009;below the median (HR&#x2009;=&#x2009;0.96, 95% CI&#x2009;=&#x2009;0.32 to 2.88). There was evidence of super-additive interaction between the CAD-PRS and left-sided RT (relative excess risk due to interaction&#x2009;=&#x2009;2.06, 95% CI&#x2009;=&#x2009;0.05 to 4.06). CONCLUSION: A genome-wide CAD-PRS was associated with nonfatal CAD risk for long-term breast cancer survivors, providing potential utility for personalized cardiovascular care, particularly after RT.

Humans↗
PubMed2025

Genome-wide Parallelism Underlies Rapid Freshwater Adaptation Fueled by Standing Genetic Variation in a Wild Fish.

A fundamental focus of ecological and evolutionary biology is determining how natural populations adapt to environmental changes. Rapid parallel phenotypic evolution can be leveraged to uncover the genetics of adaptation. Using population genomic approaches, we investigated the genetic architecture underlying rapid parallel freshwater adaptation of Neosalanx brevirostris by comparing four freshwater-resident populations with their common ancestral anadromous population. We demonstrated that the rapid parallel adaptation to freshwater followed a complex polygenic architecture and was characterized by genomic-level parallelism, which proceeded predominantly through repeated selection on the preexisting standing genetic variations. Frequencies of the genome-wide adaptive standing variations were moderate in the ancestral anadromous population, which had pre-adapted to fluctuating salinities. Relatively large allele frequency shifts were observed at some adaptive single-nucleotide polymorphisms (SNPs) during parallel adaptation to freshwater environments, with a large fraction of freshwater-favored alleles being fixed or nearly fixed. These adaptive SNPs were involved in multiple biological functions associated with osmoregulation, immunoregulation, locomotion, metabolism, etc., which were highly consistent with the polygenic architecture of adaptive divergence between the two ecotypes involving multiple complex physiological and behavioral traits. This work provides insight into the mechanisms by which natural populations rapidly evolve to changes in the environment and highlights the importance of standing genetic variation for the evolutionary potential of populations facing global environmental changes.

Animals↗