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PubMed2000

Polygenic resistance to mouse pulmonary adenomas.

Susceptibility to urethan-induced pulmonary adenomas (PA) in mice is under polygenic control. To analyze these traits in detail, we generated a set of recombinant inbred (RI) mouse strains, called SMXA, from an intercross between PA-susceptible A/J and resistant SM/J, and established a strain distribution pattern (SDP) table of 158 marker loci for SMXA RI strains. From the SDP table, it was possible to estimate the allele for 4 known PA susceptibility (Pas) loci in all members of SMXA RI strains. We compared combinations of Pas loci alleles with the data of number of PA induced by urethan. One of the RI strains, SMXA24, showed extremely low PA numbers, whereas they had the A/J-derived alleles at all 4 Pas loci. F1 hybrids of SMXA24 and A/J developed as few PA as SMXA24 on exposure to urethan. To confirm the hypothesis that SMXA24 has dominant PA resistance gene(s), we examined a backcross generation to A/J for multiplicity of PA. A preliminary genome scan followed by quantitative trait locus analysis revealed two resistance loci, one on mouse chromosome 11 (MMU11) (logarithm of odds [LOD] score 4.35) and another on MMU12 (LOD score 6.47). They were named Par1 and Par3, respectively. Both loci were epistatic to Pas1, the major susceptibility loci on MMU6. We next asked if such dominant resistance loci play some role in human lung cancer by studying possible loss of heterozygosity (LOH) at syntenic chromosomal segments in 79 human lung cancers, including 30 adenocarcinomas, 25 squamous cell carcinomas (SQ), and 24 small cell carcinomas (SCC). The map positions of Par1 and Par3 correspond to human 17q11-23 and 14q11-24. Of 30 adenocarcinomas, LOH was found in 53% at 17q and in 30% at 14q. For both SQ and SCC, LOH in 17q were about 10%, but LOH in 14q was about 30% to 42%. Therefore, a gene in 17q seemed to be selective for adenocarcinomas, probably at the level of the target cell. In contrast, another gene in 14q affected all 3 types of lung carcinomas, suggesting it is related to the progression of lung tumors in general. A comparative approach may provide useful information for understanding human cancers.

Adenocarcinoma↗
PubMedDate not supplied

Genetics of hypertension: lessons learnt from mendelian and polygenic syndromes.

This brief review discusses genetic and genomic aspects of hypertension. A special emphasis is given to currently available strategies for gene identifications, including studies of rare Mendelian hypertension, candidate gene evaluation, genome-wide scans and approaches based on the comparative genome analysis. We also discuss the growing potential for pharmacogenetic approaches and address briefly the issue of genetic testing in complex polygenic traits.

Genomics↗
PubMed1975

Genetic control of macrophage functions. I. Polygenic regulation of phagocytosis stimulation produced by Glyceryl Trioleate.

The phagocytic index K, established from the rate of blood clearance of colloidal carbon, measures the phagocytic activity of RE macrophages in contact with the circulating blood. The intravenous injection of glyceryl trioleate (triolein) produces a marked stimulation of the phagocytic activity of RE macrophages. This response is higher in the female than in the male mice. The phenotypic character "responsiveness of macrophage to triolein" presents large individual variants in population of random bred albinos mice. This character is submitted to polygenic regulation. Starting from a foundation population of 25 males and 25 females random bred albinos, mice, two lines were separated by selective breeding for the character "responsiveness to triolein": a "high" responder line, KTH, and a "low" responder line, KTL. After 26 consecutive generations of selective breeding, KTH mice present a very high response to triolein while KTL mice are almost irresponsive. The heritability of this character (h2) calculated from the interline divergence is of 12% plus or minus 1. This value of h2 indicates that the character investigated is determined by the cumulative effect of a group of about 27 independently segregating loci. The distribution of the character in (KTH plus KTL)F1 and their backcrosses with parental lines suggests that low responsiveness is dominant over high responsiveness. The genetic regulation of responsiveness to triolein is independent from the dose administered. These results are discussed in relation to the importance of genetic factors controlling macrophage functions involved in lipid metabolism and in the specific mechanisms of immunity.

Animals↗
PubMed2002

Polygenic control of human T lymphotropic virus type I (HTLV-I) provirus load and the risk of HTLV-I-associated myelopathy/tropical spastic paraparesis.

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of infection with HTLV-I. A population association study of 229 patients with HAM/TSP and 202 healthy carriers of HTLV-I in southern Japan showed that this outcome of HTLV-I infection and the HTLV-I provirus load are under polygenic control. Of 58 polymorphic sites studied in 39 non-HLA candidate gene loci, 3 new host genetic factors that influenced the risk of HAM/TSP or the provirus load of HTLV-I were identified. The promoter TNF -863A allele predisposed to HAM/TSP, whereas SDF-1 +801A 3'UTR, and IL-15 191C alleles conferred protection. Knowledge of HTLV-I-infected individuals' ages, sex, provirus load, HTLV-I subgroup, and genotypes at the loci HLA-A, HLA-C, SDF-1, and TNF-alpha allowed for the correct identification of 88% of cases of HAM/TSP in this Japanese cohort.

Alleles↗
PubMed2003

Epistasis in polygenic traits and the evolution of genetic architecture under stabilizing selection.

We consider the effects of epistasis in a polygenic trait in the balance of mutation and stabilizing selection. The main issues are the genetic variation maintained in equilibrium and the evolution of the mutational effect distribution. The model assumes symmetric mutation and a continuum of alleles at all loci. Epistasis is modeled proportional to pairwise products of the single-locus effects. A general analytical formalism is developed. Assuming linkage equilibrium, we derive results for the equilibrium mutation load and the genetic and mutational variance in the house of cards and the Gaussian approximation. The additive genetic variation maintained in mutation-selection balance is reduced by any pattern of the epistatic interactions. The mutational variance, in contrast, is often increased. Large differences in mutational effects among loci emerge, and a negative correlation among (standard mean) locus mutation effects and mutation rates is predicted. Contrary to the common view since Waddington, we find that stabilizing selection in general does not lead to canalization of the trait. We propose that canalization as a target of selection instead occurs at the genic level. Here, primarily genes with a high mutation rate are buffered, often at the cost of decanalization of other genes. An intuitive interpretation of this view is given in the discussion.

Epistasis, Genetic↗
PubMed2004

Genetic investigation of quantitative traits related to autism: use of multivariate polygenic models with ascertainment adjustment.

Autism is a severe developmental disorder of unknown etiology but with evidence for genetic influences. Here, we provide evidence for a genetic basis of several quantitative traits that are related to autism. These traits, from the Broader Phenotype Autism Symptom Scale (BPASS), were measured in nuclear families, each ascertained through two probands affected by autism spectrum disorder. The BPASS traits capture the continuum of severity of impairments and may be more informative for genetic studies than are the discrete diagnoses of autism that have been used by others. Using a sample of 201 nuclear families consisting of a total of 694 individuals, we implemented multivariate polygenic models with ascertainment adjustment to estimate heritabilities and genetic and environmental correlations between these traits. Our ascertainment adjustment uses conditioning on the phenotypes of probands, requires no modeling of the ascertainment process, and is applicable to multiplex ascertainment and multivariate traits. This appears to be the first such implementation for multivariate quantitative traits. The marked difference between heritability estimates of the trait for language onset with and without an ascertainment adjustment (0.08 and 0.22, respectively) shows that conclusions are sensitive to whether or not an ascertainment adjustment is used. Among the five BPASS traits that were analyzed, the traits for social motivation and range of interest/flexibility show the highest heritability (0.19 and 0.16, respectively) and also have the highest genetic correlation (0.92). This finding suggests a shared genetic basis of these two traits and that they may be most promising for future gene mapping and for extending pedigrees by phenotyping additional relatives.

Adolescent↗
PubMed2002

Monogene and polygene therapy for the treatment of experimental prostate cancers by use of apoptotic genes bax and bad driven by the prostate-specific promoter ARR(2)PB.

We have shown that adenovirus-mediated manipulation of apoptotic genes such as bax could be a therapeutic option for prostate cancer. Unfortunately, the response of experimental prostate tumors to a single therapeutic gene of the apoptotic pathway is short-lived, and most of these tumors relapse after a short period of time. In this investigation we present data generated with adenovirus AvARR(2)PB-Bad, in which the apoptotic gene bad was placed under the control of the dihydrotestosterone (DHT)-inducible third-generation probasin-derived promoter ARR(2)PB. This therapeutic virus was given alone or in combination with other therapeutic viruses to a variety of in vitro and in vivo experimental models of prostate cancer. On infection with AvARR(2)PB-Bad, DHT-induced Bad overexpression occurred specifically in androgen receptor-positive (AR(+)) cells of prostatic derivation. The apoptotic effect of AvARR(2)PB-Bad (group 1) was compared with that of AvARR(2)PB-Bax (which overexpresses the apoptotic protein Bax) (group 2), with that of the combination AvARR(2)PB-Bad plus AvARR(2)PB-Bax (group 3), and with that of the control virus AvARR(2)PB-CAT (group 4) in the cell line LNCaP. In addition to identifying the modality of apoptosis induction by overexpressed Bad, the results suggested that group 3 contained more apoptotic cells than any other group. In additional studies, AR(+) androgen-dependent LNCaP cells or AR(+) and androgen-independent C4-2 cells were injected subcutaneously into nude mice. Four groups of six LNCaP or C4-2 tumors were treated with the same combinations of viruses discussed above for groups 1, 2, 3, and 4. Treatment resulted in decreased tumor size in groups 1, 2, and 3 compared with group 4. There was a better response in group 3 compared with group 2, and in group 2 compared with group 1. A better response in group 3 was confirmed during a 8-week follow-up period, in which no treatment was administered. Two LNCaP and C4-2 tumors of group 3 disappeared at the end of treatment and did not recur after an 8-week follow-up period. The data suggest that polygene therapy with apoptotic molecules is more effective in experimental models of androgen-dependent or -independent prostate cancer than monogene therapy.

Adenoviridae↗
PubMed2001

Differentiated thyroid carcinoma: a polygenic disease.

Differentiated thyroid cancer is a rare disease and until recently was considered to be sporadic. However, increasing evidence has been found for a genetic basis of this disease. In approximately 5% of patients the differentiated thyroid cancer is dominantly inherited. Several families with different syndromes, of which differentiated thyroid cancer is a feature, have already been described. However, until now, single genes explain only a minority of cases. We hypothesize that differentiated thyroid cancer is a polygenic disease. Data from epidemiologic studies, about occult and multifocal carcinomas and the different response to specific risk factors contribute to this hypothesis.

Carcinoma↗
PubMed2000

Effect of He-Ne laser (632.8 nm) and Polygen on CHO cells.

OBJECTIVE: We determined the effect of He-Ne laser biostimulation in combination with Polygen (PG) on Chinese hamster ovary (CHO) cells. BACKGROUND DATA: Several studies have shown that He-Ne laser (632.8 nm), growth factors, and growth hormone can enhance cellular proliferation and that the use of low-level laser stimulation combined with growth factor stimulation has scientific support. PG, an animal protein extract containing a blend of growth factors and growth hormone, was used together with a He-Ne laser to determine their efficacy in the enhancement of cellular proliferation. METHODS: The dose-response curves for the colony-forming ability of CHO cells in 5% FCS-MEM with 6-125 microg/ml PG and He-Ne laser with an optimum power density of 1.25 mW/cm2 and cumulative doses of 60-600 mJ/cm2 was given for 3 consecutive days. The combined effects of He-Ne laser 180 mJ/cm2 with 6 and 12 microg/ml PG were determined. Quadruplicate cultures were performed. The student's t-test was used to ascertain differences of treated groups from controls. RESULTS: The mean number of colonies (MNC) was increased using 180 mJ/cm2 laser by 13.2% (p < 0.01); 6 and 12 microg/ml PG by 19.2% (p < 0.0025) and 13.2% (p = 0.01); laser + PG 6 microg/ml by 23.2% (p < 0.001) and laser + PG 12 microg/ml by 20.5% (p < 0.001). An additional significant increase of 8.8% (p < 0.05) and an insignificant 6.4% (p = 0.086) by laser + PG 6 microg/ml and laser + PG 12 microg/ml were observed, respectively, when compared to the solitary effect of laser. CONCLUSIONS: Results suggest that the He:Ne laser or PG can stimulate CHO cell proliferation and that further stimulation can be achieved by using the He:Ne laser and PG simultaneously. This combination could be useful as a new treatment modality.

Animals↗
PubMed1996

The pathogenesis of type II diabetes mellitus. A polygenic disease.

Diabetes mellitus is the most common endocrine disease, consuming almost 15% of annual health care expenditures in the United States. The focus of this review is on type II (non-insulin-dependent) diabetes mellitus, which accounts for approximately 90% of diabetic patients. The current understanding of the pathogenesis of type II diabetes is multifaceted. Complex defects in both insulin action and insulin secretion produce the metabolic derangements responsible for the disease. The pathophysiology is the result of a combination of polygene defects and environmental factors. The search for the responsible gene or genes is described and several candidate genes are discussed. Diabetogenes are addressed in the context of type II diabetes representing a prototype for the identification of the genetic basis of common diseases.

Aged↗
PubMed2026

bioETH-PRS: confidential polygenic risk scoring with smart contracts on an FHE-enabled blockchain.

Polygenic risk scores (PRSs) aggregate genetic effect estimates to predict disease susceptibility, yet calculating one through an external service can require exposing raw genotype data. Homomorphic encryption hides those data during the calculation but, in prior work, still places a designated evaluator in a position of trust. We present bioETH-PRS, a protocol that replaces the evaluator with publicly auditable smart contracts on a blockchain supporting Fully Homomorphic Ethereum Virtual Machine (fhEVM). Using integer-exact encrypted arithmetic, bioETH-PRS computes the PRS dot product entirely in the encrypted domain, so genotype dosages and, at the model provider's discretion, the GWAS weights stay hidden from the parties performing the computation. A fixed-point encoding represents signed weights as nonnegative integers within a bound that rules out overflow, recovering the score to the precision of the published weights. A four-contract architecture separates data custody, model publication, computation, and output release, and supports both a classic path that stores encrypted inputs and an appreciably cheaper streaming path that discards them. A release oracle can return a randomized risk category instead of the raw score, limiting what a repeated querier learns. Prototype evaluation on real GWAS fixtures, including a run on a public testnet, shows cost growing linearly with variant count and suggests the approach may be practical where transaction fees are low. Trust is redistributed rather than removed: the system still depends on the contracts, the blockchain, and the fhEVM services. We evaluate additive models of moderate size, not genome-wide or clinical use.

Blockchain↗
PubMed2025

XPRS: a tool for interpretable and explainable polygenic risk score.

SUMMARY: The polygenic risk score (PRS) is an important method for assessing genetic susceptibility to diseases; however, its clinical utility is limited by a lack of interpretability tools. To address this problem, we introduce eXplainable PRS (XPRS), an interpretation and visualization tool that decomposes PRSs into genes/regions and single nucleotide polymorphism (SNP) contribution scores via Shapley additive explanations (SHAPs), which provide insights into specific genes and SNPs that significantly contribute to the PRS of an individual. This software features a multilevel visualization approach, including Manhattan plots, LocusZoom-like plots, and tables at the population and individual levels, to highlight important genes and SNPs. By implementing with a user-friendly web interface, XPRS allows for straightforward data input and interpretation. By bridging the gap between complex genetic data and actionable clinical insights, XPRS can improve communication between clinicians and patients. AVAILABILITY AND IMPLEMENTATION: The XPRS software is publicly available on GitHub at https://github.com/nayeonkim93/XPRS and can see the demo through our cloud-based web service at https://xprs.leelabsg.org/.

Software↗
PubMed2025

Sparse polygenic risk score inference with the spike-and-slab LASSO.

MOTIVATION: Large-scale biobanks, with rich phenotypic and genomic data across hundreds of thousands of samples, provide ample opportunities to elucidate the genetics of complex traits and diseases. Consequently, there is growing demand for robust and scalable methods for disease risk prediction from genotype data. Inference in this setting is challenging due to the high-dimensionality of genomic data, especially when coupled with smaller sample sizes. Popular Polygenic Risk Score (PRS) inference methods address this challenge by adopting sparse Bayesian priors or penalized regression techniques, such as the Least Absolute Shrinkage and Selection Operator (LASSO). However, the former class of methods are not as scalable and do not produce exact sparsity, while the latter tends to over-shrink large coefficients. RESULTS: In this study, we present SSLPRS, a novel PRS method based on the Spike-and-Slab LASSO (SSL) prior, which offers a theoretical bridge between the two frameworks. We extend previous work to derive a coordinate-ascent inference algorithm that operates on GWAS summary statistics, which is orders-of-magnitude more efficient than corresponding individual-level-based implementations. To illustrate the statistical properties of the proposed model, we conducted experiments involving nine simulation configurations and nine quantitative phenotypes from the UK Biobank. Our results demonstrate that SSLPRS is competitive with state-of-the-art methods in terms of prediction accuracy and exhibits superior variable selection performance, especially in sparse genetic architectures. In simulations, this translates to upwards of 50% improvement in positive predictive value. In analysis of real phenotypes, we show that selected variants are highly enriched for meaningful genomic annotations and have better replication rates in larger meta-analyses. AVAILABILITY AND IMPLEMENTATION: SSLPRS is available in the open-source package https://github.com/li-lab-mcgill/penprs.

Multifactorial Inheritance↗
PubMed1984

Evidence for polygenic epistatic interactions in man?

Studies of multifactorial inheritance in man have ignored nonadditive gene action or attributed it entirely to dominance. Reanalyses of dermatoglyphic data on monozygotic and dizygotic twins, siblings and parents and offspring suggest that a substantial proportion of variation in total finger pattern intensity is due to epistatic interactions between additive genetic deviations, not dominance. Bootstrapping and power simulations support this interpretation of the data. We believe this is the strongest evidence so far for polygenic epistasis in man.

Dermatoglyphics↗
PubMed1984

The selective value of alleles underlying polygenic traits.

To define the genetic and ecological circumstances that are conducive to evolution via genetic drift at the allelic level, the selection coefficient for a constituent allele of arbitrary effect is derived for a polygenic character exposed to stabilizing selection. Under virtually all possible conditions, alleles within the class for which the absolute value of the average effect is less than 10(-2) phenotypic standard deviations are neutral with respect to each other. In addition, when the mean phenotype is at the optimum and the genetic variance is in selection-drift-mutation equilibrium, a considerable amount of neutral evolution is expected in the class of alleles with intermediate effects on the phenotype. These results help clarify how molecular evolution via genetic drift may occur at a locus despite intense selection and provide a potential mechanistic explanation for the neutral theory of molecular evolution.

Alleles↗
PubMed1992

Polygenic and single gene responses to selection for resistance to diazinon in Lucilia cuprina.

Following mutagenesis with ethyl methanesulfonate, selection in a susceptible strain with a concentration of the insecticide diazinon (0.0004%, w/v) above that required to kill 100% of the susceptible strain, the LC100 of that strain, resulted in a single gene response. The resultant four mutant resistant strains have equivalent physiological, genetical and biochemical profiles to a diazinon-resistant strain derived from a natural population and homozygous for the Rop-1 allele. Modification of the microsomal esterase E3 is responsible for resistance in each case. The Rop-1 locus maps approximately 4.4 map units proximal to bu on chromosome IV. Selection within the susceptible distribution, at a concentration of diazinon [0.0001% (w/v)] less than the LC100, resulted in a similar phenotypic response irrespective of whether the base population had been mutagenized. The responses were polygenically based, unique to each selection line and independent of Rop-1. The relevance of the results to selection for insecticide resistance in laboratory and natural populations is discussed.

Animals↗
PubMed1994

Genetic and statistical analyses of strong selection on polygenic traits: what, me normal?

We develop a general population genetic framework for analyzing selection on many loci, and apply it to strong truncation and disruptive selection on an additive polygenic trait. We first present statistical methods for analyzing the infinitesimal model, in which offspring breeding values are normally distributed around the mean of the parents, with fixed variance. These show that the usual assumption of a Gaussian distribution of breeding values in the population gives remarkably accurate predictions for the mean and the variance, even when disruptive selection generates substantial deviations from normality. We then set out a general genetic analysis of selection and recombination. The population is represented by multilocus cumulants describing the distribution of haploid genotypes, and selection is described by the relation between mean fitness and these cumulants. We provide exact recursions in terms of generating functions for the effects of selection on non-central moments. The effects of recombination are simply calculated as a weighted sum over all the permutations produced by meiosis. Finally, the new cumulants that describe the next generation are computed from the non-central moments. Although this scheme is applied here in detail only to selection on an additive trait, it is quite general. For arbitrary epistasis and linkage, we describe a consistent infinitesimal limit in which the short-term selection response is dominated by infinitesimal allele frequency changes and linkage disequilibria. Numerical multilocus results show that the standard Gaussian approximation gives accurate predictions for the dynamics of the mean and genetic variance in this limit. Even with intense truncation selection, linkage disequilibria of order three and higher never cause much deviation from normality. Thus, the empirical deviations frequently found between predicted and observed responses to artificial selection are not caused by linkage-disequilibrium-induced departures from normality. Disruptive selection can generate substantial four-way disequilibria, and hence kurtosis; but even then, the Gaussian assumption predicts the variance accurately. In contrast to the apparent simplicity of the infinitesimal limit, data suggest that changes in genetic variance after 10 or more generations of selection are likely to be dominated by allele frequency dynamics that depend on genetic details.

Fourier Analysis↗
PubMed1995

Non-locus-specific polygenes giving responses to selection for gene conversion frequencies in Ascobolus immersus.

Selection for higher and lower meiotic conversion frequencies was investigated in the fungus Ascobolus immersus. Strains carrying the same known gene conversion control factors, which have major effects on conversion frequencies at their specific target locus, sometimes gave significant differences in conversion frequency. Selection for high or low conversion frequencies at the w1-78 site was practiced for five generations, giving significant responses in both directions. These responses were due to polygenes, or genes of minor effect, not to new conversion control factors of major effect. Crosses of selected strains to strains with other mutations showed that the genes' effects were not specific to w1-78, but could affect conversion frequencies of another mutation, w1-3C1, at that locus and of two other loci, w-BHj and w9, which are unlinked to w1 or to each other. The proportional changes in gene conversion frequency due to selection varied according to the locus and site involved and according to the conversion control factor alleles present. There were differences of > or = 277% in conversion frequency between "high" and "low" strains. Selection for conversion frequency had little effect on other features of conversion, such as the frequency of postmeiotic segregation or the relative frequencies of conversion to mutant or wild type.

Alleles↗