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PubMed1998

EMS-induced polygenic mutation rates for nine quantitative characters in Drosophila melanogaster.

Polygenic mutations were induced by treating Drosophila melanogaster adult males with 2.5 mM EMS. The treated second chromosomes, along with untreated controls, were then made homozygous, and five life history, two behavioral, and two morphological traits were measured. EMS mutagenesis led to reduced performance for life history traits. Changes in means and increments in genetic variance were relatively much higher for life history than for morphological traits, implying large differences in mutational target size. Maximum likelihood was used to estimate mutation rates and parameters of distributions of mutation effects, but parameters were strongly confounded with one another. Several traits showed evidence of leptokurtic distributions of effects and mean effects smaller than a few percent of trait means. Distributions of effects for all traits were strongly asymmetrical, and most mutations were deleterious. Correlations between life history mutation effects were positive. Mutation parameters for one generation of spontaneous mutation were predicted by scaling parameter estimates from the EMS experiment, extrapolated to the whole genome. Predicted mutational coefficients of variation were in good agreement with published estimates. Predicted changes in means were up to 0.14% or 0.6% for life history traits, depending on the model of scaling assumed.

Analysis of Variance↗
PubMed1977

Spontaneous and ethyl methanesulfonate-induced mutations controlling viability in Drosophila melanogaster. III. Heterozygous effect of polygenic mutations.

Spontaneous and EMS-induced mutations were accumulated for several generations on the second chromosome of Drosophila melanogaster by keeping this chromosome heterozygous under conditions of minimal natural selection. This article reports studies of heterozygous effects of these mutants.--Both lethal and mildly deleterious mutants have a deleterious heterozygous effect. There was no discernible difference between heterozygotes in which all the mutants were on one chromosome and those where the mutants were distributed over both homologs; thus the coupling-repulsion effect of MUKAI and YAMAZAKI (1964, 1968) is not confirmed. The spontaneous polygenic mutants have a dominance of 0.4 to 0.5, and the same value is found at very low EMS doses. However, the value at higher EMS doses is only about half as high. Since the low doses have a large fraction of spontaneous mutants, the dominance of EMS mutants is less, in the range 0.1 to 0.3, but still larger than for lethals.

Animals↗
PubMed1978

Effect of postweaning feed restriction on adipose cellularity and body compositon in polygenic obese mice.

The M16 line of mice, selected for rapid postweaning gain, exhibits polygenically controlled obesity and hyperphagia. The effect of limiting postweaning energy intake on the subsequent growth and development of obesity in M16 mice was investigated. Male mice from M16 and an unselected line (ICR) were provided either ad libitum or limited (congruent to 70% of ad libitum) feed during the rapid postweaning growth period from 4 to 6 weeks of age. Body weights (g) at 6 weeks of age were: ad libitum ICR (31.0 +/- 0.6), restricted ICR (23.8 +/- 0.7), ad libitum M16 (45.0 +/- 0.6) and restricted M16 (30.1 +/- 0.6). In both lines, restricted feed intake severely depressed body fat, lean, ash, and water at 6 weeks. In addition, percent triacylglycerol, fat cell size and number in the epididymal fat pads were lower. Restricted M16 and ICR mice showed a marked compensatory gain in all body components when subsequently fed ad libitum for 10 weeks. All measurements of adiposity at 16 weeks were similar for the restricted and ad libitum regimens within each line. The relative amounts of energy deposited as fat and lean between 4 and 16 weeks were not influenced by restricted feeding, but M16 mice deposited a larger proportion of energy as fat than as lean when compared with ICR mice. The results suggest that fat cell number is determined at a relatively early age in mice and is primarily under genetic control.

Adipose Tissue↗
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 years of age who participated in the Women's Environmental 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 years after breast cancer diagnosis. Participants with CAD-PRS at or above the median had a 2.48-times increased risk of CAD (95% confidence interval [CI] = 1.44 to 4.29) relative to participants with CAD-PRS below the median. Anthracycline-based chemotherapy was associated with increased CAD risk (hazard ratio [HR] = 2.04, 95% CI = 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 at or above the median (HR = 2.90, 95% CI = 1.26 to 6.68) but not for those with CAD-PRS below the median (HR = 0.96, 95% CI = 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 = 2.06, 95% CI = 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↗
PubMed2004

Inheritance of seed desiccation sensitivity in a coffee interspecific cross: evidence for polygenic determinism.

The genetic determinism of seed desiccation sensitivity was studied using a cross between two coffee species exhibiting a large difference for this trait, Coffea pseudozanguebariae (tolerant) and C. liberica (sensitive). Throughout the whole study, seed desiccation tolerance was quantified both in terms of water content and water activity. Whatever the parameter used, the level of seed desiccation tolerance in F1 hybrids corresponded to that of the mid-parent, thus indicating an additive inheritance of seed desiccation tolerance at the F1 level. A broad variation was observed among hybrids backcrossed to C. liberica (BCs) for seed desiccation tolerance, independent of the parameter used to quantify it. This variation was continuous and BCs showed transgression in the direction of the most desiccation sensitive parent, indicating (i) that desiccation tolerance is a polygenic trait in coffee species, and (ii) that C. pseudozanguebariae does not present the most favourable alleles for all the genes involved in seed desiccation tolerance. No significant difference was observed between the two reciprocal backcrosses, F1xC. liberica and C. libericaxF1, for the level of desiccation tolerance of their seeds, showing the absence of a maternal effect on this trait. There was no significant effect of the number of seeds harvested from each BC on the level of desiccation tolerance of its seeds. Moreover, there was no significant correlation within BCs between seed size, seed viability, and water content before desiccation and desiccation tolerance.

Cell Survival↗
PubMed1981

A genetic analysis of melanoma--polygenic inheritance as a threshold trait.

A total of 214 melanoma patients and 193 age- and sex-matched controls, interviewed at the Roswell Park Memorial Institute during the years 1974--1978, provided information regarding 1134 and 1043 New York State first order relatives (parents, offspring and siblings). The vital information provided was checked against the records of the New York State Tumor Registry to find cases of melanoma among relatives. Five cases of melanoma were found among the 1027 New York State relatives of melanoma index cases alive during the period 1949--1978, inclusive. No cases of melanoma were found among New York State relatives of controls. The expected number of melanomas among a cohort of relatives of identical sex and age composition for the interval was 0.625 cases, giving a ratio of observed to expected of 8.0. A similar analysis, restricted to parent-offspring pairs, yielded a ratio of observed to expected of 12.7. A search for additional melanoma cases among second degree relatives of familial index cases yielded no further affected relatives. The incidence of melanoma among relatives of melanoma cases and in a comparable general population were used to estimate the heritability of liability to melanoma as a polygenic trait. A heritability estimate of 0.49 was obtained, using parent-offspring data, indicating that nearly half of the variability in liability to melanoma in this population may be attributed to the additive action of many genes, each with small effect. Pending the replication of these findings, the 12-fold increase in incidence of melanoma among parents and offspring of melanoma cases suggests the importance of counseling and surveillance of relatives of affected individuals by the clinician.

Adult↗
PubMed1990

A polygenic model for the evolution and maintenance of conditional strategies.

We develop a genetic model for conditional strategies which places such strategies in the context of phenotypic plasticity. The model, which treats conditional strategies as polygenic threshold traits, indicates that, given requisite genetic variation in reaction norms, conditional strategies will evolve to their optimum level and be maintained by stabilizing selection, provided environmental variation results in a fitness trade-off for the alternative conditional phenotypes. The precise value for the evolutionary optimum is found to depend primarily on the probability density function of the environmental variation that influences the production of the conditional phenotypes and the magnitude of the fitness trade-offs of the conditional phenotypes across such environmental variation. The model is tested by application to three well-studied conditional strategies. In each case the predictions of the model are in good agreement with the results of these studies.

Animals↗
PubMed2005

Sex inheritance in gynodioecious species: a polygenic view.

Gynodioecy is defined as the coexistence of two different sexual morphs in a population: females and hermaphrodites. This breeding system is found among many different families of angiosperms and is usually under nucleo-cytoplasmic inheritance, with maternally inherited genes causing male sterility and nuclear factors restoring male fertility. Numerous theoretical models have investigated the conditions for the stable coexistence of females and hermaphrodites. To date, all models rest on the assumption that restoration of a given male sterile genotype is controlled by a single Mendelian factor. Here, we review data bearing on the genetic determinism of sex inheritance in three gynodiecious plant species. We suggest that restoration of male fertility is probably best viewed as a quantitative trait controlled by many loci. We develop a threshold model that accommodates an underlying polygenic trait, which is resolved at the phenotypic level in discrete sexual morphs. We use this model to reanalyse data in Thymus vulgaris, Silene vulgaris and Plantago coronopus. A simple Mendelian inheritance of sex determinism is unlikely in all three species. We discuss how our model can shed additional light on the genetics of restoration and point towards future efforts in the modelling of gynodioecy.

Genotype↗
PubMed2024

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

Journal Article↗
PubMed2025

Polygenic Risk Factors for Comorbid Diagnoses in Individuals with Substance Use Disorders: A Phenome-Wide Survival Analysis.

OBJECTIVE: Persons with substance use disorders (SUD) often suffer from additional comorbidities. Researchers have explored this overlap via phenome wide association studies (PheWAS). However, PheWAS are largely cross-sectional, limiting our understanding of whether diagnoses predate development of an SUD. We characterize whether polygenic scores (PGS) are associated with time to comorbid diagnoses in electronic health records (EHR) after the first documented SUD diagnosis. METHODS: Using data from All of Us (N = 393,596), we explored: 1) whether social determinants of health (SDoH) are associated with lifetime risk of SUD (N cases = 42,568) and 2) within a subset those with a diagnosed SUD and available genetic data SUD (N = 21,357), whether PGS for alcohol use disorders, cannabis use disorders, depression, externalizing, post-traumatic stress disorder, and schizophrenia were associated with subsequent diagnoses via a phenome-wide survival analysis. RESULTS: Multiple SDoH were associated with lifetime SUD diagnosis, with annual household income having the largest overall associations (e.g., <$10K annually vs $100K-$150K annually: OR = 3.89, 95% CI = 3.66, 4.13). There were 101 phenome-wide significant PGS associations with subsequent diagnoses across various bodily systems. PGSs for alcohol use disorders, post-traumatic stress disorder, and schizophrenia were each associated with time to their respective diagnoses. CONCLUSIONS: Social determinants, especially those related to income, have profound associations with lifetime SUD risk. Additionally, PGS for psychiatric conditions are associated with multiple post-SUD diagnoses within those with a SUD, suggesting PGS may capture information beyond lifetime risk, including timing and severity of comorbidities related to SUD.

Journal Article↗
PubMed2025

The impact of polygenic score and socioeconomic status in predicting risk for 19 complex diseases.

Both socioeconomic circumstances and genetic predisposition shape disease risk, yet their joint contribution across diseases has not been systematically examined. We studied 19 high-burden diseases in 743,194 participants (729,928 European; 13,266 non-European ancestry) from FinnGen, the UK Biobank, and Generation Scotland. Higher educational attainment was associated with lower risk of most conditions, but with higher risk of most common cancers. These associations were largely independent of disease-specific polygenic scores (PGSs). For seven out of 19 diseases, PGSs showed stronger effects among individuals with high education. Joint inclusion of education and PGSs modestly improved prediction for 14 and 10 out of 19 diseases in FinnGen and the UK Biobank, respectively. PGS associations were consistent across ancestries, whereas education effects were less stable; results using an alternative socioeconomic measure were directionally similar but smaller. Our findings highlight the distinct and partly interacting contributions of socioeconomic and genetic factors to disease risk.

Journal Article↗
PubMed2025

A multi-ancestry polygenic risk score for Alzheimer disease is associated with cognitive decline, hippocampal atrophy and neuropathological hallmarks in diverse populations.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF A&#x3b2;42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

Journal Article↗
PubMed2005

Polygenic inherited predisposition to breast cancer.

The known breast cancer predisposing genes account for only about 20% of inherited susceptibility. Epidemiological analyses suggest that much of the remaining 80% is explained by the combined effect of many individually weak genetic variants, rather than by further rare, highly penetrant mutations. In the near term, identification of variants may indicate new pathways or mechanisms in breast cancer development. The polygenic model implies a wide distribution of risk in the population. In the longer term, it may be possible to construct individual risk profiles to guide public health interventions. The search for genetic variants has so far proved difficult. A key unanswered question is the "genetic architecture" of predisposition-that is, strong or weak alleles, common or rare. We describe a genome-wide scan designed to provide a first-pass answer to this question.

Alleles↗
PubMed2004

Polygenic control of idiopathic generalized epilepsy phenotypes in the genetic absence rats from Strasbourg (GAERS).

PURPOSE: Generalized nonconvulsive absence seizures are characterized by the occurrence of synchronous and bilateral spike-and-wave discharges (SWDs) on electroencephalographic recordings, concomitant with behavioral arrest. The GAERS (genetic absence rats from Strasbourg) strain, a well-characterized inbred model for idiopathic generalized epilepsy, spontaneously develops EEG paroxysms that resemble those of typical absence seizures. The purpose of this study was to investigate the genetic control of SWD variables by using a combination of genetic analyses and electrophysiological measurements in an experimental cross derived from GAERS and Brown Norway (BN) rats. METHODS: SWD subphenotypes were quantified on EEG recordings performed at both 3 and 6 months in a cohort of 118 GAERS x BN F2 animals. A genome-wide scan of the F2 progenies was carried out with 146 microsatellite markers that were used to test each marker locus for evidence of genetic linkage to the SWD quantitative traits. RESULTS: We identified three quantitative trait loci (QTLs) in chromosomes 4, 7, and 8 controlling specific SWD variables in the cross, including frequency, amplitude, and severity of SWDs. Age was a major factor influencing the detection of genetic linkage to the various components of the SWDs. CONCLUSIONS: The identification of these QTLs demonstrates the polygenic control of SWDs in the GAERS strain. Genetic linkages to specific SWD features underline the complex mechanisms contributing to SWD development in idiopathic generalized epilepsy.

Action Potentials↗
PubMed2004

Adult-onset Alopecia areata is a complex polygenic trait in the C3H/HeJ mouse model.

Alopecia areata (AA) is an autoimmune disease that targets actively growing (anagen) hair follicles in humans and other mammals. C3H/HeJ, but not C57BL/6J, mice spontaneously develop an adult-onset form of AA. A segregating population of C3HB6F2 female mice (n=1096), generated from crossing these two strains, was used for genome-wide linkage analysis to identify AA genetic susceptibility. Previous analysis identified susceptibility intervals on chromosomes 17 (Alaa1) and 9 (Alaa2). Using additional markers in these intervals and saturation mapping purported intervals on chromosomes 8 and 15, two additional regions were identified (Alaa3 and Alaa4, respectively). Human gene association studies identified specific human leukocyte antigen intervals comparable with those (major histocompatibility complex) found in Alaa1 in the mouse. Other human studies identified genes not found in this linkage study, but these human transcription factors are directly regulated by genes within Alaa1. These results indicate the necessity of integrating both gene association and genome-wide linkage studies in both mice and humans to understand the complex nature of these and other polygenic diseases.

Age of Onset↗
PubMed1980

Studies on the genetics of feeding behaviour in the cave fish Astyanax mexicanus f. anoptichthys. An example of apparent monofactorial inheritance by polygenes.

The Mexican characid Astyanax mexicanus gave rise to a series of cavernicolous populations ("Anoptichthys") not earlier than during the Pleistocene age. When searching for food the blind cave fish swims at an angle of about 45 degrees to the ground. The river fish, however, when having no visual information, stands vertically on its head. With the aid of infrared-videorecording and on the basis of crossing experiments it could be demonstrated that this difference in feeding behaviour is controlled by polygenes, although frequency distributions of the crossings suggest an apparent monofactorial inheritance. The evolutionary processes of adaptive reduction of headstanding and of progressive development of the gustatory equipment are genetically independent and both traits have been achieved by small genetic steps.

Animals↗
PubMed1978

A new model for measuring breeding genetic distance. II. Polygenic traits.

The breeding genetic distance measure of a single locus (Carlson & Welch, 1977) is extended to polygenic traits. For two populations with means -x and approximately x, theta(-x, approximately x) is defined as the size of the largest subpopulation with mean approximately x which can be (artificially) selected from a population with mean -x. The distance is defined as 1--theta(-x, approximately x). It is shown that theta(-x, approximately x) can be calculated from truncation selection and formulas (two loci) and tables (three and four loci) are given. Values for theta(-x, approximately x) based on a normal approximation are seen to be adequate for most cases. The measure is applied to a data example (human skin colour) and to a discussion of the idea of 'genetic inertia'.

Gene Frequency↗
PubMed2007

Bypassing of a polygenic Microcyclus ulei resistance in rubber tree, analyzed by QTL detection.

Genetic resistance components of the Hevea brasiliensis x H. benthamiana RO 38 cultivar to Microcyclus ulei disease were investigated by inoculating isolates which succeeded in partially or completely infecting genotypes of a mapping population. Progeny of a cross between RO 38 and a susceptible cultivar was inoculated under controlled conditions with three isolates and scored for two resistance traits. Interval mapping and a nonparametric test were used to detect resistance quantitative trait loci (QTLs). Eight significant QTLs were detected, all of them inherited from the interspecific parent. Among these QTLs, only one contributed to the partial resistance against a highly pathogenic isolate, and no QTL was detected for resistance against the most pathogenic isolate. As an unexpected result, a single isolate can thus completely bypass this polygenic resistance. This complex situation, where no clear relationship can be established between number of resistance factors and qualitative vs quantitative or partial vs complete resistance, is discussed and suggestions as to the detection of new and sustainable resistance sources are proposed.

Ascomycota↗