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PubMed1985

[Genetic aspects of heart and circulatory diseases].

Cardiovascular diseases (CVD) are common, heterogenous and of multifactorial origin with a variety of more or less known environmental risk factors interacting with a certain genetic predisposition. Beside some rare monogenic conditions the hereditary risk factors are polygenic and acting either on a given CVD or again on particular predisposing conditions. This is well known for type II hyperlipoproteinemia, which can be observed as a rare monogenic metabolic disorder or as the more common polygenic variant. The relative proportions of genetic and environmental risk factors for CVD can be estimated only approximately due to the various interactions. The current methods are investigations for a given phenotype (e.g. LDL-cholesterol) in first-degree relatives of index patients and studies of concordance rates in mono- and dizygotic twins. The results of a large number of epidemiological studies are indicating that there is a considerable genetic component in the liability for ischemic heart disorders (especially for cardiac infarction in younger age groups), as well as for essential hypertension.

Adult↗
PubMed2003

Quantitative trait locus analysis of fungal disease resistance factors on a molecular map of grapevine.

A full-sibling F1 population comprising 153 individuals from the cross of 'Regent' x 'Lemberger' was employed to construct a genetic map based on 429 molecular markers. The newly-bred red grapevine variety 'Regent' has multiple field-resistance to fungal diseases inherited as polygenic traits, while 'Lemberger' is a traditional fungus-susceptible cultivar. The progeny segregate quantitatively for resistances to Plasmopara viticola and Uncinula necator, fungal pathogens that threaten viticulture in temperate areas. A double pseudo-testcross strategy was employed to construct the two parental maps under high statistical stringency for linkage to obtain a robust marker frame for subsequent quantitative trait locus (QTL) analysis. In total, 185 amplified fragment length polymorphism, 137 random amplified polymorphic DNA, 85 single sequence repeat and 22 sequence characterized amplified region or cleaved amplified polymorphic sequence markers were mapped. The maps were aligned by co-dominant or doubly heterozygous dominant anchor markers. Twelve pairs of homologous linkage groups could be integrated into consensus linkage groups. Resistance phenotypes and segregating characteristics were scored as quantitative traits in three or four growing seasons. Interval mapping reproducibly localized genetic factors that correlated with fungal disease resistances to specific regions on three linkage groups of the maternal 'Regent' map. A QTL for resistance to Uncinula necator was identified on linkage group 16, and QTLs for endurance to Plasmopara viticola on linkage groups 9 and 10 of 'Regent'. Additional QTLs for the onset of berry ripening ("veraison"), berry size and axillary shoot growth were identified. Berry color segregated as a simple trait in this cross of two red varieties and was mapped as a morphological marker. Six markers derived from functional genes could be localized. This dissection of polygenic fungus disease resistance in grapevine allows the development of marker-assisted selection for breeding, the characterization of genetic resources and the isolation of the corresponding genes.

Chromosome Mapping↗
PubMed2006

The effect of semi-dwarf genes on root system size in field-grown barley.

Root system size (RSS) was measured in 12 diverse barley genotypes and 157 double-haploid lines (DHs), using electric capacitance. The parents of the DHs, Derkado and B83-12/21/5, carry different semi-dwarfing genes, sdw1 and ari-e.GP, respectively. Estimates of RSS were taken in the field thrice during plant development: stem elongation (RSS1), heading (RSS2) and grain filling (RSS3). The 12 barley genotypes were assessed over 3 years and at two or three locations each year; the DH mapping population was assessed at two locations in 2002. Among the 12 barley genotypes, those with the semi-dwarf genes had greater RSS values in all 3 years (28.9, 24.6 and 15.0% in years 1, 2 and 3, respectively) compared to non-semi-dwarf controls. The DH population showed transgressive segregation on both sides of the parent means, indicating polygenic control of RSS. Quantitative trait loci (QTLs) for RSS were found on five of the seven chromosomes: 1H, 3H, 4H, 5H and 7H and these were compared with previously mapped agronomic traits. The TotalRSS QTL on 3H was associated with sdw1 and QTLs for height, plant yield and plant weight. The RSS3 QTL on 5H was associated with ari-e.GP and QTLs for height, plant yield, plant weight, harvest index and tiller number. The RSS3 QTL on 7H was also associated with a TotalRSS QTL and QTLs for plant weight and harvest index. Other RSS QTLs were not associated with any other trait studied. RSS is considered to be a polygenic trait linked to important traits, in particular to yield. The study highlights the effects of semi-dwarfing genes and discusses the potential for breeding for root traits.

Chromosome Mapping↗
PubMed2006

Major gene detection for fusiform rust resistance using Bayesian complex segregation analysis in loblolly pine.

The presence of major genes affecting rust resistance of loblolly pine was investigated in a progeny population that was generated with a half-diallel mating of six parents. A Bayesian complex segregation analysis was used to make inference about a mixed inheritance model (MIM) that included polygenic effects and a single major gene effect. Marginalizations were achieved by using Gibbs sampler. A parent block sampling by which genotypes of a parent and its offspring were sampled jointly was implemented to improve mixing. The MIM was compared with a pure polygenic model (PM) using Bayes factor. Results showed that the MIM was a better model to explain the inheritance of rust resistance than the pure PM in the diallel population. A large major gene variance component estimate (> 50% of total variance), indicated the existence of major genes for rust resistance in the studied loblolly pine population. Based on estimations of parental genotypes, it appears that there may be two or more major genes affecting disease phenotypes in this diallel population.

Basidiomycota↗
PubMed2004

Blood pressure in 15 inbred mouse strains and its lack of relation with obesity and insulin resistance in the progeny of an NZO/HILtJ x C3H/HeJ intercross.

We characterized the systolic and diastolic blood pressures of 10-week-old males from 15 inbred mouse strains and found that blood pressures among strains were continuously distributed and that strain C3H/HeJ had the lowest mean systolic and diastolic pressure (100.5 +/- 3.2 and 66.8 +/- 3.5 mmHg), and a strain with obesity and diabetes, NZO/HILtJ, had the highest (132.4 +/- 3.1 and 86.6 +/- 6.9 mmHg). To understand the relationship of blood pressure with insulin resistance and obesity, we produced F1 and F2 progeny from reciprocal crosses of NZO, the strain with obesity, diabetes, and high blood pressure, and the strain with the lowest blood pressures, C3H/HeJ. Mean systolic pressures of 10-week-old (NZO x C3H)F1 and (C3H x NZO)F1 males were similar to each other (114.9 +/- 3.8 and 117.2 +/- 5.0 mmHg) and were intermediate to those of the parental strains. Systolic pressure of F2 males (n = 223) was distributed normally about the mean, suggesting that blood pressure is a polygenic trait. The body mass index (BMI) and plasma insulin levels of F2 progeny correlated significantly and positively with plasma leptin levels, suggesting that obesity is associated with insulin resistance. In contrast, systolic pressure did not correlate with BMI, plasma leptin levels, and plasma insulin levels, suggesting that genes underlying the development of hypertension in this intercross are not associated with the development of obesity and insulin resistance. Our results demonstrate that the progeny of NZO and C3H intercrosses are a practical and powerful tool for identifying blood pressure genes and for understanding human polygenic hypertension.

Animals↗
PubMed1996

Sensitivity to dietary obesity linked to a locus on chromosome 15 in a CAST/Ei x C57BL/6J F2 intercross.

Details of a new model of diet-dependent polygenic obesity are presented. CAST/Ei (Mus m. castaneus) mice remain lean after 12 weeks on a high-fat (32 kcal% fat) diet, while C57BL/6J mice become obese. The genes responsible for the obesity segregate in an F2 population derived from an intercross between CAST/Ei and C57BL/6J mice. Quantitative trait analysis, with simple sequence length polymorphisms (SSLPs) at loci previously linked to rodent obesities, identified a quantitative trait locus (QTL) on Chromosome (Chr) 15, accounting for approximately 9% of the variance in adiposity and 14% of the variance in mesenteric depot size. This locus appears to be at the same location as the dietary obesity-3 (Do3) locus controlling body fat content, which was previously identified in an F2 population derived from an SWR/J x AKR/J cross. This is also at the same location as the multigenic obesity-4 (Mob4) locus found in BSB mice, which display spontaneous polygenic obesity. Suggestive linkage also was found at loci close to the single gene mutations Ay on Chr 2 and tub on Chr 7.

Adipose Tissue↗
PubMed1996

Complex segregation analysis of non-myoclonic idiopathic generalized epilepsy in families ascertained from probands affected with idiopathic epilepsy with tonic-clonic seizures in Antioquia, Colombia.

In an attempt to identify the possible role of major genes, multifactorial inheritance, and cohort effects in the susceptibility to idiopathic epilepsy with generalized tonic-clonic seizures of the awakening type (GTCS), complex segregation analysis was performed in 196 nuclear families ascertained through affected probands with idiopathic epilepsy with GTCS belonging to the Paisa community of Antioquia (Colombia). Models postulating no transmission, single major locus (dominant and recessive) only, and multifactorial component only, were rejected. Since the codominant single major locus model could not be rejected and models that assign no major locus to transmission, no polygenic component to transmission, and no transmission of the major effect were rejected, complex segregation analysis suggested that a major autosomal codominant allele together with a multifactorial component (mixed model) best explained clustering of idiopathic epilepsy with GTCS in families of the Paisa community. The deficit of transmission of heterozygotes (0.17) is compatible with the existence of epistasis acting on a major gene whose frequency was estimated to be 0.0211. Its transmission variance accounts for 81% of the susceptibility to idiopathic epilepsy with GTCS. The complementary variance (19%) is due to the polygenic component.

Alleles↗
PubMed2003

The genetics of primary Sjögren's syndrome.

Primary Sjögren's syndrome is an autoimmune disease characterized clinically by dryness of the eyes and mouth. The use of different classification criteria for primary Sjögren's syndrome has led to dramatically different estimates of prevalence and incidence. Despite this, several genetic and environmental factors are thought to play a role in the susceptibility to primary Sjögren's syndrome, as is the current conceptual formulation of the pathogenesis of many other autoimmune maladies. Primary Sjögren's syndrome appears a complicated polygenic disorder with many genes interacting with environmental factors. Similar to many other polygenic autoimmune rheumatic diseases, human leukocyte antigen associations have been reported and confirmed. Additionally, other non-human leukocyte antigen candidate genes have been reported to reveal association with primary Sjögren's syndrome, but, in general, these effects are not confirmed. The authors review the human leukocyte antigen and non-human leukocyte antigen genetic associations herewith, knowing that new technologies are providing access to the entire genome for association studies. No doubt a much more comprehensive description of the genetics of this disorder will soon emerge.

Genetic Predisposition to Disease↗
PubMed1974

Heritable aspects of anomalous myelinated fibre tracts in the forebrain of the laboratory mouse.

Serial coronal or sagittal sections were stained for myelin and examined in 6 inbred, 4 hybrid, and 2 outbred mouse strains. Absent corpus callosum was seen only in BALB/cJ as reported by Wimer, but a wide range of the size of corpus callosum was also noted. The action of a major gene was not evident in backcross or F2 generations; polygenic and perhaps epistatic inheritance was indicated. In A/J, and to a lesser extent A/HeJ and BALB/cJ, the columns of fornix frequently collided with the anterior commissure and either passed around it to make a normal termination or deflected dorsally to make an abnormal termination in lateral septum. In some BALB/cJ brains the anterior commissure instead was displaced and passed behind or through the columns of fornix. Backcross and F2 data suggested inheritance was polygenic and that genetic variation affected the spatio-temporal coordination of ontogeny of the two tracts. Finally, unusual longitudinal bundles were detected in the septal region of BALB/cJ. Results of crosses were consistent with the hypothesis that a single, incompletely dominant gene was acting, but further study of both the anatomy and heredity of the defect was deemed necessary.

Agenesis of Corpus Callosum↗
PubMed1990

Levamisole resistance in Trichostrongylus colubriformis: a sex-linked recessive character.

Reciprocal crosses between susceptible and levamisole resistant strains of Trichostrongylus colubriformis produced F1 offspring consistent with resistance being inherited as a sex-linked recessive character. The resistance status of the offspring of the backcrosses of the F1 to both parental strains supported this hypothesis. The results are consistent with resistance being controlled by a single gene, or a tightly linked group of genes, but indicate that other autosomal loci have minor effects. The results contrast with the reported observations that resistance to the benzimidazole anthelmintics is polygenic and autosomal. The results are discussed relative to a general evolutionary model for anthelmintic resistance which predicts that selection from the upper extreme of an anthelmintic tolerance distribution results in polygenicity.

Animals↗
PubMed1986

Fluctuating dermatoglyphic asymmetry and the genetics of liability to schizophrenia.

Schizophrenic subjects were compared to normal and psychiatric control subjects for degree of fluctuating asymmetry in two dermatoglyphic traits, a-b ridge count and fingertip pattern. The schizophrenic group exhibited significantly greater fluctuating asymmetry than either control group. Furthermore, indicators of disease severity such as early onset and declining course of illness correlated with degree of asymmetry. Both of these observations are expected if a disorder has a polygenic basis, since fluctuating asymmetry is a marker of polygenic inheritance.

Dermatoglyphics↗
PubMed1989

Fluctuating dermatoglyphic asymmetry in psychotic twins.

Fluctuating asymmetry of bilateral morphological traits is the result of prenatal developmental instability and has been shown to be greater in organisms having more homozygous genotypes (aabb vs. AaBb, for example). This expected increase in fluctuating asymmetry has been found among individuals having a high degree of liability for schizophrenia, as this disorder appears to have a polygenic basis. We tested the additional prediction that the greater genetic liability for schizophrenia necessary for concordance between twins should be associated with greater fluctuating asymmetry in twin pairs in which both twins are mentally ill compared to twin pairs in which one individual is normal. Our analysis of asymmetry for finger ridge counts from fingerprints of concordant and discordant pairs of twins supports this prediction and provides additional indirect support for the roles of polygenic transmission and prenatal epigenetic vulnerability in schizophrenia.

Adult↗
PubMedDate not supplied

Genetic-based differences in neurotensin levels and receptors in brains of LS x SS mice.

Levels of endogenous neurotensin (NT-IR) in the LS x SS RI strains differed by 3.0-, 4.7-, 5.4-, and 6.9-fold in the ventral midbrain (VMB), hypothalamus (HY), nucleus accumbens (NA), and caudate putamen (CP), respectively. Frequency distributions and estimates of the number of genes indicate that differences in NT-IR are polygenically influenced. The NT-IR levels in NA and CP were significantly correlated, but levels in the VMB did not correlate with those in the NA or CP. Specific binding to either low (NTL)- or high (NTH)-affinity receptors as measured in the absence or presence of levocabastine differed significantly in brain regions from among LS X SS mouse strains. Results indicate a polygenic influence mediating the differences in receptor densities and suggest differences in genetic regulation of NTL and NTH receptors.

Animals↗
PubMed1990

Serine proteinase inhibitors on chromosome 14 and the genetics of familial chronic obstructive airways disease.

Environmental and genetic factors contribute to familial chronic obstructive airways disease. The genetic component could be polygenic or in some families be associated with one or two major genes. It is assumed that most cases of familial chronic obstructive airways disease are polygenic, but this conclusion is based on insufficient data. The use of linkage analysis using DNA probes for specific genes that may have a direct role in the disease process should facilitate our understanding of the genetics. Genetic deficiency of alpha1-antitrypsin is associated with predisposition to pulmonary emphysema. In the absence of alpha 1-antitrypsin deficiency I suggest that a study of serine-proteinase inhibitors on chromosome 14 may identify a significant proportion of families where only one major gene is important.

Chromosomes, Human, Pair 14↗
PubMed2006

Fibrinogen and CRP in Israeli families: genetic and environmental sources of concentrations and longitudinal changes.

OBJECTIVE: To estimate the genetic and environmental determinants of plasma fibrinogen and C-reactive protein (CRP). METHODS AND RESULTS: A complex segregation analysis was undertaken in a sample of 142 kindreds residing in Kibbutz settlements in Israel. In addition, included in this analysis were family members who were examined 10 years earlier in the framework of this study. Analysis indicated a major locus in addition to polygenic effect that explained the sex- and age-adjusted levels and longitudinal changes in plasma fibrinogen. A non-transmitted environmental major factor with no polygenic effect explained the adjusted variation in levels and change of CRP. Both the particular genotypes determined by the major genetic factor associated with fibrinogen levels and the particular ousiotypes determined by the major environmental factor associated with CRP levels were sex- and age-dependent. In addition, our results demonstrated significant interactions between polygenotype and gender, age and environmental factors such as smoking and BMI on fibrinogen and CRP levels. CONCLUSIONS: Our models that consider interactions between genotypes and gender, age and environmental exposures have the potential to improve our understanding of the genetics of fibrinogen and CRP levels.

Adult↗
PubMed2004

Inheritable nature of enological quantitative traits is demonstrated by meiotic segregation of industrial wine yeast strains.

Wine yeast strains exhibit a wide variability in their technological properties. The large number of allelic variants and the high degree of heterozygosity explain this genetic variability found among the yeast flora. Furthermore, most enological traits are controlled by polygenic systems presenting complex interactions between the alleles. Taking this into account, we hypothesized that the meiotic segregation of such alleles from a given strain might generate a progeny population with very different technological properties. In this work, a population of 50 progeny clones derived from four industrial wine strains of Saccharomyces cerevisiae was characterized for three major enological traits: ethanol tolerance, volatile-acidity production and hydrogen sulphide production. For this purpose, reliable laboratory fermentation tests were developed in accordance with enological practice. A wide variability in the values of the various parameters was found among spore clones obtained after sporulation. Many clones presenting better aptitudes than the parental strains were obtained. Moreover, analysis of the progeny demonstrated that: (1) traits are in part inheritable; (2) traits are clearly polygenic; (3) broad relations of dominance/recessivity can be established. All these findings constitute an initial step for establishing breeding strategies for wine yeast improvement.

Culture Media↗
PubMed2004

Drosophila, an emerging model for cardiac disease.

A variety of studies that are currently underway may validate the fruit fly as an in vivo model for analyzing genes involved in cardiac function. Many mutations in conserved genetic pathways have been found, including those controlling development and physiology. Because homologous genes control early developmental events as well as functional components of the Drosophila and vertebrate hearts, the fly is the simplest existing model system that can be used to assay genes involved in human congenital heart disease (CHD). The wide variety of genetic tools available to Drosophila researchers offers many technical advantages for rapidly screening through large numbers of candidate genes. Thus, an important future and long-term direction is likely to be the use of Drosophila as a vehicle for analyzing polygenic traits as an aid in human genetics. One can anticipate a time in the not too distant future when mutant lines exist for every gene in vertebrate systems, such as mice and zebrafish. However, one of the enduring problems that will not easily be addressed by such resources will be the tracking of complex traits defined by polygenic variants. For this level of genetic analysis, simple genetic model systems including yeast, Caenorhabditis elegans, and Drosophila melanogaster will undoubtedly play a crucial ongoing role. Of them, Drosophila will be critical for examining gene networks involved in organogenesis and is clearly the system of choice for studying cardiac development, function and aging, since among the simple genetic models it is the only one with a fluid pumping heart.

Animals↗
PubMed2026

Context-specific genetic effects inform endotypes and treatment in asthma.

BACKGROUND: Asthma has heterogeneous risk factors, subtypes, and treatments. It is often unclear how to stratify this heterogeneity in scientific studies and clinical care. Genetics could explain root causes of this clinical heterogeneity, called endotypes, but prior studies have used models that are not designed for complex diseases like asthma. OBJECTIVE: We aimed to find genetic effects that partly explain different asthma endotypes. METHODS: We used recent powerful and robust statistical models of context-specific genetic effects in complex traits. We identified genetic subtypes by clustering clinical asthma features in a case-control cohort, GALA II. We replicated the genetic endotypes in the UK Biobank with gene-context interaction tests. RESULTS: Asthma-associated single nucleotide polymorphisms, polygenic scores, and genome-wide heritability revealed subtype-specific genetic endotypes correlated with type 2 inflammation, allergy, and neuroticism. We validated the type 2 associations with molecular data including nasal RNA sequencing. In the UK Biobank, we replicated these endotypes and found they interact with several polygenic scores and drug-relevant genes. CONCLUSION: Our results show how context-specific genetic effects can unravel biomedically meaningful endotypes of complex disease and suggest novel precision treatment strategies.

Humans↗