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PubMed2000

The genetic heterogeneity of "schizophrenia".

The main reason for the inconsistent findings in schizophrenia research is the lack of diagnostic conformity. This has not changed markedly following the introduction of modern operational diagnostic systems. Taking schizophrenia as a disease entity or assuming schizophrenia spectrum psychoses to represent a continuum of diseases without any clear dividing lines, the results of family and twin studies point to a multifactorial etiology based on a polygenic mode of transmission. Further, then it has to be assumed a familial continuum from schizophrenia to affective psychosis and other spectrum disorders. However, in family and twin studies based on Leonhard's classification, there is clearcut evidence that schizophrenic spectrum psychoses have to be divided into clinical and etiological subgroups with a completely different genetic background. For example, systematic catatonia is, for the most part, a sporadic disease, whereas periodic catatonia aggregates in families in a manner consistent with a major gene effect. Further, the results indicate that schizophrenic spectrum psychoses consist of three main valid categories: cycloid psychoses, unsystematic schizophrenias and systematic schizophrenias. In the case of cycloid psychosis and systematic schizophrenias, genetic loading seem to be very low, while "environmental" factors, for example, birth complications, may play an important etiological role. Unsystematic schizophrenias, however, are predominantly inherited and "environmental" factors are not very prominent.

Adult↗
PubMed2003

A multigene test for the risk of sporadic breast carcinoma.

BACKGROUND: Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol-0-methyltransferase gene (COMT), the dopamine D(2) receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR). METHODS: The authors examined 67 women with postmenopausal sporadic breast carcinoma and 145 gender and race-matched controls. RESULTS: Five of these genes accounted for a significant percent of the variance (r(2)) of breast carcinoma. The following r(2) and P values were calculated: LEP: 0.073, P < or = 0.0001; LEPR: 0.064, P < or = 0.0002; COMT: 0.073, P < or = 0.0001; AR: 0.040, P < or = 0.0035; and DRD2: 0.018, P < or = 0.05. When evaluated in a multivariate regression analysis, they accounted collectively for 24% of the variance of breast carcinoma (P < or = 0.0001). These genes accounted for 40% of the variance (P < or = 0.00001) in a subset of age-matched cases. Individual gene scores were added to form a breast carcinoma risk score (BCRS) that ranged from 0 to 17. When the BCRS was evaluated in a receiver operator characteristic plot, the area under the curve was 0.80 for the full set and 0.869 for the age-matched set. The relative breast carcinoma risk for the different BCRS scores ranged from 0.10 to 11.9. CONCLUSIONS: These results demonstrate a potentially powerful method of evaluating the additive effect of multiple breast carcinoma risk genes to form a potentially clinically useful assessment of women's risk for sporadic breast carcinoma.

Adult↗
PubMed1989

Major gene polymorphism for human erythrocyte (RBC) thiol methyltransferase (TMT).

Thiol S-methylation is an important pathway in the metabolism of many sulfhydryl compounds including the antihypertensive drug captopril and the antirheumatic medication D-penicillamine. Erythrocyte (RBC) thiol methyltransferase (TMT) activity was measured in blood samples from 237 individuals from 49 nuclear families. Earlier studies have demonstrated familial aggregation of RBC TMT activity, suggesting a role for genetic determinants. Our study indicates the specific mode of inheritance and gives relative contributions of a major locus and background genotype. We found evidence for a major locus, TMT. The allele frequencies for low enzyme activity, TMTL, and high activity TMTH, estimated from a power transformed scale were 0.58 and 0.42, respectively. The high activity allele, TMTH, appears to have reduced expression in heterozygous individuals (d = 0.21) and to act in concert with a strong influence from polygenic genotype (H = 0.75) to produce a highly heritable phenotype. This major gene polymorphism may now be studied using biochemical and molecular genetic techniques.

Adolescent↗
PubMed2002

Cholesterol gallstone formation in overweight mice establishes that obesity per se is not linked directly to cholelithiasis risk.

The relationship between obesity and cholesterol cholelithiasis is not well understood at physiologic or genetic levels. To clarify whether obesity per se leads to increased prevalence of cholelithiasis, we examined cholesterol gallstone susceptibility in three polygenic (KK/H1J, NON/LtJ, NOD/LtJ) and five monogenic [carboxypeptidase E (Cpe (fat)), agouti yellow (A(y)), tubby (tub), leptin (Lep(ob)), leptin receptor (Lepr (db))] murine models of obesity during ingestion of a lithogenic diet containing dairy fat, cholesterol, and cholic acid. At 8 weeks on the diet, one strain of polygenic obese mice was resistant whereas the others revealed low or intermediate prevalence rates of cholelithiasis. Monogenic obese mice showed distinct patterns with either high or low gallstone prevalence rates depending upon the mutation. Dysfunction of the leptin axis, as evidenced by the Lep(ob) and the Lepr (db) mutations, markedly reduced gallstone formation in a genetically susceptible background strain, indicating that in mice with this genetic background, physiologic leptin homeostasis is a requisite for cholesterol cholelithogenesis. In contrast, the Cpe (fat) mutation enhanced the prevalence of cholelithiasis markedly when compared with the background strain. Since CPE converts many prohormones to hormones, a deficiency of biologically active cholecystokinin is a likely contributor to enhanced susceptibility to cholelithiasis through compromising gallbladder contractility and small intestinal motility. Because some murine models of obesity increased, whereas others decreased cholesterol gallstone susceptibility, we establish that cholesterol cholelithiasis in mice is not simply a secondary consequence of obesity per se. Rather, specific genes and distinct pathophysiological pathways are responsible for the shared susceptibility to both of these common diseases.

Animals↗
PubMed1997

Lipoproteins and cardiovascular risk-from genetics to CHD prevention.

Dyslipidemia is said to be present when lipid or lipoprotein levels lie within a range which is known from epidemiological studies to be associated with secondary complications, in particular atherosclerosis of the coronary arteries, or when a lipid or lipoprotein grossly deviates from the norm as in abetalipoproteinemia, hypobetalipoproteinemia or the HDL deficiency syndromes. In most cases, dyslipidemia is due not to a single genetic or environmental factor, but to a combination of the effects of several genes of small effect (polygenes) and environment. In other cases, however, dyslipidemia is caused by a mutation in a single gene of large effect. In such cases, the extent and nature of the phenotype depends primarily on the identity of the gene involved, but is also modulated to an important degree by the nature of the mutation and the genetic and environmental background against which this mutation occurs. In addition, many cases of hyperlipidemia are secondary to other disorders such as hypothyroidism or renal dysfunction. Such disorders may also unmask or exacerbate a genetic lipoprotein disorder. Examples of the latter are the unmasking of type III hyperlipidemia by diabetes mellitus or the exacerbation of familial hypercholesterolemia by hypothyroidism.

Clinical Trials as Topic↗
PubMed2004

Genetic complexity of an obesity QTL ( Fob3) revealed by detailed genetic mapping.

Obesity is proving to be a serious health concern in the developed world as well as an unwanted component of growth in livestock production. While recent advances in genetics have identified a number of monogenic causes of obesity, these are responsible for only a small proportion of human cases of obesity. By divergent selection for high and low fat content over 60 generations, we have created Fat (F) and Lean (L) lines of mice that represent a model of polygenic obesity similar to the situation in human populations. From previous crosses of these lines, four body fat quantitative trait loci (QTL) were identified. We have created congenic lines (F(chr15L)), by recurrent marker-assisted backcrossing, to introgress the QTL region with the highest LOD score, Fob3 on Chr 15, from the L-Iine into the F-line background. We have further mapped this QTL by progeny testing of recombinants, produced from crosses between the F-line and congenic F(chrl5L) mice, showing that the Fob3 QTL region is a composite of at least two smaller effect QTL-the proximal QTL Fob3a is a late-onset obesity QTL, whereas the distal Fob3b is an early-onset obesity QTL.

Analysis of Variance↗
PubMed2005

Biozzi mice: of mice and human neurological diseases.

In 1972 Guido Biozzi selectively bred mice to study the immunopathological mechanisms underlying polygenic diseases. One line, the Biozzi antibody high (AB/H) mouse (now designated the ABH strain) was later found to be highly susceptible to many experimentally induced diseases such as autoimmune encephalomyelitis, autoimmune neuritis, autoimmune uveitis, as well as virus-induced demyelination and has thus been a key mouse strain to study human inflammatory neurological diseases. In this paper we discuss the background of the Biozzi ABH mouse and review how studies with these mice have shed light on the pathogenic mechanisms operating in chronic neurological disease.

Alphavirus Infections↗
PubMed2001

Aggressive behavioral phenotypes in mice.

Aggressive behavior in male and female mice occurs in conflicts with intruding rivals, most often for the purpose of suppressing the reproductive success of the opponent. The behavioral repertoire of fighting is composed of intricately sequenced bursts of species-typical elements, with the resident displaying offensive and the intruder defensive acts and postures. The probability of occurrence as well as the frequency, duration, temporal and sequential patterns of aggressive behavior can be quantified with ethological methods. Classic selection and strain comparisons show the heritability of aggressive behavior, and point to the influence of several genes, including some of them on the Y chromosome. However, genetic effects on aggressive behavior critically depend upon the background strain, maternal environment and the intruder. These factors are equally important in determining changes in aggressive behavior in mice with a specific gene deletion. While changes in aggression characterize mutant mice involving a variety of genes, no pattern has emerged that links particular gene products (i.e. enzyme, peptide, receptor) to either an increase or a decrease in aggressive behavior, but rather emphasizes polygenic influences. A potentially common mechanism may be some components of the serotonin system, since alterations in 5-HT neurotransmission have been found in several of the KO mice that display unusual aggressive behavior.

Aggression↗
PubMed2001

Experimental approaches to the determination of genetic variability.

Toxicology is concerned with the interaction between xenobiotics and biological molecules directly or indirectly coded in the DNA, and can be regarded as a branch of genetics. There is genetic variation in these interactions, which has important implications for risk assessment and because it can be used as a tool in studying toxic mechanisms. The genetics of susceptibility can be studied by forward or reverse genetics. Forward genetics involves working from an observed phenotype such as susceptibility to a particular xenobiotic and identifying the susceptibility genes. Often, this involves mapping and identifying quantitative trait loci, as most toxic responses have a polygenic mode of inheritance. The use of inbred strains is almost essential. Reverse genetics involves starting with a known genetic polymorphism and determining its effects on the response to xenobiotics. Studies of 'knockout' animals are a good example, although there are many naturally occurring polymorphisms that may affect toxic responses. In both cases, care has to be taken to ensure that the genetic background is carefully controlled in any comparison between animals thought to be carrying susceptible and resistant alleles.

Animals↗
PubMed2004

The population genetic theory of hidden variation and genetic robustness.

One of the most solid generalizations of transmission genetics is that the phenotypic variance of populations carrying a major mutation is increased relative to the wild type. At least some part of this higher variance is genetic and due to release of previously hidden variation. Similarly, stressful environments also lead to the expression of hidden variation. These two observations have been considered as evidence that the wild type has evolved robustness against genetic variation, i.e., genetic canalization. In this article we present a general model for the interaction of a major mutation or a novel environment with the additive genetic basis of a quantitative character under stabilizing selection. We introduce an approximation to the genetic variance in mutation-selection-drift balance that includes the previously used stochastic Gaussian and house-of-cards approximations as limiting cases. We then show that the release of hidden genetic variation is a generic property of models with epistasis or genotype-environment interaction, regardless of whether the wild-type genotype is canalized or not. As a consequence, the additive genetic variance increases upon a change in the environment or the genetic background even if the mutant character state is as robust as the wild-type character. Estimates show that this predicted increase can be considerable, in particular in large populations and if there are conditionally neutral alleles at the loci underlying the trait. A brief review of the relevant literature suggests that the assumptions of this model are likely to be generic for polygenic traits. We conclude that the release of hidden genetic variance due to a major mutation or environmental stress does not demonstrate canalization of the wild-type genotype.

Data Interpretation, Statistical↗
PubMed2000

Genetic basis of autoimmune disease in MRL/lpr mice: dissection of the complex pathological manifestations and their susceptibility loci.

MRL/MpJ-lpr/lpr (MRL/lpr) mice spontaneously develop various forms of autoimmune disease in the same individuals, including glomerulonephritis, polyarteritis, arthritis and sialoadenitis. An MRL recombinant congenic strain of mice bearing the gld gene, MRLiMpTn-gld/gld (MRL/gld), also develops lesions similar to those in MRL/lpr mice. The lpr and gld genes are a Fas deletion mutant and a Fas ligand mutant, respectively. Thus, autoimmune disease in these mice seemed to be a single gene disease involving the complex pathological manifestations as pleiotropy. However, comparative studies with C3H/HeJ and C57BL/6J strains of mice bearing lpr or gld revealed that these lesions developed only in mice with an MRL background. Moreover, these lesions were genetically segregated among MRL/lpr x (MRL/lpr x C3H/lpr)F1 mice. This indicates that an MRL strain has particular gene(s) affecting the development of each lesion. Association studies of each lesion with polymorphic microsatellite markers using backcross mice revealed that gene loci responsible for each lesion exist at different chromosomal positions and have additive and hierarchical properties of polygenic inheritance for some of the lesions. We conclude that the complex pathological manifestations of autoimmune disease are under the control of different combinations of polygenes.

Animals↗
PubMed1998

[Genetic studies in osteoporosis].

Osteoporosis is one of the complex disease which has many responsible fractors to develop this disease. Among the causative factors for osteoporosis, genetic background is believed as the most important factor for osteoporosis. In 1994, Morrison et al reported their pioneering work looking at the close relationship between VDR genotype and bone mass. This report has generated a considerable amount of interest and conflict. The reasons for these conflicts are depending upon the nature of osteoporosis. Namely, the genetic association to the cause of osteoporosis is polygenic. Furthermore, the contribution of a gene to achieve low bone mass is polyphasic. For example, estrogen-receptor gene polymorphisms may show varied importance in the different stage of women's life span. The environmental factors may interefere the penetration of a gene effect and the presence of the other gene effect may also blunt the effect of the candidate gene. To overcome these difficulties in the research work to search osteoporosis gene, we have pay keen attention to the selections of the method of gene analysis and the subjects. The specific gene marker showed the possibility to predict the effect of the treatment of osteoporosis. This may indicate the marker gene itself or the other gene(s) linked with this marker gene regulate the biological response to the treatment. So, gene markers may utilize not only in the field of epidemiological studies but also in clinical practice in near future.

Genetic Linkage↗
PubMed2003

Interaction between blood pressure quantitative trait loci in rats in which trait variation at chromosome 1 is conditional upon a specific allele at chromosome 10.

We have used inbred and congenic rat strains in F(2) segregation studies to discover epistasis in a polygenic model of hypertension. Previously, we have found evidence that the presence of a blood pressure quantitative trait locus (QTL) on chromosome 1 is conditional upon the allele status of chromosome 10. To prove the existence of an epistatic interaction we have analyzed congenic strains for chromosome 1 and 10 carrying high blood pressure QTL alleles from the spontaneously hypertensive rat on a normotensive background of the Wistar-Kyoto (WKY) rat. Additionally, a double congenic strain was developed with both chromosome 1 and 10 high blood pressure QTL alleles on the WKY background. Analysis of variance for blood pressure phenotypes as determined by radiotelemetry showed a significant effect for chromosome 10 but not chromosome 1 QTL alleles and demonstrated a significant interaction between the two loci (P<0.05). The interaction accounted for 5 mmHg of blood pressure. Thus, the identification of epistasis is critical to the understanding of the quantitative nature of blood pressure genetics.

Alleles↗
PubMed2000

Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men and women. A randomized crossover trial.

BACKGROUND: It has been reported that walnuts reduce serum cholesterol levels in normal young men. OBJECTIVE: To assess the acceptability of walnuts and their effects on serum lipid levels and low-density lipoprotein (LDL) oxidizability in free-living hypercholesterolemic persons. DESIGN: Randomized, crossover feeding trial. SETTING: Lipid clinic at a university hospital. PATIENTS: 55 men and women (mean age, 56 years) with polygenic hypercholesterolemia. INTERVENTION: A cholesterol-lowering Mediterranean diet and a diet of similar energy and fat content in which walnuts replaced approximately 35% of the energy obtained from monounsaturated fat. Patients followed each diet for 6 weeks. MEASUREMENTS: Low-density lipoprotein fatty acids (to assess compliance), serum lipid levels, lipoprotein(a) levels, and LDL resistance to in vitro oxidative stress. RESULTS: 49 persons completed the trial. The walnut diet was well tolerated. Planned and observed diets were closely matched. Compared with the Mediterranean diet, the walnut diet produced mean changes of -4.1% in total cholesterol level, -5.9% in LDL cholesterol level, and -6.2% in lipoprotein(a) level. The mean differences in the changes in serum lipid levels were -0.28 mmol/L (95% CI, -0.43 to -0.12 mmol/L) (-10.8 mg/dL [-16.8 to -4.8 mg/dL]) (P<0.001) for total cholesterol level, -0.29 mmol/L (CI, -0.41 to -0.15 mmol/L) (-11.2 mg/dL [-16.3 to -6.1 mg/dL]) (P<0.001) for LDL cholesterol level, and -0.021 g/L (CI, -0.042 to -0.001 g/L) (P = 0.042) for lipoprotein(a) level. Lipid changes were similar in men and women except for lipoprotein(a) levels, which decreased only in men. Low-density lipoprotein particles were enriched with polyunsaturated fatty acids from walnuts, but their resistance to oxidation was preserved. CONCLUSION: Substituting walnuts for part of the mono-unsaturated fat in a cholesterol-lowering Mediterranean diet further reduced total and LDL cholesterol levels in men and women with hypercholesterolemia.

Algorithms↗
PubMed2002

Deletion of p21 (WAF-1/Cip1) does not induce systemic autoimmunity in female BXSB mice.

Cell cycle, apoptosis, and replicative senescence are all influenced by the cyclin-dependent kinase inhibitor, p21. It was previously reported that deletion of p21 in 129/Sv x C57BL/6 mixed genetic background mice induced a severe lupus-like disease, almost exclusively in females. However, we did not confirm this finding in an independently derived stock of 129/Sv x C57BL/6 p21(-/-) mice. To further address this discrepancy, we examined the effects of p21 deletion in BXSB female mice that develop late-life, mild lupus-like disease. Survival, polyclonal Igs, anti-chromatin Abs, and kidney histopathology in these mice were unremarkable and identical to wild-type littermates for up to 14 mo of age. We conclude that p21 deficiency does not promote autoimmunity even in females of a predisposed strain. The findings indicate that the use of mixed background 129/Sv x C57BL/6 mice to study effects of gene deletions in systemic autoimmunity may be confounded by the genetic heterogeneity of this cross. We suggest that studies addressing gene deletion effects in systemic autoimmunity should use sufficiently backcrossed mice to attain genetic homogeneity, include wild-type littermate controls, and preferentially use congenic inbred strains with late-life lupus predisposition to emulate the polygenic nature of this disease.

Animals↗
PubMed1997

Computerized EEG topography of normal preadolescent twins--correlating similarity of background activity with genetic relatedness.

The influence of genetic relatedness on the similarity degree of topographical EEG parameters was studied in a sample of 26 sets of monozygotic (MZ) and 46 sets of dizygotic (DZ) twins. All 144 subjects were healthy, primary school children, aged 7-15 years, 69 boys and 75 girls. Correlation coefficients were calculated for 50 quantitative EEG parameters of paired values obtained at each of 16 active electrode sites, in four groups of paired tracings: 1. MZ twins, 2. DZ twins, 3. The autocorrelated (A) group formed by correlating the spectral parameters from the same subjects in two different analyzed sequences, 4. The random (R) control group of 1200 unrelated pairs formed from DZ twin pairs. Sets of MZ twins and A group showed the highest degrees of similarity of spectral parameters over all brain areas except for significant differences only for some background features over posterior regions. In contrast, highly significant differences in topographic parameters were evident in comparison of MZ sets with DZ sets, particularly when MZ sets were compared with DZ subsets of opposite sex. Both number and degree of significant differences increased progressively in comparisons with groups 3 vs 2, 1 vs 4, and 3 vs 4. The data gave strong evidence for a complex polygenic determination of normal human EEG topography.

Adolescent↗
PubMed1997

Atorvastatin, a New HMG-CoA Reductase Inhibitor, Does Not Affect Glucocorticoid Hormones in Patients With Hypercholesterolemia.

BACKGROUND: Atorvastatin calcium (Lipitor) is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. The present study was conducted to examine the effect of pronounced cholesterol lowering on adrenal function in patients with severe hypercholesterolemia. METHODS AND RESULTS: Adrenal function was examined under basal conditions and following adrenal corticotropin hormone stimulation in 40 patients (36 with heterogeneous familial and 4 with polygenic hypercholesterolemia). The study was part of a larger study comparing the efficacy and safety of atorvastatin, colestipol, atorvastatin + colestipol, and simvastatin + colestipol treatment over a 1-year period. Maximum doses of all agents were studied: 80 mg atorvastatin once daily, 40 mg simvastatin once daily, and 20 g/day colestipol. At the end of the 1-year treatment period, reductions in low-density lipoprotein cholesterol were 57%, 54%, and 49% for the atorvastatin, colestipol + atorvastatin, and colestipol + simvastatin groups, respectively. No clinically significant changes in basal serum cortisol levels were seen in any treatment group during the 1-year treatment period. Mean serum cortisol concentrations and area under the curve for cortisol concentration versus time data following adrenal corticotropin hormone stimulation were not clinically different during treatment compared with values obtained at baseline for any of the treatment groups. CONCLUSIONS: Treatment with maximum doses of atorvastatin for 1-year did not have any adverse effects on adrenal function under basal conditions or during maximum stimulation. Similarly, colestipol therapy alone and in combination with either atorvastatin or simvastatin did not appear to affect adrenal function.

Journal Article↗
PubMed2001

Methodologic pitfalls in the determination of genetic anticipation: the case of Crohn disease.

BACKGROUND: The term genetic anticipation is used when genetically transmitted disease manifests at increasingly younger ages with each succeeding generation: that is, if the offspring of patients develop the disease, they will tend to do so at an earlier age than their parents. In some monogenetic disorders, genetic anticipation has a biological basis in expanded genetic triplet repeats; however, some have claimed that it occurs in polygenic disorders, such as Crohn disease, in which its mechanism cannot be explained. OBJECTIVE: To show how apparent changes in age at diagnosis of Crohn disease between generations, which could suggest genetic anticipation, can be an artifact of inadequate analysis based on age at diagnosis in cohorts that have not been followed for a sufficiently long time. DESIGN: Comparison of ages at diagnosis of Crohn disease among different birth cohorts, before and after adjustment for observation time. SETTING: Meyerhoff Center for Inflammatory Bowel Disease, Johns Hopkins Hospital, Baltimore, Maryland. PATIENTS: 928 consecutive outpatients with Crohn disease. MEASUREMENTS: Trends in age at diagnosis of Crohn disease among birth cohorts were determined by calculating Pearson correlation coefficients and performing Kaplan-Meyer analysis before and after adjustment for observation time. Adjustment for observation time was performed by ensuring that the time during which all included patients were at risk for Crohn disease was equal and that all patients had developed disease by the end of the risk period. RESULTS: Mean age at diagnosis decreased by approximately 5 years with each subsequent 10-year birth cohort on the basis of crude cross-sectional data that could suggest genetic anticipation between generations. However, after adjustment for observation time, the age at diagnosis decreased minimally, if at all, with each successive generation. CONCLUSIONS: Apparent genetic anticipation can be explained by observational biases without invoking any additional genetic influences. Claims for genetic anticipation must be based on methods that properly account for the duration of observation in all persons being studied.

Age of Onset↗