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PubMed1987

Etiologic heterogeneity in alcoholism.

Etiologic heterogeneity in alcohol abuse was evaluated in 195 extended pedigrees, comprising 288 nuclear families of 140 male and 55 female Caucasian American hospitalized alcoholics. Previous adoption studies in Sweden demonstrated differential heritability of two patterns of alcohol abuse in men: type-2 alcoholism exhibited early onset of abuse associated with criminal behavior, while type-1 abuse began at a later age, uncomplicated by antisocial traits. Alcohol abuse in female Swedish adoptees was relatively homogeneous and similar to the late-onset, type-1 abuse. The notion of etiologic heterogeneity, as suggested by the Stockholm Adoption Studies, was examined in the American pedigrees by contrasting the models of familial transmission of susceptibility to alcoholism obtained via segregation analyses of families of male versus female probands. Families of male probands demonstrated significant familial resemblance, accounted for by a multifactorial-polygenic background in addition to a major (gene) effect. In contrast, familial resemblance in the pedigrees of female probands was attributed solely to a multifactorial-polygenic effect. We considered whether some families of male alcoholics were similar to families of female probands, who expressed type-1 abuse predominantly. Pedigrees of male probands were separated in two groups: (1) "female-like" families had a better likelihood for the model obtained for families of female probands than the one for families of all male probands, (2) "male-like" families had a better likelihood for the model of familial transmission describing families of all male probands. A statistically significant difference in the pattern of familial transmission was observed between the "male-like" and "female-like" groups. Discriminant function analysis of alcohol-related symptoms showed that the familial subtypes differed in clinical features as well. Alcohol abuse by male relatives in "male-like" families was characterized by the early onset of inability to abstain entirely from alcohol or lack of desire to stop drinking; in contrast, abuse in "female-like" families was characterized by late onset of guilt feelings and loss of control over binge drinking.

Adolescent↗

PubMed1988

Inheritance of human platelet thermolabile phenol sulfotransferase (TL PST) activity.

Sulfate conjugation is an important pathway in the biotransformation of drugs and neurotransmitters. The thermolabile (TL) form of the enzyme phenol sulfotransferase (PST) catalyzes the sulfation of catecholamine neurotransmitters and drugs such as methyldopa and acetaminophen. Platelet TL PST activity was measured in blood samples from 232 individuals in 49 nuclear families. Correlations ranged from 0.43 to 0.45 for parent-offspring pairs and from 0.44 to 0.47 for siblings. Mother-father correlations were not significantly different from zero. Although evidence was not unequivocal, both segregation and commingling analyses provided some support for a major gene influence on TL PST activity, with other variation due to polygenic background. In both sets of analyses, however, support for a major gene hypothesis depended upon skewness in the TL PST activity distribution. A polygenic model with high heritability (0.77) was most strongly supported with the log transformed data. These results confirm and extend a previous report of high heritability of TL PST based on a study of twins. In addition, our results raise the possibility of a major gene effect on this important catecholamine- and drug-metabolizing enzyme--a possibility that can now be evaluated using biochemical techniques.

Adolescent↗

PubMed1989

Equivalence of the mixed and regressive models for genetic analysis. I. Continuous traits.

The mixed model of segregation analysis specifies major gene effects and partitions the residual variance into polygenic and environmental components. The model explains familial correlations essentially in terms of genetic causation. The regressive model, on the other hand, is constructed by successively conditioning on ancestral phenotypes and major genes. Familial patterns of dependence are described in terms of correlations without necessarily introducing a particular scheme of causal relationship. These two approaches are compared both theoretically and numerically through computer simulations for the case of continuous traits on nuclear families. The class D regressive model, which is characterized by equal sib-sib correlations, is mathematically and numerically equivalent to the mixed model. The simpler class A regressive model, which is also characterized by equal sib-sib correlations determined in this case by the common parentage, provides good estimates of the mixed model parameters: major gene parameters and residual polygenic heritability, derived from the parent-offspring correlation. However, in the absence of a major gene, the restriction imposed by the class A model on the sibling correlation can affect the conclusions of segregation analysis: False inference of a major gene was observed in two out of ten replicates. Our simulations also indicate that the mixed model allowing for different heritabilities in adults and children leads to correct estimates of the major gene parameters and residual familial correlations (parent-offspring and sib-sib) as specified by the class A model. For all the models studied, major gene effects, when present, are correctly detected and estimated.

Adult↗

PubMed1989

Segregation analysis of quantitative traits in nuclear families: comparison of three program packages.

Segregation analysis frequently is used to test for the presence of major gene effects and to estimate the various genetic and environmental components contributing to diseases. Recent advances in both theoretical models and computational algorithms have provided a number of new programs for performing segregation analyses. We compared two newer programs: REGC (part of the package "SAGE") and FISHER/MENDEL with an older established program (PAP) to determine relative accuracy in recovering parameter values and asymptotic standard errors, ability to discriminate between alternative transmission models, and execution speeds. Each program was applied to a set of computer simulations of a quantitative trait generated under a variety of genetic models. The results of these comparisons indicated that all the programs provided very similar parameter estimates, but that they differed in their abilities to identify the correct mode of transmission. In our simulations, PAP more often led to the selection of the correct transmission model, whereas REGC frequently indicated the presence of a major gene in simulations of purely polygenic transmission. Relative speeds for the programs differed, and their rank ordering varied with the complexity of the model being fitted. Although REGC was the fastest program for fitting a major gene or mixed model, it was by far the slowest program for estimating parameters in a sporadic or polygenic model.

Computer Simulation↗

PubMed1991

A variance components/major locus likelihood approximation on quantitative data.

The variance components/major locus model encompasses a major locus, a polygenic component, and shared environmental effects. The model attributes familial correlations to polygenic and shared environmental effects when testing for major locus inheritance or accounts for the major locus when estimating variance components. Because exact computation of the likelihood of the variance components/major locus model on quantitative data requires excessive computer time, I developed an approximation. The approximation retained the general shape of the likelihood surface. Accuracy of the approximation did not vary consistently with allele frequency or the size of the major locus effect.

Genetic Variation↗

PubMed1992

Detection of genetic heterogeneity for complex quantitative phenotypes.

Statistically characterizing factors responsible for quantitative phenotype expression (e.g., polygenes, major genes, shared household factors, etc.) through model selection strategies is a difficult task. A great deal of effort has been expended on refining mathematical and computational aspects of various segregation models used to characterize unique expressions of quantitative phenotypes in an effort to make these models easier to implement and evaluate for a given set of data. In this paper a slightly different angle is emphasized: namely, the explicit modeling of the potentially numerous heterogeneous genetic and environmental processes (i.e., segregation patterns, household aggregations, etiologic processes, etc.) that could contribute to the overall variation of a quantitative trait. As such, this paper describes tools for detecting quantitative trait heterogeneity that are meant to answer such questions as "are there pedigrees among a great many that show a pattern consistent with a possibly very specific single locus segregation pattern while the rest show compatibility with a polygenic or purely environmental pattern?" Methods for determining the significance of such heterogeneity are also discussed, as are the results of numerous examples and simulation studies carried out in an effort to validate and further elaborate aspects of the proposed techniques.

Genetic Linkage↗

PubMed2001

Genetic epidemiology of visceral leishmaniasis in northeastern Brazil.

Familial clustering of disease, racial differences in asymptomatic:disease ratios, and studies of mice all point to a genetic component for disease susceptibility in visceral leishmaniasis. Analysis of 87 multi-case pedigrees (824 individuals; 138 nuclear families) from a region of northeastern Brazil endemic for Leishmania chagasi demonstrates a high relative risk ratio (lambda(2S) = 34) to further siblings of affected sibling pairs. Complex segregation analysis using POINTER and COMDS show that all single locus models, as well as polygenic and multifactorial models, provide a significantly (P < 0.001) better fit to the data than a sporadic model. Of the genetic models, the general single locus model was not significantly different from additive or dominant single locus models, all of which gave a gene frequency for the putative disease susceptibility allele of approximately 0.002. The general single locus model was strongly favored (P < 0.001) over a recessive single gene model. Using POINTER, polygenic and multifactorial models were clearly rejected (P < 0.001 in all cases) in favor of the general single locus model. Using COMDS, the analysis was extended to consider two locus models. Results under a general two-locus model did not differ significantly from the dominant, additive, or general single locus models. Under this model, one locus was estimated at a gene frequency of 0.0017, i.e., in the same range as the disease susceptibility locus for the most favored single gene models, with the second locus at a much lower frequency of 0.0002. Hence, the data support the hypothesis that a single major gene may be important in determining disease susceptibility in this population. To identify the gene(s) involved, a genome scan with replication using two subsets of these larger pedigrees with power to detect linkage is in progress.

Adolescent↗

PubMed1996

Detection of a unique gamma-glutamyl transpeptidase messenger RNA species closely related to the development of hepatocellular carcinoma in humans: a new candidate for early diagnosis of hepatocellular carcinoma.

Many studies concerning gamma-glutamyl transpeptidase (GGTP) in hepatocellular carcinoma (HCC) have suggested that changes in hepatic GGTP expression may be closely related to the development of HCC. However, its mechanisms are not well known, and genomic analysis of the specific GGTP to HCC is also lacking. Recently, the human GGTP complementary DNA (cDNA) sequences from fetal liver, placenta, and HepG2 cells have been published. In the present study, we sought to clarify the distribution of the GGTP messenger RNA (mRNA) molecular species in human liver and determine whether alterations in GGTP mRNA expression occur upon the development of HCC. The specific primer sets for reverse-transcription polymerase chain reaction (PCR) corresponding to the 5'-noncoding human GGTP mRNA of fetal liver (type A), HepG2 cells (type B), and placenta (type C) were prepared. Oligonucleotide probes specific for each type of mRNA were also synthesized. Liver tissues were obtained from patients with or without HCC, and total RNA was extracted. Total RNA was also extracted from various organs obtained from one male patient upon autopsy. Types of GGTP mRNAs were analyzed using type-specific primer sets and oligonucleotide probes. The types of GGTP mRNA varied in different organs. In normal liver and diseased liver without HCC, the main type of GGTP mRNA was type A. The expression was monogenic in most cases but was polygenic in some cases. In the polygenic cases, type C was common, but type B was found occasionally. On the other hand, type B was predominant in cancerous tissues with HCC. In noncancerous tissues of livers with HCC, the main types were types A and B. The prevalence of type B was significantly higher in both cancerous and noncancerous tissues of livers with HCC than in livers without HCC. The prevalence of type A in cancerous tissue, but not in noncancerous tissue, was significantly lower than in livers without HCC. These results strongly suggested that the GGTP mRNA expression in human liver may shift from type A to type B during the development of HCC. The high prevalence of type B in noncancerous tissues suggested that the shift of the GGTP mRNA may occur from the preneoplastic stage of hepatocytes.

Base Sequence↗

PubMed2003

Exclusion of BRAFV599E as a melanoma susceptibility mutation.

Very recently, BRAF mutations were found in about 2/3 of malignant melanomas and at lower frequencies in other human cancers. The BRAF gene codes for a protein in the mitogen-activated protein kinase (MAPK) pathway. All mutations identified to date are within the kinase domain, with a single missense mutation (V599E) accounting for 80%. We investigated the hypothesis that this common somatic BRAF mutation (V599E) would contribute to melanoma predisposition in familial and polygenic malignant melanoma if occurring as a germ-line mutation. We performed comprehensive mutational screening of exon 15 of BRAF using DHPLC (denaturing high-performance liquid chromatography) and DNA sequencing techniques. No V599E mutation could be detected in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients and 106 cases with at least one first-degree relative suffering from other cancers. We therefore conclude that the common somatic BRAF mutation V599E does not contribute to polygenic and familial melanoma predisposition.

Alleles↗

PubMed1996

Familial clustering of abdominal visceral fat and total fat mass: the Québec Family Study.

The evidence for common familial factors underlying total fat mass (estimated from underwater weighing) and abdominal visceral fat (assessed from CT scan) was examined in families participating in phase 2 of the Québec Family Study (QFS) using a bivariate familial correlation model. Previous QFS investigations suggest that both genetic (major and polygenic) and familial environmental factors influence each phenotype, accounting for between 55% to 71% of the phenotypic variance in fat mass, and between 55% to 72% for abdominal visceral fat. The current study suggests that the bivariate familial effect ranges from 29% to 50%. This pattern suggests that there may be common familial determinants for abdominal visceral fat and total fat mass, as well as additional familial factors which are specific to each. The relatively high spouse cross-trait correlations usually suggest that a large percent of the bivariate familial effect may be environmental in origin. However, if mating is not random, then the spouse resemblance may reflect either genetic or environmental causes, depending on the source [i.e., through similar genes or cohabitation (environmental) effects]. Finally, there are significant sex differences in the magnitude of the familial cross-trait correlations involving parents, but not offspring, suggesting complex generation (i.e., age) and sex effects. For example, genes may turn on or off as a function of age and sex, and/or there may be an accumulation over time of effects due to the environment which may vary by sex. Whether the common familial factors are genetic (major and/or polygenic), environmental, or some combination of both, and whether the familial expression depends on sex and/or age warrants further investigation using more complex models.

Abdomen↗

PubMed1995

Segregation analysis and variance components analysis of bone mineral density in healthy families.

Bone mineral density (BMD) was measured in 1992-93 in 129 nuclear families, including 258 parents and 183 children, and was analyzed for familial resemblance factors. BMD measurements were adjusted on weight and age. Segregation analysis rejected the monogenic hypothesis and exhibited a strong polygenic component. Variance components analysis was then used to estimate the parameters of a multivariate normal model including an additive polygenic component, a common environment factor, and a residual specific to each individual. The genetic component was independent of sex and age. The common environmental factor was not significant. The variance of the residual specific factor appeared to be a quadratic function of age, reaching its minimum value at 26.4 years. Consequently, the maximum value for heritability (ratio of genetic variance to total variance) is observed at this age (h2 = 0.84). According to this model, the correlation between two relatives is a function of the ages of each individual in the pair.

Adolescent↗

PubMed2026

Joint Effects of Long-Term Obesity and Genetic Susceptibility on Sex-Specific Brain Aging.

OBJECTIVE: This study aimed to examine the associations of longitudinal obesity trajectories and polygenic risk with sex-specific brain aging. METHODS: We analyzed 35,092 UK Biobank participants (16,484 males and 18,608 females). Sex-specific XGBoost models estimated multimodal brain age. We derived 16-year longitudinal obesity trajectories from repeatedly collected anthropometric measurements. Polygenic risk scores were constructed based on 55 independent genetic loci. Multivariable logistic regression examined associations of obesity trajectories and genetic risk with brain age acceleration. RESULTS: A total of 8198 (49.73%) males and 9089 (48.84%) females had accelerated brain aging. High genetic risk significantly increased brain age acceleration odds (males: OR = 1.39; females: OR = 1.34). Crucially, the high-stable obesity trajectory exerted a stronger effect in males (OR = 1.90, 95% CI: 1.64-2.21) than in females (OR = 1.25, 95% CI: 1.12-1.40), with the joint presence of high genetic risk and high-stable obesity amplifying risk to an OR of 2.78 in males and 1.57 in females. Conversely, shifting from obesity to non-obesity reduced risk by 30% in males and 18% in females. CONCLUSIONS: These findings underscore long-term obesity as a critical, sex-dimorphic driver of accelerated brain aging, and midlife weight management offers robust neuroprotection even in genetically susceptible individuals.

brain aging↗

PubMed1976

The multifactorial/threshold concept -- uses and misuses.

The common congenital malformations have familial distributions that cannot be accounted for by simple Mendelian models, but can be explained in terms of a continuous variable, "liability," with a threshold value beyond which individuals will be affected. Both genetic and environmental factors determine liability, making the system multifactorial. Cleft palate is a useful experimental model, illustrating a number of factors that contribute to palate closure, the nature of a developmental threshold, and how genes and teratogens can alter the components of liability to increase the probability of cleft palate. The nature of the genetic component to liability in human malformations in not clear, and various possibilities, ranging from polygenic in the strict sense to a major gene with reduced penetrance are compatible with the data -- but the important feature is the threshold. Much of the confusion over the concept results from inconsistent use of terminology. The term "multifactorial" should be used for "determined by a combination of genetic and environmental factors," without reference to the nature of the genetic factor(s). "Polygenic" should be reserved for "a large number of genes, each with a small effect, acting additively." When several genes, with more major effects are involved, "multilocal" can be used. When it is not clear which of these is applicable the term "plurilocal" is suggested, in the sense of "genetic variation more complex than a simple Mendelian difference." Since teratological data often represent threshold characters the concept also has important implications for the interpretation of data on dose-response curves, synergisms, and strain differences in response to teratogens.

Abnormalities, Drug-Induced↗

PubMed1998

10 years of Genomics, chromosome 21, and Down syndrome.

During the first 10 years of Genomics (1987-1997), the molecular structure of human chromosome 21 (HC21) has been intensively investigated. Due to its small size and involvement in Down syndrome, it continues to serve as a model in the development of "genomics technologies." Increasingly more detailed genetic, radiation hybrid, physical, and transcription maps, in addition to NotI restriction and chromosomal breakpoint maps, of HC21 have been developed, and approximately 10% of its genes have been cloned. These maps have been vital in the localization of loci for 15 monogenic disorders to HC21, and 10 of these genes have been identified and characterized. The genetic maps have aided in the detailed elucidation of the origin of the supernumerary HC21 in trisomy 21 from investigations of recombination and nondisjunction events. Mouse models of Down syndrome, with partial trisomy 16, the mouse chromosome principally syntenic to HC21, have been created and initially characterized. A substantial number of the above studies related to the molecular mapping, gene cloning, and infrastructure of HC21 were published in Genomics (e.g., approximately 30% of papers describing HC21 maps were published here). The future goals of genomic analysis of HC21 will be the determination of its complete nucleotide sequence and the identification and functional analysis of all of its genes. These advances will help to provide a molecular explanation of the pathophysiology of Down syndrome and aid in the identification of genes for monogenic and polygenic disorders that map on this chromosome. Novel therapeutic interventions for Down syndrome and the monogenic and polygenic disorders that map to HC21 will be designed and tried based on the knowledge of the disease pathogenesis resulting from the genomic analysis.

Animals↗

PubMed2003

Genetic susceptibility, predicting risk and preventing cancer.

A polygenic approach to disease prevention has become a realistic goal that has arisen from the sequencing of the human genome. Some believe it will be possible to identify individuals as susceptible by their genotype and to prevent disease by targeting interventions to those at risk. However, doubts have been expressed about the magnitude of these genetic effects, and hence the potential to apply them either to individuals or to populations. Published data suggest that the familial aggregation of breast cancer not due to the known high penetrance genes is polygenic, which implies that the distribution of risk in the population is continuous. This model is likely to apply to other common cancers. The utility of a continuous distribution for identifying a high-risk group of the population for targeted preventive intervention depends on the spread of that risk distribution. For breast cancer, the data are compatible with a log-normal distribution of genetic risk in the population which is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all cases. In contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that in the future the construction and use of genetic risk profiles may provide significant improvements in the efficacy of population-based programmes of intervention for cancers and other diseases.

Breast Neoplasms↗

PubMed1979

Detection of rare major genes in lipid levels.

A statistical test of polygenic inheritance (TPI) against the alternative of a rare major gene is presented. It is designed for a random sample of quantitative observations on index cases and siblings of those index cases (probands) selected on the basis of the observed measurements of these probands. The test focuses on an increase of the variance of siblings of probands over its value under polygenic inheritance, such an increase being expected in the presence of a major gene producing a shift of the quantitative observations. Certain data on lipids are then analyzed by this test. A major gene can tentatively be confirmed for triglycerides but not for cholesterol. In addition, the values of all index cases are subjected to an analysis of a mixture of normal distributions (NOCOMP computer program), resulting in a significant second component for triglycerides but not for cholesterol. For both TPI and NOCOMP, the exponent in a power transformation is estimated by maximum likelihood simultaneously with all other parameters, so that these analysis methods are robust against a wide range of skewness in the data, which is demonstrated by manipulation of the observations and their reanalysis.

Analysis of Variance↗

PubMed1987

Heredity and blood pressure in humans: an overview.

This paper presents a review of the genetic transmission of normal blood pressure and of essential hypertension. Familial aggregation of normal blood pressure has been reported in adults, in children and even in newborns. Blood pressure aggregation phenomenon, however, is the result of both a genetic component and shared environmental factors. More specific for each etiological factor were the studies of blood pressure aggregation in twins and in adopted children. Attention was focused on the Montreal Adoption Study. In essential hypertension, a Japanese study is reviewed showing the occurrence of hypertension in the offspring of hypertensive parents. The heterogeneity of essential hypertension is underlined and two of the multiple etiological factors are particularly considered for their genetic component: the response to salt intake and erythrocyte cation fluxes. The conclusion from the literature reviewed is that essential hypertension is a polygenic disease transmitted by polygenic systems.

Adolescent↗

PubMed1979

Development of individual differences of cardiovascular regulation in the Bailey recombinant inbred mice.

Previous research has demonstrated that the cardiovascular system (CVS) is not completely developed in the rat until 20 days of age. Prior to this age the sympathetic nervous system (SNS) is dominant during resting conditions and the stress response is vagally mediated, which is the opposite of most adult rats. In the present research, using the Bailey recombinant inbred strains and their progenitor strains (C57BL/6By and BALB/cBy), we determined the developmental period for the CVS in mice. The CVS was controlled by a high SNS tone and the stress response was vagally mediated at 8 days of age. By 12 days of age, the mice had much slower baseline heart rates which were vagally controlled. Significant strain differences were also found with a polygenic model accounting for these differences. The stress response of the 12-day-old mice was not interpretable because of individual differences in the adult coping strategies. These differences were accounted for by a different polygenic model than was found in the baseline condition.

Analysis of Variance↗