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Results for “Multifactorial Inheritance”

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PubMed1985

Genetics of migraine and migraine accompagneé: a study of eighty-one children and their families.

Eighty-one patients suffering from childhood onset migraine and their families were investigated for familial prevalences of epileptic seizures and migraine. The incidence of epileptic seizures was not increased above the epidemiological risk. - In all, migraine is largely inherited from maternal ascendents, irrespective of the sex of the index case. Clinical subtypes of migraine ("non-focal migraine" and migraine accompagnée) are not accompanied by respectively increased familial prevalences. - Onset of migraine is earlier in patients with a higher familial impact. These findings are discussed in context with a proposed multifactorial pathogenesis of migraine.

Adolescent↗

PubMed2001

Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease.

Prostate cancer is a complex, multifactorial disease with genetic and environmental factors involved in its etiology. The search for genetic determinants involved in the disease has proven to be challenging, in part because such complex diseases are often not amenable to characterization by linkage analysis and positional cloning as is the case for diseases with simple Mendelian genetic inheritance. Prostate cancer susceptibility loci that have been reported so far include HPC1 (1q24-q25), PCAP (1q42-q43), HPCX (Xq27-q28), CAPB (1p36), HPC20 (20q13), HPC2/ELAC2 (17p11) and 16q23. Prostate cancer aggressiveness loci have also been reported (5q31-q33, 7q32 and 19q12). Further complicating the process is the existence of polymorphisms in several genes associated with prostate cancer including, AR, PSA, SRD5A2, VDR and CYP isoforms. These polymorphisms, however, are not thought to be highly penetrant alleles in families at high risk for prostate cancer. It is clear that prostate cancer etiology involves several genetic loci with no major gene accounting for a large proportion of susceptibility to the disease.

Genetic Heterogeneity↗

PubMed1990

Ethics and the new genetics.

Recent developments in recombinant DNA technology have resulted in a rapidly expanding range of new diagnostic and therapeutic opportunities for families with inherited disorders. They are also beginning to impinge on society as a whole as progressively more is learned about the human genome, as the community becomes more aware of the role of genes in disease, and as we start to consider the implications of being able to define individual susceptibility to both monogenic and multifactorial disorders. As we implement the new technologies, careful consideration must be given to the ethical issues which arise so that maximum benefit can be obtained by individuals and the wider community.

Ethics, Medical↗

PubMed1981

Genetic analysis of the Stanford LRC family study data. II. Structured exploratory data analysis of lipids and lipoproteins.

A newly developed methodology for the assessment of mode of inheritance of continuously distributed traits in nuclear families, structured exploratory data analysis (SEDA), is applied to lipid and lipoprotein measurements. Specifically, three measures: the major gene index (MGI), the pairwise midparental correlation coefficient (MPCC), and the offspring between parents (OBP) curves are used to determine whether these trait expressions are more major gene, sporadic, or multifactorial relative to one another. Triglycerides and the closely-related VLDL-cholesterol measurement appears to be transmitted through some major components. HDL-cholesterol measurements are more consistent with some degree of multifactorial transmission or a major gene model with additive allelic effects and similar allele frequencies. The results for LDL-cholesterol suggest a modicum of major gene influences. The composite total cholesterol measurement appears to be under multifactorial transmission but of lower order than height. Younger families who were selected through a parent with high lipid levels exhibit some major gene influences which do not appear in the older families. Several possible explanations are proposed for this difference.

Cholesterol↗

PubMed2005

Hypodontia--a retrospective review of prevalence and etiology. Part I.

A retrospective literature review was carried out to determine the prevalence of hypodontia and current knowledge of associated etiological factors. Reported studies vary widely in their reports of prevalence. The majority are retrospective radiographic studies, and reported rates vary from 2.6% to 11.3%. Racial differences have been determined: in Caucasian studies the mandibular second premolars and maxillary lateral incisors were the most frequently recorded absent and in Asian studies, the mandibular incisor was the most frequently recorded absent. Prevalence rates are higher in females compared to males (3:2, respectively). The association of hypodontia with other systemic conditions and dental anomalies is widely reported. Hypodontia can be regarded as a multifactorial condition. Recent developments in molecular genetics have established the importance of the muscle specific homeobox genes (Msx1 and Msx2) in dental development. Specific genes that are responsible for the more severe types of hypodontia, including ectodermal dysplasia, have been identified by linkage analysis. However, variable expression of the trait suggests a polygenic mode of inheritence with epistatic genes and environmental factors interacting.

Anodontia↗

PubMed2004

Current and future applications of genetics in primary care medicine.

Individualized medical treatment and prevention based on one's genetic makeup are promises likely to be fulfilled over decades. Already family history is taking a more prominent role in preventive care. Primary care clinicians and geneticists will increasingly collaborate to diagnose and manage genetic conditions: both single-gene disorders and multifactorial diseases such as infections,cancers, cardiovascular disease and mental illness. This will require society, with primary care clinicians in the forefront, to implement means for efficient family history-taking; maintaining private, personally accessible genetic health records; safeguarding people from genetic discrimination; distributing access to scarce genetic specialists and expensive technologies; rectifying lay misconceptions about inheritance; managing emotional responses and family dynamics related to genetic diagnosis; and motivating people at increased familial risk to take preventive action.

Genetic Services↗

PubMed1998

[New knowledge of heredity in inflammatory bowel disease. Specific gene mapping in a EU-project].

Chronic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are steadily increasing in prevalence, and one half to one per cent of the Swedish population are currently estimated to be affected. The aetiology remains unknown, but is probably multifactorial. Both dietary, microbiological and immunological causes have been discussed. Clinical studies, including several Swedish studies, have also shown genetic factors to be crucially involved. Findings in sophisticated molecular biological studies suggest certain specific genes to be involved, and a current EU project in which Sweden is participating has been launched to map the mode of inheritance in detail.

Chromosome Mapping↗

PubMed1996

On the genetics of hypodontia and microdontia: synergism or allelism of major genes in a family with six affected members.

Familial severe hypodontia of the permanent dentition is a rare condition. The genetics of this entity remains unclear and several modes of inheritance have been suggested. We report here an increase in the number of congenitally missing teeth after the mating of affected subjects from two unrelated Norwegian families. This condition may be the result of allelic mutations at a single gene locus. Alternatively, incompletely penetrant non-allelic genes may show a synergistic effect as expected for a multifactorial trait with interacting gene products. This and similar kindreds may allow identification of genes involved in growth and differentiation of dental tissues by linkage and haplotype association analysis. Brittle nails, delayed growth of the hair, and delayed teething in the probands support the grouping of these conditions among the ectodermal dysplasias.

Abnormalities, Multiple↗

PubMed1991

[Recent findings on the physiopathology of hypertension].

The numerous pathophysiological theories in the field of essential hypertension are often conflicting, and till now a comprehensive model is not available. The aetiology of human hypertension is probably multifactorial, the control mechanisms of hypertension are strictly interdependent, and the alteration of one induces readjustment of the others, so that it is very difficult to discriminate the "primum movens" from its consequences. In this review the recent acquisitions in the aetiology and the pathophysiology of arterial hypertension are analysed, with particular regard to the role of inheritance, of renal mechanisms of sodium retention, ions transport, humoral factors, central nervous system and of enhanced vascular reactivity. The activation of some of these pathophysiological factors induces the rise in peripheral vascular resistance, which is the final common pathway in the development of essential hypertension.

Biological Transport↗

PubMed1998

Is pseudoexfoliation syndrome inherited? A review of genetic and nongenetic factors and a new observation.

Pseudoexfoliation (PEX) syndrome is the commonest identifiable cause of open-angle glaucoma worldwide. PEX is characterized clinically by small whitish deposits of fibrillar-granular material in the anterior segment of the eye. Despite its prevalence and potential for ophthalmic morbidity, surprisingly little is known about the etiology and pathogenesis of PEX. This article reviews the literature and presents evidence regarding genetic and nongenetic arguments for the etiology of pseudoexfoliation. Lines of evidence that support a genetic basis for PEX include transmission in two-generation families, twin studies, an increased risk of PEX in relatives of affected patients, and HLA studies. Nearly all pedigrees in the literature, and our own experience with PEX families in Iceland and Canada, suggest maternal transmission, raising the possibilities of mitochondrial inheritance, X-linked inheritance, and autosomal inheritance with genomic imprinting. A number of nongenetic factors have also been evaluated for their possible implication in the development of PEX. These include ultraviolet light, autoimmunity, slow virus infection, and trauma. It is possible that a combination of genetic and nongenetic factors may be involved in the etiology and pathogenesis of PEX, i.e. it may be a multifactorial disorder. Further studies with larger numbers of patients are needed to delineate more clearly the contribution of genetic (nuclear DNA, mitochondrial DNA or both) and nongenetic factors to the development of pseudoexfoliation syndrome and pseudoexfoliation glaucoma.

Autoimmunity↗

PubMed2001

Hirschsprung disease, associated syndromes, and genetics: a review.

Hirschsprung disease (HSCR, aganglionic megacolon) is the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has dramatically decreased mortality and morbidity, which has allowed the emergence of familial cases. HSCR appeared to be a multifactorial malformation with low, sex dependent penetrance and variable expression according to the length of the aganglionic segment, suggesting the involvement of one or more gene(s) with low penetrance. So far, eight genes have been found to be involved in HSCR. This frequent congenital malformation now stands as a model for genetic disorders with complex patterns of inheritance.

Chromosome Aberrations↗

PubMed1999

Thrombophilia as a multigenic disease.

BACKGROUND AND OBJECTIVE: Venous thrombosis is a common disease annually affecting 1 in 1000 individuals. The multifactorial nature of the disease is illustrated by the frequent identification of one or more predisposing genetic and/or environmental risk factors in thrombosis patients. Most of the genetic defects known today affect the function of the natural anticoagulant pathways and in particular the protein C system. This presentation focuses on the importance of the genetic factors in the pathogenesis of inherited thrombophilia with particular emphasis on those defects which affect the protein C system. INFORMATION SOURCES: Published results in articles covered by the Medline database have been integrated with our original studies in the field of thrombophilia. STATE OF THE ART AND PERSPECTIVES: The risk of venous thrombosis is increased when the hemostatic balance between pro- and anti-coagulant forces is shifted in favor of coagulation. When this is caused by an inherited defect, the resulting hypercoagulable state is a lifelong risk factor for thrombosis. Resistance to activated protein C (APC resistance) is the most common inherited hypercoagulable state found to be associated with venous thrombosis. It is caused by a single point mutation in the factor V (FV) gene, which predicts the substitution of Arg506 with a Gln. Arg506 is one of three APC-cleavage sites and the mutation results in the loss of this APC-cleavage site. The mutation is only found in Caucasians but the prevalence of the mutant FV allele (FV:Q506) varies between countries. It is found to be highly prevalent (up to 15%) in Scandinavian populations, in areas with high incidence of thrombosis. FV:Q506 is associated with a 5-10-fold increased risk of thrombosis and is found in 20-60% of Caucasian patients with thrombosis. The second most common inherited risk factor for thrombosis is a point mutation (G20210A) in the 3' untranslated region of the prothrombin gene. This mutation is present in approximately 2% of healthy individuals and in 6-7% of thrombosis patients, suggesting it to be a mild risk factor of thrombosis. Other less common genetic risk factors for thrombosis are the deficiencies of natural anticoagulant proteins such as antithrombin, protein C or protein S. Such defects are present in less than 1% of healthy individuals and together they account for 5-10% of genetic defects found in patients with venous thrombosis. Owing to the high prevalence of inherited APC resistance (FV:Q506) and of the G20210A mutation in the prothrombin gene, combinations of genetic defects are relatively common in the general population. As each genetic defect is an independent risk factor for thrombosis, individuals with multiple defects have a highly increased risk of thrombosis. As a consequence, multiple defects are often found in patients with thrombosis.

3' Untranslated Regions↗

PubMed2002

Vestibular dysfunction in the epistatic circler mouse is caused by phenotypic interaction of one recessive gene and three modifier genes.

Vestibular dysfunction is a frequent clinical problem, leading to dizziness and imbalance. Genes play an important role in its etiology, but the genetics are complex and poorly understood. In this study we have analyzed the complex inheritance pattern in the Epistatic circler mouse, which shows circling behavior indicative of vestibular dysfunction in the mouse. This phenotype exists in a proportion of the F2-generation from an intercross between C57L/J and SWR/J mouse strains. Genetic investigation indicates that the circling behavior is caused by a major recessively inherited gene derived from the SWR/J strain (the Ecs-gene) in combination with at least three different modifier genes derived from C57L/J (the Ecl-genes). Genetic mapping made it possible to localize the Ecs-gene to chromosome 14 and the Ecl-genes to chromosome 3, 4, and 13. This study illustrates the feasibility of identifying genes for multifactorial traits in mice.

Animals↗

PubMed2006

Genetics of migraine: an update.

Observations including the long-recognized tendency of migraine to run in families, the high concordance rates for migraine in twins reared together or apart, and the association of specific mutations with a rare migraine form are consistent with a genetic contribution to the disorder. This paper summarizes major findings to date on the genetics of migraine. Study of the heritability of migraine, particularly the common forms of migraine, is beset by several challenges including the absence of easily measurable biological markers, uncertainty about the etiologic and clinical overlap among migraine types, and the apparently complex interplay of environmental and genetic factors in determining migraine phenotype. Nevertheless, significant progress has been realized in recent years. Familial hemiplegic migraine, a rare migraine variant, appears to be transmitted by a Mendelian, autosomal dominant mode of inheritance involving mutations in at least 2 genes. These genes do not seem to be critically involved in the other forms of migraine; however, several other susceptibility loci for more common forms of migraine have been identified in recent genome-wide screens and candidate-locus studies. These and other data suggest that the genetic contribution to migraine is complex, multifactorial, and subject to significant modification by environmental factors.

Calcium Channels↗

PubMed1989

[The prune belly syndrome].

The etiology and pathogenesis of PBS are still quite vague, despite very intensive investigations performed in that field. Numerous data can be found in the literature that contribute to the knowledge of PBS and to the explanation of this condition. Taking into consideration the data available (case descriptions, embryology, experimental embryology, genetics), PBS is meant to occur due to the disturbance of inductive interaction of tissues which leads to a deficient cell differentiation and to the disturbances of the primary field, resulting in multiple malformations which developmentally belong to the primary field in question. The causes inducing deficient tissue differentiation and the impediments disturbing inductive interaction are numerous and various. According to data in the literature, disturbances responsible for the occurrence of PBS can be induced by chemical agents (exposition to Tigan and Bendectin), mechanical agents (intrauterine edema), gene disturbances (described occurrence of PBS in a Nigerian family), and cases of PBS associated with chromosomal anomalies. The condition similar to PBS has been induced experimentally in animals by gene mutation (Danforth's short-tailed rats). If it is accepted that PBS is in a certain number of cases hereditary, it can be presumed that, according to the Nigerian authors, X related recessive transfer is involved here. As males suffering from PBS are sterile, they cannot transfer pathological genes, that is to say the disease itself. The only theoretical possibility for a female child whose karyotype is 46, XX, to be affected by PBS, would be when it inherits one affected X chromosome from its mother, while the second X chromosome has a mutation de novo. This could be an explanation for an extremely rare occurrence of PBS in female persons. The other explanation, according to McKusick, is that PBS can be also autosomally dominantly inherited (de novo mutation). The incidence of PBS in the female population is probably somewhat increased by "non-genic" etiological factors (chemical and mechanical agents). It is very difficult to say how strong is the influence of a certain factor on the occurrence of PBS. Therefore, it could be concluded that the etiology of PBS is heterogeneous, chromosomal, genic, and multifactorial, but regardless of the factor, it is always the primary field that is affected (in this case the ability of inductive interaction of the mesenchyme) leading to all other disturbances. Everything mentioned so far indicates that according to valid criteria, PBS can be regarded as a malformation, that is, a primary developmental disturbance.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗

PubMedDate not supplied

Genetics of human body size and shape: complex segregation analysis.

The genetic component in a mixed heritability model, including major gene, multifactorial and sibling environment transmissible components, was studied for some 20 anthropometric traits in two ethnically different samples. The first sample comprised 305 Mexican nuclear families, and the second comprised 83 Ashkenazi Jewish nuclear families living in Israel. All variables, after adjustment for age and sex, were subjected to principal-components analysis (PCA) in each sample separately. The mixed model of inheritance as implemented in the computer program POINTER was used in the present study. An attempt was made to evaluate genetic effects in the variation of the first principal components (PCs). PCA showed a clear separation of variables and was easily interpretable. The PC1 was a credibly general size factor. This factor alone accounted for about 30% of the total variance. Other components are rather shape factors for various combinations of traits. The testing of several genetic hypothesis showed the following: (1) For all factor scores the genetic component was high and statistically significant. (2) In a Mexican sample, for PC1 and PC2, both major gene and polygenes contributed significantly to the total variation of these variables; in the major locus the alleles were most probably codominant. (3) For all other PCs the major gene effect hypothesis was rejected, with more than 50% of the variation attributable to the polygenes contribution. (4) No evidence was found for sibling environmental resemblance in either sample.

Adolescent↗

PubMed1993

Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome.

We evaluated the families of 50 children with idiopathic congenital central hypoventilation syndrome (CCHS) to 1) test genetic hypotheses, 2) explore the relationship to Hirschsprung disease (HD), and 3) examine other clinical findings including sudden infant death syndrome (SIDS) in relatives of CCHS patients. A questionnaire was administered to parents of each proband to determine a detailed pedigree and medical history for 3 generations including 1,482 relatives. The data were analyzed under the unified mixed model method (assumes individual genotype composed of multifactorial [MF] and major locus [ML] components). Analysis was made of the Total dataset and on subdivided data sets: HIR1 = families of probands with HD (n = 8) vs. HIR2 = families of probands without HD; then under a premise that severe, chronic constipation may be a milder form of HD (i.e., ganglion cells present but dysfunctional), CON1 = families of probands with HD or constipation (n = 13) vs. CON2 = families of probands without HD or constipation. By statistical genetic analysis of the Total, HIR1, and CON1 datasets, the MF and ML hypotheses were about equally likely, with the MF model slightly more parsimonious. Although HIR2 and CON2 datasets indicated no familiality, statistical evidence of heterogeneity between the results of HIR1 and HIR2, or between CON1 and CON2 was lacking. A SIDS incidence of 11.2/1,000 was documented among the relatives of CON1 vs. 1.8/1,000 among relatives of CON2. Our results are consistent with familiality by either MF or ML models. Recurrence risk is likely < 5%. The relationship of CCHS to the high familial incidence of SIDS is intriguing and demands further investigation.

Female↗

PubMed1998

Evidence for multiple determinants of the body mass index: the National Heart, Lung, and Blood Institute Family Heart Study.

The body mass index (BMI) is a complex phenotype representing the amount of fat mass, lean mass, body build and proportions, and it is likely to be affected by various metabolic processes, hormonal effects, energy intake and expenditure, and interactions within and among these broad categories of etiologic factors. Nonetheless, several previous studies have reported evidence for major gene segregation for the BMI in various populations. Data on a random sample of Caucasian families participating in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study were analyzed to document the extent of familial resemblance and to investigate whether a similar monogenic inheritance pattern could be detected. Genetic analysis was carried out on age- and sex-adjusted BMI values. Familial correlations were significant implying a maximal heritability, including all genetic and environmentally inherited additive factors, of 41% to 59%. Segregation analysis revealed the presence of two maximum likelihood solutions, one characterized as a recessive Mendelian gene and the other as a major effect with an ambiguous transmission pattern. The presence of two such solutions is consistent with detection of two separate factors, each influencing the BMI distribution in a substantive manner. The evidence also supports a multifactorial background for BMI and suggests that the frequencies of these two factors, one of which appears to be a gene, may vary among diverse populations in the United States.

Body Mass Index↗