Complex segregation analysis provides evidence for a major gene acting on serum triglyceride levels in 55 British families with familial combined hyperlipidemia.
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Abstract:
Familial combined hyperlipidemia (FCHL) was first described as an autosomal dominant inherited trait with primary action on triglyceride levels and secondary effects on cholesterol metabolism. This conclusion has since been questioned by several groups despite subsequent supportive biochemical and metabolic studies. To reexplore the genetics of FCHL, we assembled 55 families from the United Kingdom comprising 559 persons ascertained through probands with both hypercholesterolemia and hypertriglyceridemia. The results of univariate complex segregation analysis were consistent with a major gene acting on triglyceride and explaining two thirds of the genetic variability and 20% of the phenotypic variance in triglyceride levels. Univariate analysis did not identify a major genetic component acting on cholesterol levels. Bivariate segregation analysis rejected a major gene model. We also reexamined the original FCHL pedigrees collected by Goldstein et al and obtained results similar to those in the UK families. The prospects for mapping putative major genes determining triglyceride levels in FCHL patients by linkage analysis are discussed.Keywords:
Pedigree chart
Major gene
Hyperlipidemia
Genetic Analysis
The most generally accepted model for cleft lip/palate not associated to specific syndromes has been the one that postulates multifactorial inheritance with a threshold. Recent studies using complex analytical techniques have suggested the existence of a major gene with decreased penetrance in its etiology. Some authors have postulated that only a fraction of all cases of non-syndromic CL (P) would be explained by a single major gene. Other cases may be due to different genes, to environmental agents or to the interaction between them. The present study tests the monogenic inheritance model for CL (P) using segregation analysis in a sample of 211 extended pedigrees collected through CL (P) affected probands. The hypotheses of an autosomic recessive gene was analyzed in 151 sibships (size 2 or more) using "Apert's" method, "maximum likelihood method", "singles method" and "sib's, method" (single incomplete ascertainment). Results obtained do not support the hypotheses of autosomal recessive inheritance. Instead, the hypothesis of an autosomal dominant mode of inheritance with low penetrance is not rejected when analyzing the proportion of normal and affected progeny in certain types of matings in a subsample of 30 extended pedigrees with two or more affected individuals.
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W403(a round-shaped) and W405(a pear-shaped var.cerasiforme) were employed to establish six genealogical pop-ulations(P1,F1,P2,B1,B2 and F2).The Fruit length of the populations were analyzed by means of classic genetics and the ma-jor gene + polygene mixed inheritance model of quantitative traits;The analysis indicated that the Fruit length in W403 was controlled by a recessive major gene and the inheritance of the Fruit length fitted one major gene plus polygene model.Heri-tability values of the major genes of B1,B2 and F2 population were estimated as 0%,19.94% and 26.67% respectively,while those polygene were 70.20%,54.73% and 48.78%.These results indicated that major gene in F2 was a key factor and environ-ment factor was also relatively important.This implies that in the genetic improvement of Fruit length major gene is a main fac-tor whereas environmental effect should be taken care of.
Polygene
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Genetic Analysis
Lycopersicon
genetic model
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Genetic epidemiology
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Genetic linkage
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Hyperlipidemia
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315 pedigrees with idiopathic mental retardation (MR) have been studied by complex segregation analysis. The results show that there is no major gene effect in the mild MR, but in the medium and severe MR there are major gene effect. The pattern of inheritance of the medium MR may be codominant and the penetrance of the dominant gene is 0.91. The mode of inheritance of the severe MR may be recessive and probably without sporadic cases.
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Serum concentrations of cholesterol, triglycerides, high density lipoprotein-cholesterol (HDL-C), apoproteins (apo) A and B were compared in 36 hemodialysis patients and in 20 normal controls. Hyperlipidemia was present in 22 patients (59.4%); 15 of them had simple hypertriglyceridemia and 7 had combined hyperlipidemia (i.e., hypertriglyceridemia and hypercholesterolemia). All hemodialysis patients, whether normo- or hyperlipidemic, had normal apo A and low HDL-C serum concentrations. Positive risk factors for atherosclerosis other than low HDL-C (high serum apo B concentration and low apo A/apo B ratio) were present in hyperlipidemic patients only, with no difference between those with simple hypertriglyceridemia and combined hyperlipidemia. These results suggest that the risk for atherosclerosis related to lipid abnormalities may be considered as substantial in hyperlipidemic hemodialysis patients, but not in normolipidemic ones, regardless of the cholesterolemic values.
Hyperlipidemia
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The present study was undertaken to examine the pattern inheritance of Cleft Lip/Palate (CLP) in pedigrees ascertained from Antioquia, Colombia. Ninety-five extended and multigenerational pedigrees, constituted by 201 nuclear components and 1.136 records were analyzed. Ten hypothetical models were contrasted using likelihood ratio tests. The hypotheses of no familial transmission, multifactorial component compared against that of the existence of a major gene only, the existence of a recessive major gene, that of non major component in the mixed model and that of the non transmission of major effect (t1 = t2 = t3) were rejected. In contrast, hypotheses postulating a major locus (dominant, codominant) and that of no polygenic component in the mixed model could not be rejected. Iteration of the parameter t2 was the most parsimonious. Thus far, the most parsimonious model is that of a major gene (dominant, codominant) without multifactorial effects but, taking into account, that the t2 iteration in the major gene model with unrestricted d, result in a significantly improving of the model likelihood, oligogenic interactions can not be underrated.
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Nonsyndromic cleft lip with or without cleft palate (CL/P) has an incidence of 1.5 per 1,000 live births in Chile, with 1.7 per 1,000 in males and 1.3 per 1,000 in females, which is nearly the same as the level found in Asian populations. The high rate of occurrence of CL/P in Chile is probably due to the presence of Amerindian genes in Chilean populations. Using the computer program PAP, a complex segregation analysis of CL/P was conducted for 67 multigeneration pedigrees from Chile, each ascertained from one affected proband. These pedigrees yielded 162 affected individuals and over 898 family members who were included in the analysis. The most parsimonious model of transmission indicated the presence of an autosomal dominant gene with reduced (20-25%) penetrance.
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Segregation analysis using a model with age and gender effects was applied to 101 pedigrees ascertained through a proband with idiopathic scoliosis. The transmission probability model was used to detect major gene effect. When we analyzed the pedigrees where affected status was assigned to persons with a Cobb's angle of more than 5 degrees we did not detect a significant major gene effect. However, when the affected status was assigned to persons with pronounced forms of disease only (a curve of at least 11 degrees) a significant contribution of a major causal gene could be established and inheritance could be described according to a dominant major gene diallele model, assuming incomplete sex and age dependent penetrance of genotypes. According to this model, the pronounced forms of idiopathic scoliosis should never occur in the absence of the mutant allele. This indicates that only the carriers of the mutant allele develop pronounced forms of the disease. At the same time, only a fraction of the carriers of the mutant gene should manifest the disease (30% of males and 50% of females). Am. J. Med. Genet. 86:389–394, 1999. © 1999 Wiley-Liss, Inc.
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Segregation analysis using a model with age and gender effects was applied to 101 pedigrees ascertained through a proband with idiopathic scoliosis. The transmission probability model was used to detect major gene effect. When we analyzed the pedigrees where affected status was assigned to persons with a Cobb's angle of more than 5 degrees we did not detect a significant major gene effect. However, when the affected status was assigned to persons with pronounced forms of disease only (a curve of at least 11 degrees) a significant contribution of a major causal gene could be established and inheritance could be described according to a dominant major gene diallele model, assuming incomplete sex and age dependent penetrance of genotypes. According to this model, the pronounced forms of idiopathic scoliosis should never occur in the absence of the mutant allele. This indicates that only the carriers of the mutant allele develop pronounced forms of the disease. At the same time, only a fraction of the carriers of the mutant gene should manifest the disease (30% of males and 50% of females). Am. J. Med. Genet. 86:389–394, 1999. © 1999 Wiley-Liss, Inc.
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