Common major gene inheritance of extreme overweight

We studied 3925 individuals in 961 families to determine the mode of inheritance of overweight. As an index of overweight, we examined body mass index. Our analyses indicate that the most likely genetic model for susceptibility to overweight included moderate polygenic inheritance (34% of variance resulting from many genes with small effects) and common (21% frequency) recessively expressed major genes (a few genes with large effects on the individuals who possess them). Standard statistical criteria for accepting both polygenic and major gene inheritance were met, including tests of Mendelian transmission. These results suggest that recessive major gene inheritance of overweight may be common and that homozygosity for overweight susceptibility alleles often results in overweight. Clinical, biologic, and empirical observations all suggest genetic heterogeneity, that is, more than one predisposing gene.     

A genetic study of Hirschsprung disease

Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed to be a sex-modified multifactorial trait. To test this hypothesis, complex segregation analysis was performed on data on 487 probands and their families. Demographic information on probands and the recurrence risk to relatives of probands are presented. An increased sex ratio (3.9 male:female) and an elevated risk to sibs (4%), as compared with the population incidence (0.02%), are observed, with the sex ratio decreasing and the recurrence risk to sibs increasing as the aganglionosis becomes more extensive. Down syndrome was found at an increased frequency among affected individuals but not among their unaffected sibs, and the increase was not associated with maternal age. Complex segregation analysis was performed on these family data. The families were classified into separate categories by extent of aganglionosis. For cases with aganglionosis beyond the sigmoid colon, the mode of inheritance is compatible with a dominant gene with incomplete penetrance, while for cases with aganglionosis extending no farther than the sigmoid colon, the inheritance pattern is equally likely to be either multifactorial or due to a recessive gene with very low penetrance. A model of gene action with random effects during morphogenesis is compatible with our observations.     

Bivariate analyses of cholesterol and triglyceride levels in families in which probands have type IIb lipoprotein phenotype.

Univariate and bivariate analyses of cholesterol and triglycerides are performed after appropriate age adjustment on 247 individuals in 33 families where the probands have elevations of cholesterol, low density lipoprotein and triglycerides, and type IIb lipoprotein phenotype. Mixture of lognormal distributions are fitted by maximum likelihood to the data. Best fitting single and mixtures of lognormal distributions are compared with empirical cumulative plots, and the likelihood-ratio criterion is used to test for significance. A mixture of two lognormal distributions fits significantly better than one lognormal distribution for cholesterol but not for triglycerides. When a mixture of bivariate lognormals is fitted to the data, only one local maximum is found, suggesting action of a single genetic determinant in this sample. The best cutoff line is almost parallel to the triglyceride axis, indicating the relatively high involvement of cholesterol compared to triglycerides in separating the normal and abnormal groups. Using the best linear function, the difference in the two bivariate means is found to account for 61% of the total variation in log cholesterol and log triglycerides. To determine if the results are due to enrichment of the sample with familial hypercholesterolemia syndrome, seven families where the proband and/or any relative has tendon xanthomas are removed and the analyses repeated on the remaining 26 kindreds. The results of these analyses are virtually the same as those of the total sample. Also, a subsample of 21 families in which the proband and at least one additional kindred member are affected is analyzed in the same manner with similar results. For comparison, data from a study of families with combined hyperlipidemia [1] are analyzed in an analogous manner, bearing in mind that the populations sampled are probably different. Fitting a mixture of two bivariate distributions and finding the best cutoff to these data indicate that triglycerides are more involved in separating the two groups. Probably because of major differences in ascertainment, the distribution of lipid levels in oour patient group is practically indistinguishable from that of hypercholesterolemia, and the Seattle data [1] are more nearly similar to hypertriglyceridemia. It may be premature to consider familial combined hyperlipidemia as an entity distinct from both hypercholesterolemia and hypertriglyceridemia. We hope it will eventually be possible to analyze these data using a refined genetic model that includes both major gene and polygenic effects and to combine this form of analysis with quantitative tissue culture methods.     

Segregation analysis of schizophrenia and related disorders

Segregation analysis was applied to 79 nuclear families ascertained through chronic schizophrenic probands. Analysis was performed on the diagnosis of schizophrenia alone and on schizophrenia and schizotypal personality disorder (milder phenotype) combined. The models used were the transmission probability model and the mixed model. Because the disease is associated with reduced fertility, all likelihoods were calculated conditional on parental phenotypes. However, compatibility of the mating-type distribution predicted by each model with the observed was also examined. In all analyses, results suggested consistency with genetic transmission. In the analysis of schizophrenia alone, discrimination among models was difficult. In the analysis including the milder phenotypes, all single-locus models without polygenic background were excluded, while pure polygenic inheritance could not be eliminated. The polygenic model also gave good agreement with supplementary observations (lifetime disease incidences, mating-type distribution, and monozygotic twin concordance). The estimated components of variance for the polygenic model were: polygenes (H) 81.9%; common sib environment (B) 6.9%; random environment (R) 11.2%. Although the polygenic model was parsimonious, segregation analysis and the supplementary observations were also consistent with a mixed model, with a single major locus making a large contribution to genetic liability. Such a locus is more likely to be recessive than dominant, with a high gene frequency and low penetrance. The most likely recessive mixed model gave the following partition of liability variance: major locus, 62.9%; polygenes, 19.5%; common sib environment, 6.6%; and random environment, 11.0%.     

Inheritance of cholesterol metabolism of probands with high or low cholesterol absorption

Heredity of cholesterol absorption and synthesis was studied in siblings of hypercholesterolemic probands with low and high serum cholestanol to cholesterol ratio (assumed to indicate low and high absorption of cholesterol, respectively). Cholesterol synthesis was assayed with sterol balance technique and measuring serum cholesterol precursor to cholesterol ratios (synthesis markers of cholesterol), and cholesterol absorption with measuring dietary cholesterol absorption percentage and serum plant sterol and cholestanol to cholesterol ratios (absorption markers of cholesterol). In the siblings of the low absorption families, cholesterol absorption percentage and ratios of absorption markers were significantly lower, and cholesterol and bile acid synthesis, cholesterol turnover, fecal steroids and ratios of synthesis markers significantly higher than in the siblings of the high absorption families. The ratios of absorption and synthesis markers were inversely interrelated, and they were correlated with cholesterol absorption and synthesis in the siblings. In addition, low absorption was associated with high body mass index, low HDL cholesterol, and serum sex hormone binding globulin levels, suggesting that low absorption was associated with metabolic syndrome. Intrafamily correlations were significant for serum synthesis markers, cholestanol, triglycerides, and blood glucose level. In conclusion, cholesterol absorption efficiency and synthesis are partly inherited phenomena, and they can be predicted by the ratios of non-cholesterol sterols to cholesterol in serum.     

Analysis of family resemblance. IV. Operational characteristics of segregation analysis.

In simulated data, segregation analysis of quantitative traits was found to be powerful for resolving a major locus from polygenic and cultural inheritance. It is reasonably robust against a variety of deviations from the model if and only if a major locus, polygenic heritability, and environment common to sibs are simultaneously included in the model, and heterogeneity tests among mating types are performed. Most of the information in quantitative data about a major locus is lost when reduced to affection status.     

Segregation analysis of cleft lip with or without cleft palate in the First Nations (Amerindian) people of British Columbia and review of isolated cleft palate etiologies

BACKGROUND: The First Nations (Amerindian) population of British Columbia, Canada, has the highest reported birth prevalence in the world of cleft lip with or without cleft palate (CL/P) at nearly 3 per 1000 births. In addition, a substantial proportion of cleft palate only (CPO) cases in this population has been reported to be X‐linked. The aims of this study were to perform complex segregation analysis to investigate the mode of inheritance of CL/P in the First Nations people of British Columbia and to review the etiology of the CPO cases. METHODS: All First Nations children born in British Columbia between 1952 and 1971 with an orofacial cleft were included in the study. Multiple sources of ascertainment were used, so that nearly 100% of live births were identified and included during this time. No stillbirths were found but would likely have been ascertained. Extended pedigrees were constructed from these probands and examination of immediate family members, e.g., parents and siblings, was done wherever possible. Complex segregation analysis included all family members. In addition, a CPO case review was conducted. RESULTS: Complex segregation analysis supports the hypothesis that the most likely mode of inheritance of CL/P in this population is a mixed model; that is, an autosomal major gene with polygenic component. The review of 26 CPO cases showed that a substantial proportion are syndromic. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

The Design of Inheritance Studies

In a study of the inheritance of a quantitative trait in the general population, data are collected from the three-generational nuclear families of many index cases. The question arises as to the optimal choice of family members to maximise the power of testing a hypothesis of polygenic and environmental effects against an alternative of environmental effects only. The method chosen is to minimise the asymptotic variance of the ratio of polygenic to environmental variance, for fixed total variance and the environmental correlations between family members. Using Taylor expansions in the region where the ratio is close to zero, an approximate expression for the variance of the ratio is obtained. This expression can then be evaluated for all possible structures of a three-generational nuclear family of a given size.     

Genetics of obesity in adult adoptees and their biological siblings.

An adoption study of genetic effects on obesity in adulthood was carried out in which adoptees separated from their natural parents very early in life were compared with their biological full and half siblings reared by their natural parents. The adoptees represented four groups who by sampling from a larger population were categorised as either thin, medium weight, overweight, or obese. Weight and height were obtained for 115 full siblings of 57 adoptees and for 850 half siblings of 341 adoptees. In full siblings body mass index (kg/m2) significantly increased with weight of the adoptees. Body mass index of the half siblings showed a steady but weaker increase across the four weight groups of adoptees. There were no significant interactions with sex of the adoptees, sex of the siblings, or (for the half siblings) sex of the common parent. In contrast with the findings in half siblings and (previously) the natural parents there was a striking, significant increase in body mass index between full siblings of overweight and obese adoptees. The degree of fatness in adults living in the same environment appears to be influenced by genetic factors independent of sex, which may include polygenic as well as major gene effects on obesity.     

Exomphalos in four consecutive pregnancies

Summary Four consecutively born siblings were affected by Exomphalos. In 2 cases, major and minor anomalies were associated. Cytogenetic examination of the fourth infant revealed a normal karyogram. The parents and their families did not exhibit any relevant genetic defect. On the other hand it is unlikely that such a series of exomphalos was due to chance.The increased liability to exomphalos might be conditioned by a polygenic multifactorial system and induced by environmental influences of an unknown nature. Recessive inheritance is not excluded.     

Hypercholesterolemia in five Israeli Christian-Arab kindreds is caused by the “Lebanese” allele at the low density lipoprotein receptor gene locus and by an additional independent major factor

Summary Segregation analyses were performed for plasma low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) in five Christian Arab kindreds identified through probands with familial hypercholesterolemia. In this subset of the Christian Arab community, the results were consistent with major gene determination of LDL-C with allele frequency (q) of 0.042 (95% confidence interval 0.008–0.079) in addition to polygenic transmission (h ²= 0.34). The Lebanese allele was identified directly by polymerase chain reaction and HinfI restriction analysis. Analysis of this mutation permits direct diagnosis of familial hypercholesterolemia in most affected individuals although our results indicated the possible existence of an additional independent factor leading to elevated LDL-C levels. The segregation results for TG indicated the presence of a major effect, although the existence of a major gene could not be demonstrated. There was also no evidence of a major locus effect on HDL-C levels.     

A maximum likelihood-based method for mining major genes affecting a quantitative character

In this article, we present a maximum likelihood-based analytical approach for detecting a major gene of large effect on a quantitative trait in a progeny population derived from a mating design. Our analysis is based on a mixed genetic model specifying both major gene and background polygenic inheritance. The likelihood of the data is formulated by combining the information about population behaviors of the major gene during hybridization and its phenotypic distribution densities. The EM algorithm is implemented to obtain maximum likelihood estimates for population and quantitative genetic parameters of the major locus. This approach is applied to detect an overdominant gene governing stem volume growth in a factorial mating design of aspen trees. It is suggested that further molecular genetic research toward mapping single genes affecting aspen growth and production based on the same experimental data has a high probability of success.     

Estimation of environmental and genetic components of quantitative traits with application to serum cholesterol levels.

A mixed model of environmental, polygenic, and major locus effects is developed, allowing for environmental correlations between first-degree relatives and spouses. Maximum-likelihood techniques are used to determine the relative contributions of each of these effects to a quantitative trait. Inclusion of a nuclear family in the sample is assumed to depend on the value of the quantitative trait of one member of the family, so conditional distributions are used. Application of the method to serum cholesterol data from the general population shows that the addition of a polygenic effect to a model that assumes only an environmental effect makes a significant improvement. A completely dominant single gene is also found to be influencing serum cholesterol levels. Although cholesterol levels have been adjusted for a range of factors, such as age, sex, weight/height, and marital status, environmental factors still account for about half the variability in the residual values.     

Inheritance of acute appendicitis: familial aggregation and evidence of polygenic transmission.

We explored familiality as well as the heritability and possible mode(s) of inheritance of acute appendicitis in childhood and early adolescence. Our case-control study showed that a positive family history for reported appendectomy was significantly more frequent in families of 80 consecutive patients eventually proved to have histopathologic acute appendicitis than in families of surgical controls matched for sex, age, and number of siblings. The relative risk was 10.0 (95% confidence limits 4.7-21.4). The pattern of familial aggregation was further supported by the fact that the age-standardized morbidity ratio was four times greater among family members of cases than among controls. We then applied the unified mixed model of segregation analysis, as implemented in the computer program POINTER, to a new set of 100 multigenerational pedigrees of children with histopathologically confirmed acute appendicitis that were broken down into 674 nuclear families. Age-specific morbidity risk and lifetime incidence of acute appendicitis were estimated from relatives of controls matched for age and sex to probands. Complex segregation analysis supported a polygenic or multifactorial model with a total heritability of 56%. There was no evidence to support a major gene, although a rare gene could not be ruled out as the cause of a small proportion of cases. Specific studies to address genetic and environmental factors in this serious disease seem worthwhile; but, for now, a positive family history of appendicitis might join other evidence leading to improved clinical recognition of acute appendicitis.     

Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families

Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair, the result of loss of melanocytes from involved areas. The most common disorder of pigmentation, vitiligo occurs with a frequency of 0.1-2.0% in various populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance. We surveyed 2624 vitiligo probands from North America and the UK regarding clinical characteristics, familial involvement, and association with other autoimmune disorders, the largest such survey ever performed. More than 83% of probands were Caucasians, and the frequency of vitiligo appeared approximately equal in males and females. The frequency of vitiligo in probands' siblings was 6.1%, about 18 times the population frequency, suggesting a major genetic component in disease pathogenesis. Nevertheless, the concordance of vitiligo in monozygotic twins was only 23%, indicating that a non-genetic component also plays an important role. Probands with earlier disease onset tended to have more relatives affected with vitiligo, suggesting a greater genetic component in early onset families. The frequencies of six autoimmune disorders were significantly elevated in vitiligo probands and their first-degree relatives: vitiligo itself, autoimmune thyroid disease (particularly hypothyroidism), pernicious anaemia, Addison's disease, systemic lupus erythematosus, and probably inflammatory bowel disease. These associations indicate that vitiligo shares common genetic aetiologic links with these other autoimmune disorders. These results suggest that genomic analysis of families with generalized vitiligo and this specific constellation of associated autoimmune disorders will be important to identify the mechanisms of genetic susceptibility to autoimmunity.     

Evidence of a major gene from Bayesian segregation analyses of liability to osteochondral diseases in pigs

Bayesian segregation analyses were used to investigate the mode of inheritance of osteochondral lesions (osteochondrosis, OC) in pigs. Data consisted of 1163 animals with OC and their pedigrees included 2891 animals. Mixed-inheritance threshold models (MITM) and several variants of MITM, in conjunction with Markov chain Monte Carlo methods, were developed for the analysis of these (categorical) data. Results showed major genes with significant and substantially higher variances (range 1.384-37.81), compared to the polygenic variance (sigmau2). Consequently, heritabilities for a mixed inheritance (range 0.65-0.90) were much higher than the heritabilities from the polygenes. Disease allele frequencies range was 0.38-0.88. Additional analyses estimating the transmission probabilities of the major gene showed clear evidence for Mendelian segregation of a major gene affecting osteochondrosis. The variants, MITM with informative prior on sigmau2, showed significant improvement in marginal distributions and accuracy of parameters. MITM with a "reduced polygenic model" for parameterization of polygenic effects avoided convergence problems and poor mixing encountered in an "individual polygenic model." In all cases, "shrinkage estimators" for fixed effects avoided unidentifiability for these parameters. The mixed-inheritance linear model (MILM) was also applied to all OC lesions and compared with the MITM. This is the first study to report evidence of major genes for osteochondral lesions in pigs; these results may also form a basis for underpinning the genetic inheritance of this disease in other animals as well as in humans.     

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

In an attempt to identify the possible role of major genes, multifactorial inheritance, and cohort effects in the susceptibility to idiopathic epilepsy with generalized tonic-clonic seizures of the awakening type (GTCS), complex segregation analysis was performed in 196 nuclear families ascertained through affected probands with idiopathic epilepsy with GTCS belonging to the Paisa community of Antioquia (Colombia). Models postulating no transmission, single major locus (dominant and recessive) only, and multifactorial component only, were rejected. Since the codominant single major locus model could not be rejected and models that assign no major locus to transmission, no polygenic component to transmission, and no transmission of the major effect were rejected, complex segregation analysis suggested that a major autosomal codominant allele together with a multifactorial component (mixed model) best explained clustering of idiopathic epilepsy with GTCS in families of the Paisa community. The deficit of transmission of heterozygotes (0.17) is compatible with the existence of epistasis acting on a major gene whose frequency was estimated to be 0.0211. Its transmission variance accounts for 81% of the susceptibility to idiopathic epilepsy with GTCS. The complementary variance (19%) is due to the polygenic component. Received: 19 January 1996 / Revised: 11 March 1996     

A rapid screening method for hepatocyte nuclear factor 1 alpha frameshift mutations; prevalence in maturity-onset diabetes of the young and late-onset non-insulin dependent diabetes

Non-insulin dependent diabetes (NIDDM) is a polygenic heterogeneous disorder of glucose homeostasis. Maturity-onset diabetes of the young (MODY) is a monogenic subtype of NIDDM characterised by early-onset (< 25 years) and autosomal dominant inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1α) gene have recently been shown to cause MODY. The incidence of mutations in this gene in MODY and late-onset NIDDM is not known. We have developed a rapid specific polymerase chain reaction test for HNF-1α mutations; this test involves the use of fluorescently labelled forward primers and modified reverse primers to detect length polymorphisms resulting from frameshift mutations. With this method, we have screened 102 MODY probands, viz. 60 defined according to strict diagnostic criteria (autosomal dominant inheritance and at least one member diagnosed age < 25 years) and 95 late-onset NIDDM probands (diagnosed 35–70 years with ≥ 1 affected relative), for the presence of 9 known HNF-1α frameshift mutations, including 6 that occur at two sites for recurring mutation (residues 291/292 and 379). Mutations were detected in 11 of the strictly defined MODY probands and one mutation was also found in a single subject with early-onset NIDDM but no family history of the disease. The HNF-1α frameshift mutations were not detected in any late-onset NIDDM subjects, suggesting these mutations do not have a major role in the pathogenesis of NIDDM. Our results indicate that the prevalence of the nine frameshift mutations in strictly defined UK MODY is 18%, with the P291fsinsC mutation alone having a frequency of 13%. Received: 13 May 1997 / Accepted: 13 August 1997     

Genetics of nonsyndromic cleft lip with or without cleft palate: is there a Mendelian sub-entity?

The mode of inheritance of nonsyndromic cleft lip with or without cleft palate (NSCLP) is still a matter of dispute. We performed segregation analysis on three data sets of families ascertained through an affected child with NSCLP. The first two data sets were selected in France and were pooled for a global analysis. No major gene effect could be evidenced in spite of a very large number of families (666 pedigrees including 719 nuclear families). The third data set was British and consisted of three-generation families including the offspring of probands. A major gene effect, as well as a strong residual multifactorial component, were highly significant and we could show that this evidence almost entirely came from the information on probands' offspring. We conclude that a mixture of monogenic and of multifactorial cases is probably the best explanation for the observations made in this study. Analyses performed in pedigrees with multiple cases closely related might allow reducing heterogeneity and help identifying those Mendelian sub-entities.