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PubMed1998

Genetic influence on the prevalence of torus palatinus.

Torus palatinus (TP) represents a benign anatomic variation. It has been suggested that genetic factors play a leading role in its occurrence. The purpose of the present study was to determine, by segregation analysis, the inheritance of TP. Data were collected from members of 37 randomly selected Israel Jewish families and analyzed using the segregation analysis. Vertical transmission of TP was found in 19 families suggesting autosomal dominant transmission, which was supported by the results of the segregation analysis test. A significantly higher number of affected offspring (60.3%) was observed compared to the expected figure (50%) for an autosomal dominant trait with full penetrance. This is explained by the high gene frequency of TP and the relatively high proportion of homozygous parents.

Adult↗
PubMed1998

Familial clustering of rheumatoid arthritis with other autoimmune diseases.

Previous studies have shown that rheumatoid arthritis aggregates within families. However, no formal genetic analysis of rheumatoid arthritis in pedigrees together with other autoimmune diseases has been reported. We hypothesized that there are genetic factors in common in rheumatoid arthritis and other autoimmune diseases. Results of odds-ratio regression and complex segregation analysis in a sample of 43 Caucasian pedigrees ascertained through a rheumatoid arthritis proband or matched control proband, revealed a very strong genetic influence on the occurrence of both rheumatoid arthritis and other autoimmune diseases. In an analysis of rheumatoid arthritis alone, only one inter-class measure, parent-sibling, resulted in positive evidence of aggregation. However, three inter-class measures (parent-sibling, sibling-offspring, and parent-offspring pairs) showed significant evidence of familial aggregation with odds-ratio regression analysis of rheumatoid arthritis together with all other autoimmune diseases. Segregation analysis of rheumatoid arthritis alone revealed that the mixed model, including both polygenic and major gene components, was the most parsimonious. Similarly, segregation analysis of rheumatoid arthritis together with other autoimmune diseases revealed that a mixed model fitted the data significantly better than either major gene or polygenic models. These results were consistent with a previous study which concluded that several genes, including one with a major effect, is responsible for rheumatoid arthritis in families. Our data showed that this conclusion also held when the phenotype was defined as rheumatoid arthritis and/or other autoimmune diseases, suggesting that several major autoimmune diseases result from pleiotropic effects of a single major gene on a polygenic background.

Adult↗
PubMed2005

A genetic contribution to intraocular pressure: the beaver dam eye study.

PURPOSE: To investigate a potential genetic contribution to intraocular pressure (IOP), we performed a complex segregation analysis on 2337 individuals in 620 extended pedigrees ascertained through a population-based cohort, the Beaver Dam Eye Study (BDES). IOP is a principal risk factor for primary open-angle glaucoma (POAG) a leading cause of blindness worldwide. METHODS: Segregation analysis is an analytical method that provides statistical evidence supporting the involvement of a major gene or polygenes in a particular phenotype. Detailed medical histories and eye examinations were performed on all participants. From the two eyes, the higher IOP measurement was used as a continuous trait after adjustment for covariates. A genome-wide scan (GWS) using affected sib pair linkage analysis was performed on 218 sibling pairs. RESULTS: In this segregation analysis the model that allowed for an unmeasured major environmental effect plus a polygenic/multifactorial effect provided the best fit and was the most parsimonious model. The lack of an adequate fit for the Mendelian single-gene models is consistent with a multifactorial model of inheritance that may include multiple genes and environmental factors that contribute to IOP. The results of the GWS yielded two novel loci as potential linkage regions for IOP on chromosomes 6 (P = 0.008) and 13 (P = 0.0007). Neither of these regions has previously been identified in GWS of POAG. CONCLUSIONS: The segregation and familial correlation analyses of IOP suggest a polygenetic component with environmental influences. The pilot linkage study further confirms the heterogeneity of IOP with the identification of two novel genetic loci.

Adult↗
PubMed1996

Conclusion of LOD-score analysis for family data generated under two-locus models.

The power to detect linkage by the LOD-score method is investigated here for diseases that depend on the effects of two genes. The classical strategy is, first, to detect a major-gene (MG) effect by segregation analysis and, second, to seek for linkage with genetic markers by the LOD-score method using the MG parameters. We already showed that segregation analysis can lead to evidence for a MG effect for many two-locus models, with the estimates of the MG parameters being very different from those of the two genes involved in the disease. We show here that use of these MG parameter estimates in the LOD-score analysis may lead to a failure to detect linkage for some two-locus models. For these models, use of the sib-pair method gives a non-negligible increase of power to detect linkage. The linkage-homogeneity test among subsamples differing for the familial disease distribution provides evidence of parameter misspecification, when the MG parameters are used. Moreover, for most of the models, use of the MG parameters in LOD-score analysis leads to a large bias in estimation of the recombination fraction and sometimes also to a rejection of linkage for the true recombination fraction. A final important point is that a strong evidence of an MG effect, obtained by segregation analysis, does not necessarily imply that linkage will be detected for at least one of the two genes, even with the true parameters and with a close informative marker.

Alleles↗
PubMed2002

Evaluation of the genetic basis of tricuspid valve dysplasia in Labrador Retrievers.

OBJECTIVE: To quantify inheritance of tricuspid valve dysplasia (TVD) in a population of Labrador Retrievers and evaluate the possibility of the effect of a major locus on TVD. ANIMALS: 521 Labrador Retrievers (345 with known phenotypes and 176 related dogs with unknown phenotypes). PROCEDURES: Dogs were considered normal, equivocal, and affected for TVD on the basis of echocardiographic appearance of the tricuspid valves. Information on related dogs was collected for estimation of heritability of the 3 categories of phenotype, using a threshold model. Complex segregation analysis was performed to evaluate the possibility of the effect of a major locus on TVD. RESULTS: Heritability of TVD in this population of dogs was found to be 0.71, a value sufficiently large to suggest a segregating major locus. Subsequent complex segregation analysis did not provide sufficiently strong evidence to indicate influence of a major locus on the prevalence of TVD. However, complex segregation analysis for 2 categories of phenotype (eg, equivocal dogs were grouped with affected dogs) suggested that there was a single recessive allele with a substantial impact on the expression of TVD. CONCLUSIONS AND CLINICAL RELEVANCE: In Labrador Retrievers, TVD is a heritable disorder. Affected dogs and dogs closely related to affected dogs should not be used for breeding. There was insufficient evidence to suggest the influence of a major locus on TVD, although this conclusion was affected by the classification of dogs for diagnosis of the condition.

Alleles↗
PubMed2003

Site and gender specificity of inheritance of bone mineral density.

UNLABELLED: Differences in genetic control of BMD by skeletal sites and genders were examined by complex segregation analysis in 816 members of 147 families with probands with extreme low BMD. Spine BMD correlated more strongly in male-male comparisons and hip BMD in female-female comparisons, consistent with gender- and site-specificity of BMD heritability. INTRODUCTION: Evidence from studies in animals and humans suggests that the genetic control of bone mineral density (BMD) may differ at different skeletal sites and between genders. This question has important implications for the design and interpretation of genetic studies of osteoporosis. METHODS: We examined the genetic profile of 147 families with 816 individuals recruited through probands with extreme low BMD (T-score < -2.5, Z-score < -2.0). Complex segregation analysis was performed using the Pedigree Analysis Package. BMD was measured by DXA at both lumbar spine (L1-L4) and femoral neck. RESULTS: Complex segregation analysis excluded purely monogenic and environmental models of segregation of lumbar spine and femoral neck BMD in these families. Pure polygenic models were excluded at the lumbar spine when menopausal status was considered as a covariate, but not at the femoral neck. Mendelian models with a residual polygenic component were not excluded. These models were consistent with the presence of a rare Mendelian genotype of prevalence 3-19%, causing high BMD at the hip and spine in these families, with additional polygenic effects. Total heritability range at the lumbar spine was 61-67% and at the femoral neck was 44-67%. Significant differences in correlation of femoral neck and lumbar spine BMD were observed between male and female relative pairs, with male-male comparisons exhibiting stronger lumbar spine BMD correlation than femoral neck, and female-female comparisons having greater femoral neck BMD correlation than lumbar spine. These findings remained true for parent-offspring correlations when menopausal status was taken into account. The recurrence risk ratio for siblings of probands of a Z-score < -2.0 was 5.4 at the lumbar spine and 5.9 at the femoral neck. CONCLUSIONS: These findings support gender- and site-specificity of the inheritance of BMD. These results should be considered in the design and interpretation of genetic studies of osteoporosis.

Bone Density↗
PubMed2006

RAPD-based SCAR marker SCA 12 linked to recessive gene conferring resistance to anthracnose in sorghum [Sorghum bicolor (L.) Moench].

Anthracnose, caused by Colletotrichum graminicola, infects all aerial parts of sorghum, Sorghum bicolor (L.) Moench, plants and causes loss of as much as 70%. F(1) and F(2) plants inoculated with local isolates of C. graminicola indicated that resistance to anthracnose in sorghum accession G 73 segregated as a recessive trait in a cross with susceptible cultivar HC 136. To facilitate the use of marker-assisted selection in sorghum breeding programs, a PCR-based specific sequence characterized amplified region (SCAR) marker was developed. A total of 29 resistant and 20 susceptible recombinant inbred lines (RILs) derived from a HC 136 x G 73 cross was used for bulked segregant analysis to identify a RAPD marker closely linked to a gene for resistance to anthracnose. The polymorphism between the parents HC 136 and G 73 was evaluated using 84 random sequence decamer primers. Among these, only 24 primers generated polymorphism. On bulked segregant analysis, primer OPA 12 amplified a unique band of 383 bp only in the resistant parent G 73 and resistant bulk. Segregation analysis of individual RILs showed the marker OPA 12(383) was 6.03 cM from the locus governing resistance to anthracnose. The marker OPA 12(383) was cloned and sequenced. Based on the sequence of cloned RAPD product, a pair of SCAR markers SCA 12-1 and SCA 12-2 was designed using the MacVector program, which specifically amplified this RAPD fragment in resistant parent G 73, resistant bulk and respective RILs. Therefore, it was confirmed that SCAR marker SCA 12 is at the same locus as RAPD marker OPA 12(383) and hence, is linked to the gene for resistance to anthracnose.

Base Sequence↗
PubMed1997

Interactions between genetic and reproductive factors in breast cancer risk in a French family sample.

Considerable progress has been made in the characterization of the genetic component of breast cancer (BC). However, BC still remains a complex disease involving a genetic component and many other risk factors essentially linked to reproductive-life factors. To search for interactions between genetic and reproductive-life factors in the etiology of BC, a systematic family study was performed in two French hospitals from December 1987 to January 1990 and led to recruitment of 288 families, the IGRC data ("IGRC" refers to the Institut Gustave Roussy and Institut Curie, where the data were obtained). Detailed information on reproductive factors was recorded for probands and female first-degree relatives. Segregation analysis of BC was conducted by taking into account a variable age at onset of disease, by use of the class D regressive logistic model, as implemented in the REGRESS computer program. Segregation analyses of BC in IGRC data showed evidence for the segregation of a dominant gene and additional sister-sister dependence, both when reproductive factors were ignored and when they were included. A significant interaction was detected between the dominant gene and age when reproductive factors were taken into account. Among the reproductive factors included in segregation analysis, parity was found to interact with the dominant-gene effect, and there was an indication of an interaction, albeit not significant, between the dominant gene and age at menarche. Whereas the usual protective effect conferred on breast-cancer risk by high parity remained in nonsusceptible women, it disappeared in susceptible women. The increased BC risk associated with a late age at menarche was higher in susceptible women than in nonsusceptible women. Interactions between inherited predisposition to BC and reproductive factors were detected here for the first time by segregation analysis. It would be of major interest to confirm these results by family studies in other populations.

Abortion, Spontaneous↗
PubMed1991

Analysis of the patterns of inheritance of splenomegaly and serum IgM levels in the Watut of Papua New Guinea.

Hyperreactive malarious splenomegaly (HMS) reflects abnormal immune responses to malarial infection. The central question is whether HMS results from unusual patterns of malarial infection or from immune incompetence in the host. Family distributions of two features of the syndrome, splenomegaly and excessively high IgM levels, have been examined in a Papau New Guinea population in which HMS is exceptionally common. Segregation analysis of spleen grade shows that a major sex-linked gene controls hyperresponsiveness to malaria. This finding is supported by additional segregation analysis, which shows that an autosomal locus cannot account for a significant proportion of variation in spleen grade, and by path analysis, which rejects a model that assumes that parents contribute equally to the child's genotype. The sex-linked gene contributing to HMS was not mediated through sex linkage of a major gene for IgM concentrations, as shown by segregation analysis. It has yet to be determined whether this pattern of inheritance also applies to HMS occurring sporadically in other less severely affected populations. The applicability of these findings to the general variability in "normal" IgM responses to malaria also remains to be established.

Adult↗
PubMed1986

The effects of a known family-size distribution on the estimation of genetic parameters.

We consider the question: In a segregation analysis, can knowledge of the family-size distribution (FSD) in the population from which a sample is drawn improve the estimators of genetic parameters? In other words, should one incorporate the population FSD into a segregation analysis if one knows it? If so, then under what circumstances? And how much improvement may result? We examine the variance and bias of the maximum likelihood estimators both asymptotically and in finite samples. We consider Poisson and geometric FSDs, as well as a simple two-valued FSD in which all families in the population have either one or two children. We limit our study to a simple genetic model with truncate selection. We find that if the FSD is completely specified, then the asymptotic variance of the estimator may be reduced by as much as 5%-10%, especially when the FSD is heavily skewed toward small families. Results in small samples are less clear-cut. For some of the simple two-valued FSDs, the variance of the estimator in small samples of one- and two-child families may actually be increased slightly when the FSD is included in the analysis. If one knows only the statistical form of the FSD, but not its parameter, then the estimator is improved only minutely. Our study also underlines the fact that results derived from asymptotic maximum likelihood theory do not necessarily hold in small samples. We conclude that in most practical applications it is not worth incorporating the FSD into a segregation analysis. However, this practice may be justified under special circumstances where the FSD is completely specified, without error, and the population consists overwhelmingly of small families.

Family Characteristics↗
PubMed1996

Within birth cohort segregation analyses support recessive inheritance of body mass index in white and African-American families.

OBJECTIVE: We conducted segregation analyses of body mass index within birth cohort to determine whether previously reported support for recessive major gene inheritance in white and African-American families could have been due to higher rates of obesity in offspring than in parents, which are caused by temporal increases in obesity in recent decades. DESIGN: Segregation analysis of family data. MEASUREMENT: The body mass index (BMI), adjusted for effects of gender, linear and non-linear effects of age, education and occupation of head of household, and clinic from which family was ascertained. RESULTS: Segregation analysis results support a recessive mode of major gene inheritance of body mass index, even though we restricted our analysis to siblings born within the same post-1945 cohort. We also found support for substantial polygenic heritability of body mass index, which is consistent with a multigenic heritability. There was no significant heterogeneity between white and African-American families in support for a recessive mixed model. However, some differences in particular parameters were found, with higher gene frequency, lower polygenic heritability and a larger variance associated with the major gene model in African-Americans. CONCLUSION: Our present segregation analysis shows that the recessive pattern, whether due to single or multiple genes, cannot be explained by inter-generational differences in obesity prevalence or family correlation. There was suggestive evidence of a higher major gene frequency and larger gene effect size in African-American families.

Black People↗
PubMed1993

The genetic basis of response in mouse lines divergently selected for body weight or fat content. II. The contribution of genes with a large effect.

Gene action underlying selection responses has been studied using crossbreeding. Maximum likelihood based segregation analysis has been presented for analysing backcross data for the presence of genes with a large effect. Two sets of divergently selected lines (P-lines for body weight and F-lines for fat content) were reciprocally crossed and the F1s were crossed to the high and low lines to produce all possible backcrosses. Earlier analysis had shown that the difference in body weight at 10 weeks (n = 595) between the high and low P-lines was largely (75-80%) explained by autosomal, additive genes with the remainder explained by additive genes on the X chromosome. Maximum likelihood segregation analysis suggested the presence of a major effect on the X chromosome, but as there was only one round of recombination between the X chromosomes in the forming of the backcrosses, linked genes on the X chromosome could have acted together to give the appearance of a single major gene. The difference in fat content between the F-lines (n = 578) could be explained by autosomal genes of largely additive effect. Segregation analysis suggested the presence of a major gene with complete dominance, but this was attributed to a relationship between the mean and the variance: transformation of the data resulted in only polygenic additive genes being of importance. This study concluded that maximum likelihood based analysis and crosses between selected lines provide a powerful means for studying the gene action underlying responses to selection.

Adipose Tissue↗
PubMed1992

A genetic model for control of hypertriglyceridemia and apolipoprotein B levels in the Johns Hopkins colony of St. Thomas Hospital rabbits.

The St. Thomas Hospital (STH) rabbit has been previously shown to have a Mendelian form of hypertriglyceridemia, accompanied by accelerated atherosclerosis, and these animals may serve as a useful model for human dyslipoproteinemia syndromes. Here we describe the establishment of a new colony of these STH animals, and present genetic analysis of triglyceride (TG) and apolipoprotein B (apoB) levels. Segregation analysis of TG in 39 STH animals and 24 controls gave evidence of Mendelian segregation for an allele leading to both elevated TG levels and increased variability in these levels. Predicted means from the most parsimonious model for the Johns Hopkins STH colony were quite similar to that seen in the original London colony, and this model accounted for 80% of the variation in TG seen in the sample. This hypertriglyceridemia locus indirectly influenced the mean apoB levels in these rabbits, and segregation analysis of mean apoB levels suggested a second locus controlling apoB levels. Analysis of residual apoB levels (adjusted for predicted effects of the hypertriglyceridemia locus) revealed clearer evidence for a second locus controlling mean apoB levels in this colony. Arguments for two distinct genetic mechanisms operating in these STH animals are presented.

Animals↗
PubMed2001

Familial history, age and smoking are important risk factors for disc degeneration disease in Arabic pedigrees.

The present study used computed tomography imaging to evaluate the extent and pattern of the intergenerational transmission of spinal disc degeneration disease (DDD) in complex pedigrees. Contribution of a number of the potential covariates was also studied using univariate and multivariate logistic regression analysis, as well as two types of complex segregation analysis models. Among 161 individuals studied, DDD was diagnosed in 60 individuals. The number of protruded discs varied from 1 to 4, mostly in lumbar or lumbosacral regions. The average age at onset of the disease was similar for both women (36.0 years) and men (34.8 years). The proportion of the individuals affected by the DDD status of their parents ranged from 10% in families of two healthy parents to 55.5% of two affected parents (p < 0.01). The results of the logistic regression analyses and complex segregation analysis were qualitatively the same: DDD status of parents, age and smoking were the main risk factors for disc herniation in the Arabic families we examined. All analyses showed a predominating role of the family history as a risk factor for DDD in offsprings. It showed, for example, four times higher risk at age 50 for individuals with two affected parents vs. those who have two non-affected parents. However, the results of models-fitting genetic analysis, did not confirm a monogenic Mendelian pattern of inheritance.

Adult↗
PubMed1985

Family-size distribution and Ewens' equivalence theorem.

Segregation analysis of a data set containing nuclear families of more than one sibship size is considered, and two different formulations of the likelihood are examined. One is the "separate-multinomials" formulation, which treats each family size as representing a separate multinomial distribution; the other is the "grand-multinomial" formulation, which treats the entire data set as representing one distribution. It is shown that these two formulations are equivalent, if and only if the population distribution of family sizes is completely unknown. However, if anything is known about the family-size distribution, the grand-multinomial formulation, although more cumbersome, makes more complete use of the data; moreover, it enables the use of one-child families in a segregation analysis. The relationship of this work to Ewens' equivalence theorem concerning "unconditional" and "conditional" likelihoods is discussed. The findings are illustrated with a simple example, and their practical relevance to real-life segregation analysis is discussed.

Family Characteristics↗
PubMed2001

Genetic epidemiology of glioma.

The present study performed a segregation analysis of a cohort of first-degree relatives (FDR) of glioma patients. The families with two or more gliomas were also expanded to determine if any more gliomas could be detected, and if any other types of cancers were associated. These glioma-prone families (n = 24/432) were extended to include first-, second- and third-degree relatives (n = 807) and a cohort was assembled, the standardized incidence risk for other types of cancer calculated and the pedigrees investigated for a possible mode of inheritance. A segregation analysis of the 2141 FDR in 297 families, performed using the Pointer software, did not clearly reject a multifactorial model chi(2)(3) = 6.13, P< 0.2. However, when letting all parameters be free, the recessive model provided the best fit. In the extended families, no increased risk of other types of cancer was found. This population-based study proposes that familial glioma occurs in about 5% of all glioma cases and that 1% have a possible autosomal dominant inheritance. This first segregation analysis performed in familial glioma must be cautiously interpreted, but an autosomal recessive gene provided the best fit, which could possibly explain 2% of all glioma cases.

Adolescent↗
PubMedDate not supplied

Cluster headache is an inherited disorder in some families.

We investigated the familial occurrence of cluster headache in 370 probands with cluster headache, diagnosed according to the operational diagnostic criteria of the international Headache Society. Seven probands belonged to three families. A positive family history of cluster headache was found in 7% (25 of 366) of the families. Compared with the general population, the first- and second-degree relatives of the 370 probands with cluster headache had a 14- and 2-fold increased risk of having cluster headache, after standardization for sex and age. This increased familial risk strongly suggests that cluster headache has a genetic cause. The patterns of segregation were assessed by complex segregation analysis performed with the computer program, POINTER. The segregation analysis suggests that cluster headache has an autosomal dominant gene with a penetrance of 0.30 to 0.34 in males and 0.17 to 0.21 in females. The gene is present in 3% to 4% of males and 7% to 10% of females with cluster headache.

Adolescent↗
PubMed2006

A major susceptibility locus for HTLV-1 infection in childhood maps to chromosome 6q27.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is a human oncoretrovirus causing adult T-cell leukemia/lymphoma and chronic neuromyelopathy. We previously showed by segregation analysis that a dominant gene controls HTLV-1 infection through breast-feeding in children of African origin. Here, we report the mapping of this locus by a genome-wide linkage analysis based on the genetic model provided by segregation analysis. Five pedigrees of African origin with HTLV-1 seropositive children were included in the study. Significant evidence for linkage (LOD score of 3.36, P=0.00004) was obtained for chomosomal region 6q27 when using the robust analysis including only HTLV-1-infected subjects. When HTLV-1 seronegative children born to infected mothers were added in the analysis, a maximum LOD score of 2.79 (P=0.0002) was obtained for chomosome 2p25. This result was mostly due to the largest pedigree of our sample, which alone gave a LOD score of 2.90 (P=0.00013). We further excluded the role of exonic variants of two candidate genes located in the linked regions, CCR6 (chemokine receptor 6) in 6q27 and ID2 (inhibitor of DNA binding 2) in 2p25. Our results, mapping a major susceptibility locus to chromosome 6q27 and suggesting genetic heterogeneity with another locus at 2p25, pave the way to the determination of the molecular basis of predisposition to HTLV-1 infection in children.

Adolescent↗