Classical Segregation Analysis Research Articles

The role of parametric linkage methods in complex trait analyses using microsatellites

Many investigators of complexly inherited familial traits bypass classical segregation analysis to perform model-free genome-wide linkage scans. Because model-based or parametric linkage analysis may be the most powerful means to localize genes when a model can be approximated, model-free statistics may result in a loss of power to detect linkage. We performed limited segregation analyses on the electrophysiological measurements that have been collected for the Collaborative Study on the Genetics of Alcoholism. The resulting models are used in whole-genome scans. Four genomic regions provided a model-based LOD > 2 and only 3 of these were detected (p < 0.05) by a model-free approach. We conclude that parametric methods, using even over-simplified models of complex phenotypes, may complement nonparametric methods and decrease false positives.

This month in gastroenterology

This month in gastroenterology

Estimation of penetrance from twin data.

A simple method for estimating the gene frequency p and the penetrance value K from data on polymorphic monogenic characteristics on monozygotic twin pairs is presented. In spite of the method here presented having limited value because the results it yields cannot be evaluated on their own, the estimates of p and K it provides can be indirectly tested by comparing them to the ones obtained in familial aggregates through classical segregation analysis or by using the latter to calculate the expected proportions of dominant-dominant, dominant-recessive and recessive-recessive monozygotic twin pairs. When the method is applied to data on tongue-rolling ability published in the literature, a good agreement is observed between twin and familial estimates, thus indicating that the method is reliable and that it can be used as an ancillary way of corroborating or otherwise evidence of monogenic autosomal dominant mechanism inferred from the analysis of familial data.

Estimation of penetrance from twin data

A simple method for estimating the gene frequency p and the penetrance value K from data on polymorphic monogenic characteristics on monozygotic twin pairs is presented. In spite of the method here presented having limited value because the results it yields cannot be evaluated on their own, the estimates of p and K it provides can be indirectly tested by comparing them to the ones obtained in familial aggregates through classical segregation analysis or by using the latter to calculate the expected proportions of dominant–dominant, dominant–recessive and recessive– recessive monozygotic twin pairs. When the method is applied to data on tongue-rolling ability published in the literature, a good agreement is observed between twin and familial estimates, thus indicating that the method is reliable and that it can be used as an ancillary way of corroborating or otherwise evidence of monogenic autosomal dominant mechanism inferred from the analysis of familial data. Twin Research (2000) 3, 294–298.

Evidence for a major gene for bone mineral density in idiopathic osteoporotic families.

Although there have been a number of studies indicating a heritable component for osteoporosis in middle to late adulthood, the etiology of osteoporosis in young people is uncertain. The present study aims to evaluate the extent to which genetic factors influence familial resemblance for bone mineral density (BMD) in families ascertained on the basis of young osteoporotic probands. The sample comprises eight families (74 total individuals) that were identified through a proband under the age of 35 years with a history of two or more fractures and a spinal bone density of at least 2.5 SDs below the mean for age and sex (Z score). Secondary causes of osteoporosis were excluded in the probands. In total, 27% (18/66) of the probands' relatives had osteoporosis and an additional 30% (20/66) had osteopenia. Classical segregation analysis was performed to evaluate the extent to which a genetic etiology could account for familial resemblance in these families. The results indicate a major gene of codominant inheritance for spinal BMD. Model-fitting comparisons revealed no support for environmental effects or for polygenic inheritance.

Segregation analysis of microcephaly.

Microcephaly is a heterogeneous disorder with genetic and environmental causes. However, there is little information on what proportion of cases are caused by inherited susceptibility, or the mode of inheritance in familial cases. To address these questions, we have performed classical and complex segregation analyses for microcephaly on 2 sets of family data collected from genetic counseling clinics in Vancouver and Jerusalem. These samples consisted of 143 affected individuals in 127 families ascertained from Vancouver, and 101 affected individuals in 59 families ascertained from Jerusalem. The results of the segregation analyses for the Vancouver sample indicated that approximately half of all microcephaly cases were due to highly penetrant recessive mutant alleles, with the remainder being sporadic. Although a recessive model allowing for the occurrence of sporadic cases fit the data from Vancouver best, a dominant model could not be statistically rejected. The classical segregation analysis on the Jerusalem sample suggested that both a dominant model with 29% of the cases being sporadic and a purely recessive model provided adequate fit to the data. Although the complex segregation analysis of this sample indicated that a dominant model provided a more parsimonious explanation for the observed familial variation, a recessive model was only marginally rejected. It should be noted that in the Jerusalem sample, families tended to be ascertained in the genetic counseling clinic only after the birth of a second affected child. This could be a potential bias which could inflate the segregation ratio, thus giving the impression of dominant inheritance. Our analyses, while confirming the complex nature of the cause of microcephaly, indicate that it may be necessary to await the results of genetic linkage analysis before a definitive mode of inheritance can be determined.

Testing Models for Genetic Determination in Migraine

We collected two clinically matched samples of patients, one sample affected by migraine with aura the other by migraine without aura, to investigate the genetic determination of these conditions. A maternal and X-linked transmission for both these diseases was considered unlikely after pedigree analysis. Classical segregation analysis indicated a likely autosomal recessive kind of transmission for both. Reduced penetrance and the h2 values, however, imply the presence of additional genetic and/or environmental factors controlling the phenotypic expression of migraine.

Genetic epidemiological studies of early-onset deafness in the U.S. school-age population.

Profound, early-onset deafness is present in 4-11 per 10,000 children, and is attributable to genetic causes in at least 50% of cases. Family history questionnaires were sent to 26,152 families of children with profound, early-onset deafness not known to be related to an environmental cause. The probands were ascertained through the 1988-89 Gallaudet University Annual Survey of Hearing Impaired Children and Youth. The analysis is based on the responses that were received from 8,756 families. Classical segregation analysis was used to analyze the family data, and to estimate the proportions of sporadic, recessive and dominant causes of deafness in the families. These data were consistent with 37.2% of the cases due to sporadic causes, and 62.8% due to genetic causes (47.1% recessive, and 15.7% dominant). An earlier study using the 1969-70 Annual Survey found 49.3% sporadic cases and 50.6% genetic, demonstrating that the proportion of sporadic cases of early-onset deafness has significantly decreased since 1970.

Concordance and recessive inheritance of Leber congenital amaurosis.

Pedigrees were obtained on 43 patients with confirmed Leber congenital amaurosis, a rare form of blindness caused by congenital dysfunction of the retina. All of the pedigrees were consistent with autosomal recessive inheritance and the segregation frequency using classical segregation analysis was 0.24 +/- 0.07. Six of the 7 affected sib pairs were concordant in regards to systemic abnormalities. Despite previous reports that Leber congenital amaurosis can be inherited either as an autosomal dominant or recessive condition, our findings support only an autosomal recessive inheritance of this disorder.

Segregation analysis of autosomal dominant polycystic kidney disease.

The results of classical segregation analysis on 159 families with polycystic kidney disease (PKD) are presented. It had been previously estimated that about 95% of autosomal dominant PKD (ADPKD) families have PKD1, the gene localized to chromosome 16p. The main purpose of the study was to determine if PKD shows any segregation distortion and to obtain new estimates of the age-dependent penetrance. Penetrance at the early ages of onset has increased during the last decade, presumably because of improvements in renal imaging and consequent earlier age of diagnosis. In the current study, the mean age of diagnosis was estimated to be 20 years, with a standard deviation (SD) of 15.94. Under the best fitting model (autosomal dominant), over 70% penetrance was estimated by age 30 years, over 95% by 50 years, and 99% by 55 years. Thus, diagnosis of this disease at an early age is possible without total reliance on DNA typing. The segregation ratio defined through the transmission probability in our model was not significantly different from 0.50, but its confidence limits were broad: 0.36 to 0.64. Neither transmission probability nor penetrance was significantly influenced by gender. The mutation rate was estimated to be 6.9 x 10(-5), in accordance with the previously observed high mutation rate for PKD. However, the mutation rate in our study may be overestimated because it neglects low penetrance alleles and phenocopies.

Genetic transmission of colorectal cancer: exploratory data analysis from a population based registry.

Classical segregation analysis was conducted on 605 families of probands with colorectal carcinoma ascertained through the Cancer Registry of the Province of Modena in Italy. The families were classified as 28 suspected hereditary non-polyposis colorectal cancer (HNPCC) syndromes and 577 presumed non-HNPCC. In 11 of these, both parents had colorectal carcinoma, in 130 one parent was affected, and in 436 both parents were normal. In the suspected HNPCC families, segregation was compatible with dominant transmission of susceptibility to carcinoma. In families with one parent affected, the segregation frequency was almost exactly equal to the frequency of segregation in families where both parents were normal. The model of dominant transmission of susceptibility through a major gene with greatly reduced penetrance in heterozygotes fitted the data acceptably.

Ascertainment: An Overwiew of the Classical Segregation Analysis Model for Independent Sibships

AbstractSeveral different methodologies for parameter estimation under various ascertainment sampling schemes have been proposed in the past. In this article, some of the methodologies that have been proposed for independent sibships under the classical segregation analysis model are synthesized, and the general likelihoods derived for single, multiple and complete ascertainment. The issue of incorporating the sibship size distribution into the analysis is addressed, and the effect of conditioning the likelihood on the observed sibship sizes is discussed. It is shown that when the number of probands in a sibship is not specified, the corresponding likelihood can be used for a broader class of ascertainment schemes than is subsumed by the classical model.

Rheumatic Fever Susceptibility in Four Ascertainments: Regressive Segregation on a Geometric Ascertainment Pattern

On resolving the ascertainment biases of the observed data in the geometric continuum vaffected-1 x P(sibship), where 0 less than v----infinity, four published ascertainments of rheumatic fever show excellent conformation with Mendelian recessive segregation, even in multiplex sibships. In two surveys in which ascertainment bias is near or a little above random sampling (v = 1), this conclusion is further corroborated by classical segregation analysis. The other two surveys have bias trends declining (v less than 1) very much below random sampling. Such levels of ascertainment bias, if defined through the ascertainment probability parameter pi, would be out of range because the range is from single ascertainment, where pi----0 to random sampling where pi = 1 and probability cannot exceed unity. Highly successful antimicrobial measures that would reduce the number of diseased sibs independent of the distribution of susceptible sibs could produce a dissociation of the gene-to-"rheumatic" relationship and thus explains the declining ascertainment bias.

Segregation analysis of 1885 DMD families: significant departure from the expected proportion of sporadic cases

The proportion of sporadic cases of Duchenne muscular dystrophy has been estimated by classical segregation analysis in a pooled sample of 1885 sibships from 7 different countries. A significant departure from the theoretical expectations based on mutation-selection equilibrium is observed (segregation frequency = 0.439 +/- 0.017; frequency of sporadic cases = 0.229 +/- 0.026, at the maximum likelihood). The occurrence of germinal mosaicism in some of the mothers of Duchenne cases may account for this peculiar finding, although a possible role of inequality of mutation rates in the two sexes cannot be ruled out.

Evidence for a major gene in familial anencephaly

A 21-year-old white woman sought counseling after the birth of two consecutive anencephalic male fetuses with complete rachischisis and discordant renal dysplasia. The presence of parental consanguinity prompted reconsideration of recessive inheritance. The segregation ratio from 23 additional consanguineous cases was compared with that observed in 294 presumably nonconsanguineous families previously reported. Using classical segregation analysis, the segregation ratios in the non-sporadic cases were consistent with a major autosomal recessive locus in both populations.

Segregation and Sporadic Cases of Duchenne Muscular Dystrophy in the Henan Province, China

In the Henan province, China, the segregation ratio of Duchenne muscular dystrophy, estimated through classical segregation analysis on 103 sibships, is p = 0.462, and the maximum likelihood proportion of sporadic cases is x = 0.264. These figures are in agreement with the results of segregation analysis on 1,800 families from different countries; also, the Henan population shows a slight segregation distortion and lacks a fraction of the sporadic cases predicted under mutation-selection equilibrium. Although not statistically significant, the downward departure of the estimated parameters from their expectations under the mendelian equilibrium hypothesis (p = 0.5; x = 0.333) confirms an anomalous segregation pattern for Duchenne muscular dystrophy. A possible role of germinal mosaicism in concealing a fraction of sporadic cases is discussed.

Neurofibromatosis-1: a maximum likelihood estimation of mutation rate

Methods of classical segregation analysis were applied to a sample of 129 sibships with one or more individuals affected by neurofibromatosis-1 (NF-1). The sample consists only of subjects with NF-1; all the probands had been referred for genetic counselling because of café-au-lait spots, and a diagnostic protocol was invariably applied. No deviation from the segregation ratio expected for a fully penetrant Mendelian dominant gene was observed. A maximum likelihood estimate of the proportion of sporadic cases was obtained, and the mutation rate was estimated to be 6.5 x 10(-5) gametes per generation (95% CI 5.0-8.1).

Trials, tribulations, and triumphs of the EM algorithm in pedigree analysis.

The EM algorithm is an iterative method for finding maximum-likelihood estimates. Its advantages often include numerical stability, simplicity of computer implementation, and natural incorporation of parameter constraints. However, the EM algorithm must be tailored to each specific problem. Smith (1957) and Ott (1977, 1979) have accomplished this for a variety of problems in human pedigree analysis. The present paper clarifies their theory by presenting it from a modern perspective. Five practical numerical examples are also given in an attempt to assess the value of the EM algorithm in realistic genetic modelling. These examples deal with racial admixture, linkage homogeneity, classical segregation analysis, a Mendelian latent trait model for schizophrenia, and a heterozygote detection assay for Ataxia-telangiectasia. Comparison with a quasi-Newton method of optimization reveals that the EM algorithm generally converges more slowly, but also more stably.

Genetic epidemiology of Duchenne muscular dystrophy in Japan: classical segregation analysis.

Classical segregation analysis was performed on 651 male probands in 597 families with Duchenne muscular dystrophy (DMD) collected from 20 of 25 National Institutions for Muscle Diseases in Japan. The proportion of sporadic cases is compatible with 1/3 expected for an X-linked lethal trait with an equal mutation rate in egg and sperm, the estimated mutation rates being 9.2 X 10(-5) and 10.9 X 10(-5)/gamete/generation, respectively. The incidence and prevalence among males were estimated to be 29.2 X 10(-5) and 6.7 X 10(-5), respectively. These results indicated no difference from the patterns of DMD in Western countries.

Genetic analysis of cleft lip with or without cleft palate in Chinese kindreds.

Cleft lip with or without cleft palate (CL +/- P) affects 1 in 500-1,000 newborns worldwide; the cause remains unclear. For CL +/- P, Asians are at higher risk than Caucasians or Blacks. This report presents the results of a genetic analysis of 163 CL +/- P proband families ascertained in Shanghai, China. Based on statistical tests of several predictions from the classical multifactorial/threshold model, no evidence could be found to support it. Further, goodness-of-fit (PGOODFIT) tests of this model were also unsupportive, there being more families with two or more affected sibs than expected. Classical segregation analysis for Mendelian inheritance showed a maximum likelihood estimate of the segregation ratio of 0.187 +/- 0.068. This value was not significantly less than 0.25 (recessive inheritance) but was significantly less than 0.50 (dominant inheritance). Sex ratio data from these Chinese families suggest that manifestation of the putative single major gene is sex influenced. The apparent reduced penetrance is likewise to be expected if manifestation of CL +/- P also depends on in utero exposure to deleterious environmental agents, as demonstrated in a variety of human and animal model studies.