SEARCH · Search PubMed

Results for “Segregation analysis”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources

PubMed1994

Segregation analysis of smoking-associated malignancies: evidence for Mendelian inheritance.

Tobacco consumption is an established risk factor for cancer at a number of sites: oral cavity, esophagus, nasopharynx, lung, larynx, pancreas, bladder, kidney, and uterine cervix. These sites also demonstrate familial aggregation. To determine if evidence exists for a major gene controlling susceptibility to smoking-associated cancers, maximum likelihood segregation analyses were performed on 337 families (3,276 individuals) ascertained through a deceased lung cancer proband. Models were fitted that allowed for personal tobacco use and variable age of onset. The hypotheses of environmental transmission and no major gene were rejected (P < 0.005), but none of the Mendelian models could be distinguished. According to Akaike's Information Criterion, Mendelian dominant inheritance of an allele that produces cancer at an earlier age of onset provided the best fit to the data. The model suggests that 62% of the population are susceptible, and that the mean age-of-onset differs for men and women: at the mean level of tobacco exposure, female gene carriers are affected, on average, 24 years earlier than non-carriers (77 vs. 101), while in males the difference was 20 years (71 vs. 91). These findings extend our earlier observations on the genetic epidemiology of lung cancer and suggest that Mendelian factors may influence the risk of cancers that are known to be smoking associated.

Environment↗

PubMed2000

Genetic epidemiology of breast cancer: segregation analysis of 389 Icelandic pedigrees.

A genetic epidemiologic investigation of breast cancer involving 389 breast cancer pedigrees including information on 14,721 individuals from the Icelandic population-based cancer registry is presented. Probands were women born in or after 1920 and reported to have breast cancer in the cancer registry. The average age of the 389 probands was 45.5 years (SD 8.92). Segregation analyses was performed evaluating residual maternal effects, a dichotomous cohort effect, and assuming the age at diagnosis followed a logistic distribution after log-transformation. Familial aggregation could be best explained by the inheritance of a high-risk allele leading to early onset breast cancer among the homozygotes, which represent approximately 2.6% of the population. A Mendelian codominant model was selected as the best fitting model, with an estimated age at diagnosis of 51.8 years among these high-risk homozygotes, 64.0 years for heterozygotes and 76.3 years for the low-risk genotype. The predicted cumulative risk for homozygote carriers of the high-risk allele is 32.2% by age 60, compared to 16.4% for heterozygotes and 5.0% for non-carriers of the same age. These predicted age profiles in the current study complement recent reports from Iceland of a majority of BRCA2 mutation carriers being diagnosed with breast cancer below the age of 50 years, and 60 years being the mean age at diagnosis for non-carriers. This model also predicted a high background risk of breast cancer for women in this population (estimated susceptibility gamma = 0.44 +/- 0.08). This implies that if carriers and non-carriers did not die of competing causes, the estimated risk of being diagnosed with breast cancer by age 80 years irrespective of carrier status is 11.4%.

Age of Onset↗

PubMed1986

Characterization, chromosome assignment, and segregation analysis of endogenous proviral units of mouse mammary tumor virus.

In the course of analyzing sites of proviral integration in tumors induced by mouse mammary tumor virus (MMTV), we have isolated recombinant DNA clones corresponding to the 5' and 3' ends of four endogenous MMTV proviruses present in BALB/c and BR6 mice. This has permitted the structural characterization of each locus by detailed restriction mapping and the preparation of DNA probes specific for the cellular sequences flanking each provirus. These probes have been used to trace the segregation patterns of the proviruses, designated Mtv-8, Mtv-9, Mtv-17, and Mtv-21, in a panel of inbred strains of laboratory mice and to map Mtv-17 and Mtv-21 to mouse chromosomes 4 and 8, respectively. The unambiguous resolution of these four proviruses on Southern blots has greatly facilitated the analysis of other endogenous MMTV proviruses in these inbred mice.

Animals↗

PubMed2002

Genetics of the apnea hypopnea index in Caucasians and African Americans: I. Segregation analysis.

Differences in age of presentation and anatomic risk factors for obstructive sleep apnea (OSA) in Caucasians and African Americans suggest possible racial differences in the genetic underpinnings of the disorder. In this study, we assess transmission patterns in a Caucasian sample consisting of 177 families (N = 1,195) and in an African American sample consisting of 125 families (N = 720) for two variables: 1) apnea hypopnea index (AHI) log transformed and adjusted for age, and 2) AHI log transformed and adjusted for age and body mass index (BMI). We allowed for residual familial correlations and sex-specific means in all models. Analysis of the Caucasian sample showed transmission patterns consistent with that of a major gene that were stronger in the age-adjusted variable than in the age- and BMI-adjusted variable. However, in the African American families, adjusting for BMI in addition to age gave stronger evidence for segregation of a codominant gene with an allele frequency of 0.14, accounting for 35% of the total variance. These results provide support for an underlying genetic basis for OSA that in African Americans is independent of the contribution of BMI.

Black or African American↗

PubMed1993

Complex segregation analysis of LDL peak particle diameter.

A predominance of small low-density lipoprotein (LDL) particles, as determined by gradient gel electrophoresis (GGE), has been proposed to be a common genetic marker for risk of coronary heart disease. Previous analyses of the families in the Berkeley data set defined a dichotomous trait based on the LDL size distribution by GGE: subjects with a predominance of small LDL particles have LDL subclass "pattern B," while those with a predominance of large LDL particles have LDL subclass "pattern A." Using this definition, previous complex segregation analyses demonstrated a single major gene effect on pattern B with a dominant or additive mode of inheritance, and reduced penetrance in young males and premenopausal women. In the present analyses, a continuous variable denoted LDL peak particle diameter is used, reflecting the size (diameter in A) of the major LDL subclass, for comparison with the dichotomous LDL subclass pattern classification. After adjusting for age and gender, the results demonstrate a single major Mendelian gene effect, but the exact mode of inheritance could not be established. Thus, analysis of the continuous variable was not superior to that of the dichotomous classification in determining the mode of inheritance of the proposed single gene controlling LDL subclasses.

Coronary Disease↗

PubMed2000

Segregation analysis of IgE levels in 335 French families (EGEA) using different strategies to correct for the ascertainment through a correlated trait (asthma).

The main objective of this study was to search for a major gene controlling total serum immunoglobulin E (IgE) levels, an intermediate phenotype for asthma and allergy. We studied 335 French nuclear families of the EGEA study (Epidemiological study of the Genetics and Environment of Asthma), ascertained through asthmatic probands (123 are parents in the family, 212 children). Segregation analyses were performed by regressive models, which can take into account a major gene effect, various sources of familial covariation (genetic and/or environmental) as well as measured risk factors (i.e. , age, sex, smoking habits). Different strategies were considered to account for the mode of ascertainment of the families through a correlated trait (asthma): the ascertainment mode was either ignored (strategy A) or taken into account by adjusting IgE levels for the position in the family, i.e., probands, blood relatives, spouses (strategy B) or excluding the asthmatic children-probands and computing the likelihood of each family conditionally on parents' IgE levels (strategy C). Whereas a major gene effect could not be detected with strategy A, strategies B and C showed evidence for the transmission of a dominant major gene for high IgE levels, which was more significant with strategy B. This gene does not interact with any of the covariates and is responsible for approximately 15% of IgE variation (the allele frequency is 0.65).

Adolescent↗

PubMedDate not supplied

Familial correlation and segregation analysis of forced expiratory volume in one second (FEV1), with and without smoking adjustments, in a Tucson population.

BACKGROUND: Previous researchers have found significant familial aggregation but no evidence of Mendelian inheritance of forced expiratory volume in one second (FEV1) in general population studies. However, the influence of cigarette smoking on familial aggregation of FEV1 has been difficult to assess in these studies. OBJECTIVES: The main objective of our study was to attempt to discern the effects of smoking on familial correlation and segregation models of FEV1. SUBJECTS AND METHODS: In a randomly selected sample of white, non-Mexican American families in Tucson, Arizona, we performed two separate familial correlation and segregation analyses of FEV1, one adjusted for cigarette smoking and one unadjusted for smoking. In both, initial survey measures of FEV1 for 1329 females and 1291 males in 746 families were standardized for gender, age, height and height-squared using piecewise linear regression models. In the smoking-adjusted model, total number of pack-years smoked, current and ex-smoking status, and the interaction between total pack-years and current smoking status were also included. RESULTS: FEV1 was significantly correlated among sibling pairs and parent-offspring pairs (both p < 0.001), regardless of smoking adjustment, but sibling correlation was significantly higher than parent-offspring correlation (p < 0.05), suggesting additional effects beyond common parentage. Spousal correlations were not significant even when both spouses smoked. We found no evidence of major gene segregation of FEV1, with or without smoking adjustment, and all of the segregation models were significantly different from the unrestricted model. CONCLUSIONS: The best-fitting model was an environmental model with three distinct distributions of FEV1 and significant residual familial effects. A significant familial component suggests the presence of polygenic factors and/or effects due to a shared environment (multifactorial). That familial correlations of smoking-adjusted and smoking-unadjusted residuals were not appreciably different suggests that current smoking status and number of pack-years smoked do not account for the observed familial aggregation of FEV1.

Adolescent↗

PubMed2001

Meiotic segregation analysis by FISH investigation of spermatozoa of a 46,Y,der(X),t(X;Y)(qter-->p22::q11-->qter) carrier.

Chromosome analysis performed on a 30-year-old man revealed a 46,Y,der(X),t(X;Y)(qter-->p22::q11-->qter) karyotype, confirmed by fluorescence in situ hybridization (FISH). The man was of short stature, and no mental retardation was noticed; genitalia and testes were normal, as were the patient's FSH, LH, and testosterone blood levels. Sperm analysis showed azoospermia at the time of the first sampling and severe oligozoospermia, with 125,000 spermatozoa/milliliter, at the time of the second sampling. The sperm gonosomal complement of this patient and of a 46,XY donor were analyzed using multicolor FISH with X- and Y-chromosome probes. Our results clearly indicated that germinal cells carrying the translocation are able to complete the meiotic process by producing spermatozoa compatible with normal embryonic development, with more than 80% of the spermatozoa having either a Y chromosome or a der(X); however, a high level of spermatozoa with gonosomal disomies was observed. We also found a significant increase in the frequency of autosomal disomies in the carrier, which would suggest an interchromosomal effect. All previously reported cases in adult males were associated with azoospermia; testicular histological studies, performed in patients carrying the same X;Y translocation, showed spermatogenetic arrest after pachytene. To our knowledge, this is the first molecular analysis of the gonosomal complement in spermatozoa of men with a t(X;Y)(qter-->p22::q11-->qter).

Adult↗

PubMed1980

Cytogenetic study of a large black kindred: inversions, heteromorphisms, and segregation analysis.

Q-and C-band heteromorphisms were determined by sequentially staining cells from 81 members of an American Black kindred. The incidence of heteromorphs is reported for 14 people who married into the family. Small pericentric inversions of chromosome 3 were found in 23 kindred members, three of whom were homozygous. Six 'complete' chromosome 9 inversions and a single 'partial' inv9 were detected. there was no apparent phenotypic effect associated with the inversions, nor were duplication-deficiency chromosomes observed. Evidence for preferential segregation of Q-heteromorphs is reported, and comparison with data from other authors points to chromosome 13 as showing the most distortion.

Black People↗

PubMed2004

Cancer aggregation and complex segregation analysis of families with female non-smoking lung cancer probands in Taiwan.

Previous studies have found that having a first-degree blood relative with lung cancer was a possible predictor of lung cancer risk, but some studies have indicated that the association is non-significant or only significant for a subset of the studied population. To determine the familial aggregation and whether there is any evidence for a gene controlling the susceptibility to developing lung cancer in female non-smokers, multiple logistic regression methods for estimating covariate effects and maximum likelihood segregation analyses were performed using data from 216 female non-smoking lung cancer probands (2328 individuals) in a population-based case-control study. Having a family history of lung cancer was found to be a significant predictor of lung cancer for non-smoking females (Adjusted Odds Ratio (OR)=5.7, 95% Confidence Interval (CI)=1.9-16.9). Having a female relative with lung cancer (adjusted OR=14.4, 95% CI=2.7-75.5) was more strongly associated with the lung cancer risk than was having a male relative with lung cancer. This association was stronger for probands aged less than 60 years at onset (adjusted OR=11.2, 95% CI=2.2-56.9). All of the Mendelian models fitted the data significantly better than the sporadic (no major type) model or the environmental model (P<0.00l). The Mendelian codominant models provided the best fit of the data for the early onset probands and showed a stronger effect for a major susceptibility locus for non-smoking lung cancer probands. The results of this study provide evidence that a rare autosomal codominant gene may influence the risk lung cancer in non-smoker and is responsible for the familial aggregation observed in non-smoking lung cancer patients.

Adult↗

PubMed1989

Direct segregation analysis of reciprocal translocations: a study of 283 sperm karyotypes from four carriers.

Using the technique of in vitro human-hamster fertilization, sperm of four men heterozygous for 4 reciprocal translocations--t(4;17),t(5;13),t(6;7), and t(9;18)--was studied. Frequencies of numerical abnormalities unrelated to the translocations range from 8.3% to 13.3%, and the incidence of imbalances ranges from 23.0% to 66.0%. Results are pooled with data from the nine other reciprocal translocations reported elsewhere, and the combined data demonstrate that male meiotic segregation is not random: whatever the type of translocation may be, the distribution of imbalances in sperm is constant, with approximately 72.0% adjacent 1, 18.5% adjacent 2, and 9.5% 3:1 segregations. The same prevalence of adjacent 1 segregations as that reported at term for translocations of paternal origin is observed. There is a strong postzygotic elimination process; for a given translocation it affects selectively the maximum-imbalance zygotes so that imbalanced segregations observed at term are always predetermined.

Chromosomes, Human↗

PubMed1984

Linkage and segregation analysis of HLA and congenital hypoaldosteronism due to corticosterone methyl-oxydase deficiency type I and type II.

To determine the genetic relations between HLA and deficiencies of steroidogenic enzymes other than 21-hydroxylase, we investigated HLA and congenital hypoaldosteronism in two families with corticosterone methyl-oxidase type 2 (CMO2) and one family with type 1 (CMO1) deficiency, respectively. Apart from a first documentation of HLA in CMO1 deficiency, our results, combined with those reported previously, excluded close linkage of HLA and CMO2 deficiency. However, loose linkage could not be encluded and the segregation of HLA haplotypes in sibships with CMO2 deficiency deviated significantly from random segregation. We suggest that HLA and CMO2 deficiency may not be independent.

Aldosterone↗

PubMed1992

Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients.

This paper presents the analysis of familial cancer data collected in a hospital-based study of 159 childhood soft-tissue-sarcoma patients. Two different statistical models detected excess aggregation of cancer, which could be explained by a rare dominant gene. For each kindred, we estimated the probability of the observed cancer distribution under the dominant-gene model and identified 12 families that are the most likely to be segregating the gene. Two of those families have confirmed germ-line mutations in the p53 tumor-suppressor gene. The relative risk of affection for children who are gene carriers was estimated to be 100 times the background rate. Females were found to have a slightly higher age-specific penetrance, but maternal and paternal lineages made equal contributions to the evidence in favor of the dominant gene. The proband's histology, ethnicity, and age at diagnosis were evaluated to determine whether any of these altered the probability of affection in family members. Only embryonal rhabdomyosarcoma was found to be a significant covariate under the dominant-gene model. While molecular genetic studies of familial cancer will eventually provide answers to the questions of genetic heterogeneity, age- and site-specific penetrance, mutation rates, and gene frequency, information from statistical models is useful for setting priorities and defining hypotheses.

Adolescent↗

PubMed1993

Genetic segregation analysis of red blood cell (RBC) histamine N-methyltransferase (HNMT) activity.

Methylation is an important pathway in the biotransformation of many drugs, neurotransmitters, and xenobiotic compounds. Histamine N-methyltransferase (HNMT) catalyzes the N tau-methylation of histamine and structurally related compounds. Measurement of HNMT activity in the RBC makes it possible to access variation in the enzyme activity that may reflect differences in less accessible tissues such as brain. Previously reported high family correlations for RBC HNMT activity suggested that genetic inheritance plays a major role in the regulation of variation in this enzyme. In the present study we completed complex segregation analyses of RBC HNMT activity of 241 individuals in 51 nuclear families that were randomly ascertained through children in the Rochester, Minnesota public school system in order to characterize the mode of inheritance of this important enzyme. We found evidence for major gene influence on the regulation of RBC HNMT activity. Both transformed and untransformed data support the presence of Mendelian major gene segregation, but the gene frequency differences do not indicate a direct correspondence between genotypes inferred from the two sets of analyses. Analyses of the skewed untransformed data indicated the presence of a relatively rare (Q = 0.121) additive major gene for high activity, with the three overlapping genotype distributions representing 77, 21, and 2% of individuals. Analyses of the normalized transformed data indicated the presence of a common (Q = 0.71) additive major gene for high activity, with the three overlapping genotype distributions accounting for 9, 41, and 50% of individuals. The analyses of transformed data give the best fit as well as the most parsimonious Mendelian major gene model.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1991

Segregation analysis of the structural genes of the major fibrillar collagens provides further evidence of molecular heterogeneity in type II Ehlers-Danlos syndrome.

Type II Ehlers-Danlos syndrome (EDS) is one of a group of disorders characterized by striking abnormalities of the soft connective tissues. The major fibrillar collagens (types I and III) found in these tissues have important stress-bearing functions and abnormal collagen could therefore account for the clinical features of this condition. We have used a number of restriction site dimorphisms, tightly linked to the structural genes of type I collagen (COL1A1 COL1A2) and type III collagen (COL3A1), to investigate the segregation of corresponding alleles in three pedigrees in which type II EDS was clearly inherited as a dominant trait. Discordant segregation of all three collagen genes was seen in a large pedigree that included 17 affected individuals with the typical phenotype of type II EDS. Thus mutations in neither type I nor type III collagen genes were responsible for the disease in this family. In a second small pedigree discordant segregation of the disease with both type I collagen loci was observed while the concordant segregation seen at COL3A1 could easily have arisen by chance (P = 0.5). The third pedigree was uninformative at all three collagen loci because of inability to discriminate between the parental alleles. These results suggest that there may be molecular heterogeneity of type II EDS since abnormalities of type I collagen have been described in other individuals phenotypically similar to those in our study.

Collagen↗

PubMed2002

Segregation analysis of 389 Icelandic pedigrees with Breast and prostate cancer.

Breast cancer and prostate cancer are the most commonly occurring cancers in females and males, respectively. The objective of this project was to test the hypothesis that breast cancer in females and prostate cancer in males represent homologous cancers that may be controlled by one or more common unidentified genes that may explain some of the observed familial aggregation. We modeled the transmission of a breast-prostate cancer phenotype in 389 pedigrees ascertained through a breast cancer proband drawn from the Icelandic Cancer Registry. Assuming that age at diagnosis of this combined phenotype followed a logistic distribution, segregation analyses were performed to evaluate residual parental effects, a sibship covariate, and a dichotomous cohort effect. The most parsimonious model was a Mendelian codominant model, which could partly explain the familial aggregation of both cancers. Inheritance of a putative high-risk allele (A) predicted gender-specific mean ages of onset for females as 53.8 years, 59.7 years, and 65.6 years for the putative AA, AB, and BB genotypes, respectively. Similarly, the predicted means were 73.7 years, 75.6 years, and 78.3 years, respectively, among males. Under this codominant model, the lifetime risk of a woman being affected was 19% by age 80 years. This implies that when prostate cancer among male relatives of breast cancer probands (unselected for family history or early-onset disease) is considered a pleiotrophic effect of the same gene that increases the risk for breast cancer, women are predicted to have a less than 1 in 5 risk of developing breast cancer when they carry the putative high-risk allele. However, this is a higher risk than in the general Icelandic population. Our results suggest that BRCA2 mutations alone are inadequate to explain all of the excess clustering of prostate cancer cases in families of breast cancer probands, and that additional genes conferring excess risk to both breast and prostate cancer may exist in this population.

Aged↗

PubMed1995

Segregation analysis of human red blood cell thiopurine methyltransferase activity.

Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine (6-MP). Inherited differences in the activity of this enzyme are related to individual differences in the therapeutic efficacy and toxicity of 6-MP and other thiopurine drugs. Variation of TPMT activity in the red blood cell (RBC) has been found to reflect activity differences in less accessible tissues. Previously reported qualitative analyses of inheritance of RBC TPMT in families suggested that a major gene plays a role in the regulation of activity of this enzyme. In the present study we completed complex segregation analyses of RBC TPMT activity of 213 individuals in 49 families that were randomly ascertained through children in the Rochester, MN, public school system. We found clear evidence of a major gene effect on RBC TPMT activity. Both transformed and untransformed data supported the segregation of a Mendelian major gene with frequency of 0.94 for the allele conferring high enzyme activity. The genotype distributions of individuals who were homozygous for the low activity allele, heterozygous, and homozygous for the high activity allele accounted for approximately 0.3%, 11.2%, and 88.5%, respectively, of the individuals in the sample. This major locus accounted for 66% of the total variance in untransformed RBC TPMT activity. Although there were significant residual family correlations among probable high activity homozygotes, there was insufficient power to detect additional major locus or polygenic inheritance effects on the residual variance.

Adolescent↗

PubMed2003

Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle.

The heritability of hypoadrenocorticism (Addison's disease) was evaluated in 778 standard poodles with known Addisonian phenotypes. Addisonian status was confirmed clinically by adrenocorticotropic hormone (ACTH) challenge and 8.6 per cent of the poodles enrolled in the study were classified as being Addisonian. Hypoadrenocorticism affected both sexes with equal probability (P > 0.1). The most common coat colours had a negligible effect on the incidence of hypoadrenocorticism (P > 0.09), although red coat colour had a significant impact on the disease, probably due to the relatively small numbers of dogs with that coat colour. The heritability of hypoadrenocorticism in the standard poodle was estimated to be 0.75. Complex segregation analyses suggested that hypoadrenocorticism in the breed is influenced by an autosomal recessive locus. Clarification of both the heritability and mode of inheritance of hypoadrenocorticism in the standard poodle allows for better-informed breeding decisions.

Adrenal Insufficiency↗