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At least 19 recordsLinked to original sources

PubMed2004

[Pedigree analysis and sequence analysis of mtDNA 12srRNA, tRNA(Leu(UUR)), tRNA(Ser(UCN)) gene in nonsyndromic inherited deafness pedigrees].

OBJECTIVE: To investigate the proportion of mtDNA mutation in the non-syndromic genetic hearing loss (NSHL) pedigrees and the genetics statistical formulae for maternal inheritance, to study the relationship of mtDNA mutation and inherited deafness, to identify the incidence of the mtDNA mutation in such pedigrees and sporadic patients with Sensorineural hearing loss (SNHL). METHOD: Twenty-nine pedigrees with NSHL were collected. Pedigree Investigation was taken. Modal Genetics Analysis. Segregation Analysis were taken. Blood samples were obtained from these pedigrees. DNA was extracted from the isolated leukocytes. The mtDNA 1555G, 7445G, 3243G mutation were examined by multiplex PCR. The sequence of 12SrRNA, tRNA(Leu(UUR)) and tRNA(Ser(UCN)) gene were examined. RESULT: There are 12 pedigrees with mtDNA mutation (i.e. 10 with 1555G and 2 with 7445G) examing by multiplex PCR. Modal Genetics Analysis showed that in irregular dominate genetic pedigrees, the incidence of mtDNA mutation is higher than that of regular dominate pedigrees. Segregation Analysis with Screening for mtDNA mutation showed that maternal inherited pedigrees did not have the segregate ratio that the autosomal inheritance had. Sequence analysis confirmed that the 12 pedigrees carried mtDNA mutation, among them 10 pedigrees with 1555G mutation, 2 pedigrees with 7445G mutation, no pedigrees with 3243G. CONCLUSION: Maternal inherited pedigrees do not have the segregate ratio of the autosomal inheritance, mtDNA mutation have high incidence in NSHL, mostly are 1555G and 7445G mutation. Screening for mtDNA 7445G mutation combined with 1555G examination is of value to clinical use. Multiplex PCR can diagnose mtDNA multi-mutation quickly and facilely.

DNA, Mitochondrial↗

PubMed2005

The role of pedigree information in combined linkage disequilibrium and linkage mapping of quantitative trait loci in a general complex pedigree.

Combined linkage disequilibrium and linkage (LDL) mapping can exploit historical as well as recent and observed recombinations in a recorded pedigree. We investigated the role of pedigree information in LDL mapping and the performance of LDL mapping in general complex pedigrees. We compared using complete and incomplete genotypic data, spanning 5 or 10 generations of known pedigree, and we used bi- or multiallelic markers that were positioned at 1- or 5-cM intervals. Analyses carried out with or without pedigree information were compared. Results were compared with linkage mapping in some of the data sets. Linkage mapping or LDL mapping with sparse marker spacing ( approximately 5 cM) gave a poorer mapping resolution without considering pedigree information compared to that with considering pedigree information. The difference was bigger in a pedigree of more generations. However, LDL mapping with closely linked markers ( approximately 1 cM) gave a much higher mapping resolution regardless of using pedigree information. This study shows that when marker spacing is dense and there is considerable linkage disequilibrium generated from historical recombinations between flanking markers and QTL, the loss of power due to ignoring pedigree information is negligible and mapping resolution is very high.

Alleles↗

PubMed1995

Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors.

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to > 100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.

Genetic Counseling↗

PubMed2000

A test for linkage and association in general pedigrees: the pedigree disequilibrium test.

Family-based tests of linkage disequilibrium typically are based on nuclear-family data including affected individuals and their parents or their unaffected siblings. A limitation of such tests is that they generally are not valid tests of association when data from related nuclear families from larger pedigrees are used. Standard methods require selection of a single nuclear family from any extended pedigrees when testing for linkage disequilibrium. Often data are available for larger pedigrees, and it would be desirable to have a valid test of linkage disequilibrium that can use all potentially informative data. In this study, we present the pedigree disequilibrium test (PDT) for analysis of linkage disequilibrium in general pedigrees. The PDT can use data from related nuclear families from extended pedigrees and is valid even when there is population substructure. Using computer simulations, we demonstrated validity of the test when the asymptotic distribution is used to assess the significance, and examined statistical power. Power simulations demonstrate that, when extended pedigree data are available, substantial gains in power can be attained by use of the PDT rather than existing methods that use only a subset of the data. Furthermore, the PDT remains more powerful even when there is misclassification of unaffected individuals. Our simulations suggest that there may be advantages to using the PDT even if the data consist of independent families without extended family information. Thus, the PDT provides a general test of linkage disequilibrium that can be widely applied to different data structures.

Alleles↗

PubMed2003

The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates.

We have extended our previous analysis of the pedigree rate of control-region divergence in the human mitochondrial genome. One new germline mutation in the mitochondrial DNA (mtDNA) control region was detected among 185 transmission events (generations) from five Leber hereditary optic neuropathy (LHON) pedigrees. Pooling the LHON pedigree analyses yields a control-region divergence rate of 1.0 mutation/bp/10(6) years (Myr). When the results from eight published studies that used a similar approach were pooled with the LHON pedigree studies, totaling >2,600 transmission events, a pedigree divergence rate of 0.95 mutations/bp/Myr for the control region was obtained with a 99.5% confidence interval of 0.53-1.57. Taken together, the cumulative results support the original conclusion that the pedigree divergence rate for the control region is approximately 10-fold higher than that obtained with phylogenetic analyses. There is no evidence that any one factor explains this discrepancy, and the possible roles of mutational hotspots (rate heterogeneity), selection, and random genetic drift and the limitations of phylogenetic approaches to deal with high levels of homoplasy are discussed. In addition, we have extended our pedigree analysis of divergence in the mtDNA coding region. Finally, divergence of complete mtDNA sequences was analyzed in two tissues, white blood cells and skeletal muscle, from each of 17 individuals. In three of these individuals, there were four instances in which an mtDNA mutation was found in one tissue but not in the other. These results are discussed in terms of the occurrence of somatic mtDNA mutations.

Base Sequence↗

PubMed2001

Test of association for quantitative traits in general pedigrees: the quantitative pedigree disequilibrium test.

Many statistical methods have been proposed in recent years to test for genetic linkage and association between genetic markers and traits of interest through unrelated nuclear families. However, most of these methods are not valid tests of association in the presence of linkage when some of the nuclear families are related. As a result, related nuclear families in large pedigrees cannot be included in a single analysis to test for linkage disequilibrium. Recently, Martin et al. [Am J Hum Genet 67:146-54, 2000] proposed the pedigree disequilibrium test (PDT) to test for linkage and association in general pedigrees for qualitative traits. In this article, we develop a similar quantitative pedigree disequilibrium test (QPDT) to test for linkage and association in general pedigrees for quantitative traits. We apply both the PDT and the QPDT to analyze the sequence data from the seven candidate genes in the simulated data sets in the Genetic Analysis Workshop 12.

Chromosome Mapping↗

PubMed1983

Evaluating pedigree data. I. The estimation of pedigree error in the presence of marker mistyping.

Pedigrees used in the analysis of genetic or medical data are usually ascertained from sources subject to a variety of errors including misidentification of individuals, faults in historical documents or record linkage, nonpaternity, and unidentified adoption. Genetic markers can be used to verify putative family and pedigree data through the search for inconsistencies, or genetic exclusions, between putative parents and offspring. The probability of observing an exclusion given the occurrence of an error depends upon the gene frequencies at the loci under study and the forms of error. In addition, inconsistencies can arise from laboratory errors in marker determination. Together, these problems make the proper statistical analysis of such data desirable. Here we give a model that specifies the combined effects of various kinds of pedigree error along with genetic marker error. This model allows the maximum-likelihood estimation of the rates of various forms of pedigree error and laboratory error from genetic marker data collected on putative families. The method is illustrated by applying it to data obtained from a South Pacific island population, Tokelau. From the observed distribution of genetic marker inconsistencies between the parents and offspring of putative families, derived from the extensive genealogy of this population, we are able to estimate that the error of a paternal link is 4%, the error of a maternal link is zero, and the overall system typing error is 1%.

Alleles↗

PubMed1975

Extensions to pedigree analysis I. Likehood calculations for simple and complex pedigrees.

A graph theoretic definition of pedigrees is given and a distinction drawn between simple and complex pedigrees. Algorithms are presented to calculate the likeihood of any kind of pedigree, assuming only segregation at a finite set of loci, nonassortative mating and no environmental correlations; multiple births and consanguineous marriages are explicity allowed for. The formulation given can lead to more powerful genetic counselling, segregation analysis and linkage analysis.

Genetic Linkage↗

PubMed1996

Pedigree analysis package vs. MIXD: fitting the mixed model on a large pedigree.

Results of a simulation study with two methods of analysis of data simulated under the mixed model on a 232-member pedigree are presented. The programs Pedigree Analysis Package (PAP), which approximate the likelihoods needed in a complex segregation analysis, and MIXD, which uses Monte Carlo Markov chain (MCMC), to estimate likelihoods were used. PAP obtained unbiased estimates of the major locus genotype means and the gene frequency, but biased estimates of the environmental variance component, and thus the heritability. A substantial fraction of the runs did not converge to an internal set of parameter estimates when analyzed with PAP. MIXD, which uses the Gibbs sampler to perform the MCMC sampling, produced unbiased estimates of all parameters with considerably more accuracy than obtained with PAP, and did not suffer from convergence of estimates to the boundary of the parameter space. The difference in behavior and accuracy of parameter estimates between PAP and MIXD was most apparent for models with either high or low residual additive genetic variance. Thus in situations where accuracy of the model is important, use of MCMC methods may be useful. In situations where less accuracy is needed, approximation methods may be adequate. Practical issues in using MCMC as implemented in MIXD to fit the mixed model are also discussed. Results of the simulations indicate that, unlike PAP, the starting configurations of most parameter estimates do not substantially influence the final parameter estimates in analysis with MIXD.

Analysis of Variance↗

PubMed1987

PEDIGREE-PLOT: a computer program for plotting pedigrees.

PEDIGREE-PLOT is a FORTRAN program which can be used for the drawing of pedigrees in either a horizontal or a circular shape. Eight different symbols are available for characterizing a person. Special symbols for stillbirth, abortion, unspecified sex, twins and half sibships exist.

Humans↗

PubMed1998

Pedigree analysis package (PAP) vs. MORGAN: model selection and hypothesis testing on a large pedigree.

The MORGAN package of programs is compared to a commonly used package, PAP, with respect to model selection in segregation analysis of a quantitative trait. MORGAN uses Monte Carlo Markov chain (MCMC) methods to estimate the likelihood, whereas both versions of PAP used employ an approximation to the likelihood for the mixed model. Comparisons are done by using results obtained from simulated data. All simulations were done on the same 232-member pedigree using data generated under each of several variations of models, which included different combinations of environmental, polygenic, and major gene components. PAP, version 4.0, and MORGAN gave similar results with respect to model selection for the majority of situations, suggesting that MCMC methods provide a computationally tractable approach for analysis of more complex models that cannot be analyzed by more direct computational methods. PAP, version 3.0, gave somewhat more disparate results compared with either PAP version 4.0 or MORGAN. Both MORGAN and the two versions of PAP confirmed that the major gene component is much easier to detect in the presence of some dominance. All three packages frequently falsely accepted the polygenic model when there was high residual heritability.

Computer Simulation↗

PubMed2001

Pedigree selection and tests of linkage in a Hutterite asthma pedigree.

We explored methods for kinship and linkage analysis in a Hutterite pedigree comprising 1,544 individuals, 72 of whom were diagnosed with asthma. Subpedigrees were selected by (a) identifying nuclear families containing asthmatics, (b) identifying couples with many asthmatic descendants in an ad hoc manner, and (c) finding the most recent common ancestors of all asthmatics. Markov chain Monte Carlo (MCMC) methods were used to estimate allele sharing in the larger subpedigrees and transmission/disequilibrium tests were performed on nuclear families. On chromosome 5q near the cytokine cluster, modest evidence for linkage to asthma was obtained. Using MCMC, we were able to evaluate the evidence for linkage in complex subpedigrees of several hundred individuals, and hence, incorporate some of the co-ancestry of this founder population.

Adult↗

PubMed2004

Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate.

Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attention-deficit/hyperactivity disorder (ADHD) has been suggested by case-control- and nuclear-family-based studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele.

Alleles↗

PubMed2006

Localization of a prostate cancer predisposition gene to an 880-kb region on chromosome 22q12.3 in Utah high-risk pedigrees.

Chromosome 22q has become recently a region of interest for prostate cancer. We identified previously a logarithm of odds (LOD) of 2.42 at chromosome 22q12.3. Additionally, this region has been noted by eight other studies, with linkage evidence ranging from LOD of 1.50 to 3.57. Here, we do fine mapping and localization of the region using a pedigree-specific recombinant mapping approach in 14 informative, high-risk Utah pedigrees. These 14 pedigrees were chosen because they were either "linked" or "haplotype-sharing" pedigrees or both. "Linked" pedigrees were those with significant pedigree-specific linkage evidence (LOD, >0.588; P < 0.05) to the 22q12.3 region, regardless of the number of prostate cancer cases sharing the segregating haplotype. "Haplotype-sharing" pedigrees were those with at least five prostate cancer cases sharing a segregating haplotype in the 22q12.3 region, regardless of the linkage evidence. In each pedigree, the most likely haplotype configuration (in addition to the multipoint LOD graph for linked pedigrees) was used to infer the position of recombinant events and delimit the segregating chromosomal segment in each pedigree. These pedigree-specific chromosomal segments were then overlaid to form a consensus recombinant map across all 14 pedigrees. Using this method, we identified a 881,538-bp interval at 22q12.3, between D22S1265 and D22S277, which is the most likely region that contains the 22q prostate cancer predisposition gene. The unique Utah extended high-risk pedigree resource allows this powerful localization approach in pedigrees with evidence for segregating predisposition to prostate cancer. We are mutation screening candidate genes in this region to identify specific genetic variants segregating in these pedigrees.

Aged↗

PubMed2003

Sampling correction in pedigree analysis.

Usually, a pedigree is sampled and included in the sample that is analyzed after following a predefined non-random sampling design comprising several specific procedures. To obtain a pedigree analysis result free from the bias caused by the sampling procedures, a correction is applied to the pedigree likelihood. The sampling procedures usually considered are: the pedigree ascertainment, determining whether a population unit is to be sampled; the intrafamilial pedigree extension, determining what part of the pedigree is to be sampled; and selective censoring of the sampled pedigree, determining whether it should be included in the sample to be analyzed. The probability of pedigree ascertainment is determined by the total set of potential probands in the true pedigree from which the sampled pedigree is obtained and we indicate how the necessary information on this set can be collected. If insufficient information on this set is observed, it is impossible to correct the pedigree likelihood adequately. Here we show that, if only the structure of this set is known, then an ascertainment-model-based pedigree likelihood can be obtained by conditioning on this structure. An ascertainment-model-free (AMF) pedigree likelihood can be correctly constructed by conditioning on all the data in this set, i.e. on both its structure and its phenotypic content. However, if this set has missing data, the AMF likelihood becomes undefined, which limits the utility of this AMF approach originally proposed by Ewens and Shute (1986). We also consider the sampling correction necessary when the pedigrees included in the sample analyzed have been subjected to censoring. The forms of likelihood correction developed here provide asymptotically unbiased estimators of the genetic model only if the formulated model is correct, which means that it must correctly allow for the most important features of the true inheritance of the trait studied. Otherwise, if no special case of the formulated general model is close to the true inheritance model, then the forms of likelihood correction proposed here result in biases, the magnitude and direction of which depend on both the true model and the general analysis model that should subsume it.

Journal Article↗

PubMed1998

Privacy and confidentiality in the publication of pedigrees: a survey of investigators and biomedical journals.

CONTEXT: Pedigree diagrams efficiently communicate family information to genetics investigators; however, the publication of pedigrees poses a risk to the privacy and confidentiality of individuals depicted in the diagrams. Two sets of authoritative guidelines have been published to protect the privacy and confidentiality of subjects, but the influence of these guidelines on publication practices for pedigrees is unknown. OBJECTIVE: To determine the attitudes, practices, and experiences of investigators and journals with respect to privacy and confidentiality concerns in the publication of pedigrees. DESIGN: Investigators who have published pedigrees and editors of 26 biomedical journals were surveyed. Journals were reviewed for content in their "information for authors" sections and for documentation of informed consent in articles containing pedigrees. OUTCOME MEASURES: Practices regarding confidentiality and privacy reported by investigators and editors. RESULTS: Of 226 surveys sent to investigators, 177 were returned (78% response rate). Sixty-one investigators (36%) stated that family members were not informed that their pedigree would be published; 131 (78%) do not obtain informed consent specifically for pedigree publication and only 12 (28%) of the 43 who obtained consent obtained consent from all family members depicted. Thirty-two individuals (19%) reported having altered published pedigrees and 14 (45%) of 31 who had altered pedigrees stated that alterations were not disclosed to journals. Of the 14 journals that responded (54% response rate), only 3 reported written policies for managing potentially identifying information. Two journals reported having asked authors to alter pedigrees and 3 stated they had permitted alterations. A review of 5 genetics journals over a 2-year period revealed no documentation of consent for pedigree publication. CONCLUSIONS: Current practices in the publication of pedigrees do not conform with established recommendations and risk the privacy and confidentiality of subjects, often without informed consent. Attempts to address this problem through the alteration of data are being used, although this practice impairs the integrity of scientific communication.

Confidentiality↗

PubMed2001

Clustering of pedigrees using marker allele frequencies: impact on linkage analysis.

Ethnicity may form the basis for locus heterogeneity at certain susceptibility loci for complex diseases. Classification of pedigrees into ethnic groups is usually based upon self-report, but this may not be sensitive or specific. We investigated whether it is possible to cluster families from an admixed population using pedigree-specific marker allele frequencies. We used 323 autosomal microsatellite markers from 216 pedigrees who described themselves as either Caucasian or African American. First, we compared the stated ethnicity of pedigrees with clusters using pedigree-specific marker allele frequencies as input for a self-organizing map, a type of neural network. Using data from different chromosomes, nine pedigrees which were self-reported as African American were clustered with the Caucasian pedigrees. Removal of these nine pedigrees from the African American group did not markedly affect linkage results. We then proceeded to determine whether there was further heterogeneity between pedigrees using 1 x 3 nodes. Forty-four pedigrees were clustered in a group intermediate to the African American or Caucasian clusters. This group was composed of 36 and 8 pedigrees that described themselves as African American and Caucasian, respectively. Linkage analysis was performed in this group and results compared with the groups based upon self-reported ethnicity. Linkage to a region on chromosome 3 was observed in this intermediate group, which was more significant than any of the results obtained when pedigrees were grouped using self-reported ethnicity. Use of marker data may assist in clustering pedigrees with similar, ethnic backgrounds and may increase the power for genetic linkage studies.

Adult↗

PubMed2001

Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees.

OBJECTIVE: Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schizophrenia or the consequence of a gene-environment interaction. Alternatively, traumatic brain injury and schizophrenia could be spuriously associated if those who are predisposed to develop schizophrenia have greater amounts of trauma for other reasons. The authors investigated the relationship between traumatic brain injury and psychiatric diagnoses in a large group of subjects from families with at least two biologically related first-degree relatives with schizophrenia, schizoaffective disorder, or bipolar disorder. METHOD: The Diagnostic Interview for Genetic Studies was used to determine history of traumatic brain injury and diagnosis for 1,275 members of multiplex bipolar disorder pedigrees and 565 members of multiplex schizophrenia pedigrees. RESULTS: Rates of traumatic brain injury were significantly higher for those with a diagnosis of schizophrenia, bipolar disorder, and depression than for those with no mental illness. However, multivariate analysis of within-pedigree data showed that mental illness was related to traumatic brain injury only in the schizophrenia pedigrees. Independent of diagnoses, family members of those with schizophrenia were more likely to have had traumatic brain injury than were members of the bipolar disorder pedigrees. The members of the schizophrenia pedigrees also failed to show the gender difference for traumatic brain injury (more common in men than in women) that was expected and was present in the bipolar disorder pedigrees. Subjects with a schizophrenia diagnosis who were members of the bipolar disorder pedigrees (and thus had less genetic vulnerability to schizophrenia) were less likely to have had traumatic brain injury (4.5%) than were subjects with schizophrenia who were members of the schizophrenia pedigrees (and who had greater genetic vulnerability to schizophrenia) (19.6%). CONCLUSIONS: Members of the schizophrenia pedigrees, even those without a schizophrenia diagnosis, had greater exposure to traumatic brain injury compared to members of the bipolar disorder pedigrees. Within the schizophrenia pedigrees, traumatic brain injury was associated with a greater risk of schizophrenia, consistent with synergistic effects between genetic vulnerability for schizophrenia and traumatic brain injury. Posttraumatic-brain-injury schizophrenia in multiplex schizophrenia pedigrees does not appear to be a phenocopy of the genetic disorder.

Adult↗