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American Family Physician Aug 2005The collection of a family history ranges from simply asking patients if family members have the same presenting illness to diagramming complex medical and psychosocial... (Review)
Review
The collection of a family history ranges from simply asking patients if family members have the same presenting illness to diagramming complex medical and psychosocial relationships as part of a family genogram. The three-generation pedigree provides a pictorial representation of diseases within a family and is the most efficient way to assess hereditary influences on disease. Two recent events have made family history assessment more important than ever: the completion of the Human Genome Project with resultant identification of the inherited causes of many diseases, and the establishment of national clinical practice guidelines based on systematic reviews of preventive interventions. The family history is useful in stratifying a patient's risk for rare single-gene disorders and more common diseases with multiple genetic and environmental contributions. Major organizations have endorsed using standardized symbols in pedigrees to identify inherited contributions to disease.
Topics: Genetic Predisposition to Disease; Genetic Testing; Humans; Medical History Taking; Pedigree
PubMed: 16100858
DOI: No ID Found -
Genetic Epidemiology Apr 2017Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can...
Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. Finally, many pedigrees are available as an important legacy from the era of linkage analysis. Unfortunately, pedigree likelihoods are notoriously hard to compute. In this paper, we reexamine the computational bottlenecks and implement ultra-fast pedigree-based GWAS analysis. Kinship coefficients can either be based on explicitly provided pedigrees or automatically estimated from dense markers. Our strategy (a) works for random sample data, pedigree data, or a mix of both; (b) entails no loss of power; (c) allows for any number of covariate adjustments, including correction for population stratification; (d) allows for testing SNPs under additive, dominant, and recessive models; and (e) accommodates both univariate and multivariate quantitative traits. On a typical personal computer (six CPU cores at 2.67 GHz), analyzing a univariate HDL (high-density lipoprotein) trait from the San Antonio Family Heart Study (935,392 SNPs on 1,388 individuals in 124 pedigrees) takes less than 2 min and 1.5 GB of memory. Complete multivariate QTL analysis of the three time-points of the longitudinal HDL multivariate trait takes less than 5 min and 1.5 GB of memory. The algorithm is implemented as the Ped-GWAS Analysis (Option 29) in the Mendel statistical genetics package, which is freely available for Macintosh, Linux, and Windows platforms from http://genetics.ucla.edu/software/mendel.
Topics: Genetic Linkage; Genome, Human; Genome-Wide Association Study; Humans; Models, Genetic; Models, Statistical; Pedigree; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Software
PubMed: 27943406
DOI: 10.1002/gepi.21988 -
Bioinformatics (Oxford, England) Feb 2016PRIMUS is a pedigree reconstruction algorithm that uses estimates of genome-wide identity by descent to reconstruct pedigrees consistent with observed genetic data....
UNLABELLED
PRIMUS is a pedigree reconstruction algorithm that uses estimates of genome-wide identity by descent to reconstruct pedigrees consistent with observed genetic data. However, when genetic data for individuals within a pedigree are missing, often multiple pedigrees can be reconstructed that fit the data. We report a major expansion of PRIMUS that uses mitochondrial (mtDNA) and non-recombining Y chromosome (NRY) haplotypes to eliminate many pedigree structures that are inconsistent with the genetic data. We demonstrate that discordances in mtDNA and NRY haplotypes substantially reduce the number of potential pedigrees, and often lead to the identification of the correct pedigree.
AVAILABILITY AND IMPLEMENTATION
We have implemented PRIMUS updates in PERL and it is available at primus.gs.washington.edu.
Topics: Algorithms; Chromosomes, Human, Y; Computer Simulation; DNA, Mitochondrial; Genetics, Population; Haplotypes; Humans; Linkage Disequilibrium; Pedigree; Software
PubMed: 26515822
DOI: 10.1093/bioinformatics/btv618 -
Nucleic Acids Research Feb 2021The maternal mode of mitochondrial DNA (mtDNA) inheritance is central to human genetics. Recently, evidence for bi-parental inheritance of mtDNA was claimed for...
The maternal mode of mitochondrial DNA (mtDNA) inheritance is central to human genetics. Recently, evidence for bi-parental inheritance of mtDNA was claimed for individuals of three pedigrees that suffered mitochondrial disorders. We sequenced mtDNA using both direct Sanger and Massively Parallel Sequencing in several tissues of eleven maternally related and other affiliated healthy individuals of a family pedigree and observed mixed mitotypes in eight individuals. Cells without nuclear DNA, i.e. thrombocytes and hair shafts, only showed the mitotype of haplogroup (hg) V. Skin biopsies were prepared to generate ρ° cells void of mtDNA, sequencing of which resulted in a hg U4c1 mitotype. The position of the Mega-NUMT sequence was determined by fluorescence in situ hybridization and two different quantitative PCR assays were used to determine the number of contributing mtDNA copies. Thus, evidence for the presence of repetitive, full mitogenome Mega-NUMTs matching haplogroup U4c1 in various tissues of eight maternally related individuals was provided. Multi-copy Mega-NUMTs mimic mixtures of mtDNA that cannot be experimentally avoided and thus may appear in diverse fields of mtDNA research and diagnostics. We demonstrate that hair shaft mtDNA sequencing provides a simple but reliable approach to exclude NUMTs as source of misleading results.
Topics: Cell Nucleus; DNA Copy Number Variations; DNA, Mitochondrial; Female; Genome, Human; Humans; Male; Pedigree; Sequence Analysis, DNA
PubMed: 33450006
DOI: 10.1093/nar/gkaa1271 -
Radiation Research Jul 2022Previous epidemiological studies have demonstrated elevated susceptibility to ionizing radiation in some families, thus suggesting the presence of genetic components...
Previous epidemiological studies have demonstrated elevated susceptibility to ionizing radiation in some families, thus suggesting the presence of genetic components that conferred increased rate of radiation-associated meningioma (RAM). In this study, we exome-sequenced and investigated the segregation pattern of rare deleterious variants in 11 RAM pedigrees. In addition, we performed a rare-variant association analysis in 92 unrelated familial cases of RAM that were ancestry-matched with 88 meningioma-free controls. In the pedigree analysis, we found that each family carried mostly a unique set of rare deleterious variants. A follow-up pathway analysis of the union of the genes that segregated within each of the 11 pedigrees identified a single statistically significant (q value = 7.90E-04) "ECM receptor interaction" set. In the case-control association analysis, we observed no statistically significant variants or genes after multiple testing correction; however, examination of ontological categories of the genes that associated with RAM at nominal P values <0.01 identified biologically relevant pathways such as DNA repair, cell cycle and apoptosis. These results suggest that it is unlikely that a small number of highly penetrant genes are involved in the pathogenesis of RAM. Substantially larger studies are needed to identify genetic risk variants and genes in RAM.
Topics: Case-Control Studies; Exome; Genetic Predisposition to Disease; Humans; Pedigree; Radiation, Ionizing
PubMed: 35405740
DOI: 10.1667/RADE-21-00035.1 -
Scientific Reports Jan 2020Local ancestry, defined as the genetic ancestry at a genomic location of an admixed individual, is widely used as a genetic marker in genetic association and...
Local ancestry, defined as the genetic ancestry at a genomic location of an admixed individual, is widely used as a genetic marker in genetic association and evolutionary genetics studies. Many methods have been developed to infer the local ancestries in a set of unrelated individuals, a few of them have been extended to small nuclear families, but none can be applied to large (e.g. three-generation) pedigrees. In this study, we developed a method, FamANC, that can improve the accuracy of local ancestry inference in large pedigrees by: (1) using an existing algorithm to infer local ancestries for all individuals in a family, assuming (contrary to fact) they are unrelated, and (2) improving its accuracy by correcting inference errors using pedigree structure. Applied on African-American pedigrees from the Cleveland Family Study, FamANC was able to correct all identified Mendelian errors and most of double crossovers.
Topics: Algorithms; Computer Simulation; Ethnicity; Genetics, Population; Genotype; Haplotypes; Humans; Models, Genetic; Models, Statistical; Pedigree; Polymorphism, Single Nucleotide
PubMed: 31932708
DOI: 10.1038/s41598-019-57039-w -
Bioinformatics (Oxford, England) Feb 2024Pedigree-based analyses' prime role is to unravel relationships between individuals in breeding programs and germplasms. This is critical information for decoding the...
SUMMARY
Pedigree-based analyses' prime role is to unravel relationships between individuals in breeding programs and germplasms. This is critical information for decoding the genetics underlying main inherited traits of relevance, and unlocking the genotypic variability of a species to carry out genomic selections and predictions. Despite the great interest, current lineage visualizations become quite limiting in terms of public display, exploration, and tracing of traits up to ancestral donors. PERSEUS is a user-friendly, intuitive, and interactive web-based tool for pedigree visualizations represented as directed graph networks distributed using a force-repulsion method. The visualizations do not only showcase individual relationships among accessions, but also facilitate a seamless search and download of phenotypic traits along the pedigrees. PERSEUS is a promising tool for breeders and scientists, advantageous for evolutionary, genealogy, and diversity analyses among related accessions and species.
AVAILABILITY AND IMPLEMENTATION
PERSEUS is freely accessible at https://bioinformatics.cragenomica.es/perseus and GitHub code is available at https://github.com/aranzana-lab/PERSEUS.
Topics: Humans; Software; Pedigree; Genomics; Genome; Internet
PubMed: 38310342
DOI: 10.1093/bioinformatics/btae060 -
Genetic Epidemiology Mar 2018Construction of multifactorial disease models from epidemiological findings and their application to disease pedigrees for risk prediction is nontrivial for all but the...
Construction of multifactorial disease models from epidemiological findings and their application to disease pedigrees for risk prediction is nontrivial for all but the simplest of cases. Multifactorial Disease Risk Calculator is a web tool facilitating this. It provides a user-friendly interface, extending a reported methodology based on a liability-threshold model. Multifactorial disease models incorporating all the following features in combination are handled: quantitative risk factors (including polygenic scores), categorical risk factors (including major genetic risk loci), stratified age of onset curves, and the partition of the population variance in disease liability into genetic, shared, and unique environment effects. It allows the application of such models to disease pedigrees. Pedigree-related outputs are (i) individual disease risk for pedigree members, (ii) n year risk for unaffected pedigree members, and (iii) the disease pedigree's joint liability distribution. Risk prediction for each pedigree member is based on using the constructed disease model to appropriately weigh evidence on disease risk available from personal attributes and family history. Evidence is used to construct the disease pedigree's joint liability distribution. From this, lifetime and n year risk can be predicted. Example disease models and pedigrees are provided at the website and are used in accompanying tutorials to illustrate the features available. The website is built on an R package which provides the functionality for pedigree validation, disease model construction, and risk prediction. Website: http://grass.cgs.hku.hk:3838/mdrc/current.
Topics: Disease; Genetic Predisposition to Disease; Humans; Internet; Models, Genetic; Multifactorial Inheritance; Pedigree; Reproducibility of Results; Risk Factors; Software
PubMed: 29178360
DOI: 10.1002/gepi.22101 -
Bioinformatics (Oxford, England) Nov 2021The use and functionality of Electronic Health Records (EHR) have increased rapidly in the past few decades. EHRs are becoming an important depository of patient health...
MOTIVATION
The use and functionality of Electronic Health Records (EHR) have increased rapidly in the past few decades. EHRs are becoming an important depository of patient health information and can capture family data. Pedigree analysis is a longstanding and powerful approach that can gain insight into the underlying genetic and environmental factors in human health, but traditional approaches to identifying and recruiting families are low-throughput and labor-intensive. Therefore, high-throughput methods to automatically construct family pedigrees are needed.
RESULTS
We developed a stand-alone application: Electronic Pedigrees, or E-Pedigrees, which combines two validated family prediction algorithms into a single software package for high throughput pedigrees construction. The convenient platform considers patients' basic demographic information and/or emergency contact data to infer high-accuracy parent-child relationship. Importantly, E-Pedigrees allows users to layer in additional pedigree data when available and provides options for applying different logical rules to improve accuracy of inferred family relationships. This software is fast and easy to use, is compatible with different EHR data sources, and its output is a standard PED file appropriate for multiple downstream analyses.
AVAILABILITY AND IMPLEMENTATION
The Python 3.3+ version E-Pedigrees application is freely available on: https://github.com/xiayuan-huang/E-pedigrees.
Topics: Humans; Pedigree; Software; Algorithms; Electronic Health Records
PubMed: 34086863
DOI: 10.1093/bioinformatics/btab419 -
Journal of Thrombosis and Haemostasis :... Mar 2024Most family studies on venous thromboembolism (VTE) have focused on first-degree relatives.
BACKGROUND
Most family studies on venous thromboembolism (VTE) have focused on first-degree relatives.
OBJECTIVES
We took a pedigree-based approach and examined the risk of VTE and cardiometabolic disorders in offspring from extended pedigrees according to the densities of VTE in pedigrees.
METHODS
From the Swedish population, we identified a total of 482 185 pedigrees containing a mean of 14.2 parents, aunts/uncles, grandparents, and cousins of a core full sibship that we termed the pedigree offspring (n = 751 060). We then derived 8 empirical classes of these pedigrees based on the density of cases of VTE. The risk was determined in offspring for VTE and cardiometabolic disorders as a function of VTE density in their pedigrees. Bonferroni correction for multiple comparisons was performed.
RESULTS
VTE was unevenly distributed in the population; the Gini coefficient was 0.59. Higher VTE density in pedigrees was associated in the offspring with a higher risk of different VTE manifestations (deep venous thrombosis, pulmonary embolism, pregnancy-related VTE, unusual thrombosis, and superficial thrombophlebitis), thrombophilia, and lower age of first VTE event. Moreover, VTE density in pedigrees was significantly associated in the offspring with obesity, diabetes, gout, varicose veins, and arterial embolism and thrombosis (excluding brain and heart). No significant associations were observed for retinal vein occlusion, hypercholesterolemia, hypertension, coronary heart disease, myocardial infarction, ischemic stroke, atrial fibrillation, heart failure, primary pulmonary hypertension, cerebral hemorrhage, aortic aneurysm, peripheral artery disease, and overall mortality.
CONCLUSION
Offspring of pedigrees with a high density of VTE are disadvantaged regarding VTE manifestations and certain cardiometabolic disorders.
Topics: Humans; Venous Thromboembolism; Pedigree; Risk Factors; Thrombophlebitis; Pulmonary Embolism
PubMed: 38072377
DOI: 10.1016/j.jtha.2023.11.024