Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Exchangeable models of complex inherited diseases.

ABSTRACT: A model of unlinked diallelic loci affecting the risk of a complex inherited disease is explored. The loci are equivalent in their effect on disease risk and are in Hardy-Weinberg and linkage equilibrium. The goal is to determine what assumptions about dependence of disease risk on genotype are consistent with data for diseases such as schizophrenia, bipolar disorder, autism, and multiple sclerosis that are relatively common (0.1-2% prevalence) and that have high concordance rates for monozygotic twins (30-50%) and high risks to first-degree relatives of affected individuals (risk ratios exceeding 4). These observations are consistent with a variety of models, including generalized additive, multiplicative, and threshold models, provided that disease risk increases rapidly for a narrow range of numbers of causative alleles. If causative alleles are in relatively high frequency, then the combined effects of numerous causative loci are necessary to substantially elevate disease risk.

SUBMITTER: Slatkin M

PROVIDER: S-EPMC2516095 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Exchangeable models of complex inherited diseases.

Slatkin Montgomery M

Genetics 20080809 4

A model of unlinked diallelic loci affecting the risk of a complex inherited disease is explored. The loci are equivalent in their effect on disease risk and are in Hardy-Weinberg and linkage equilibrium. The goal is to determine what assumptions about dependence of disease risk on genotype are consistent with data for diseases such as schizophrenia, bipolar disorder, autism, and multiple sclerosis that are relatively common (0.1-2% prevalence) and that have high concordance rates for monozygoti ...[more]

PMID: 18689899

Similar Datasets

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases.

Project description:Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.

| S-EPMC7078110 | biostudies-literature

EDGE EXCHANGEABLE MODELS FOR INTERACTION NETWORKS.

Project description:Many modern network datasets arise from processes of interactions in a population, such as phone calls, email exchanges, co-authorships, and professional collaborations. In such interaction networks, the edges comprise the fundamental statistical units, making a framework for edge-labeled networks more appropriate for statistical analysis. In this context we initiate the study of edge exchangeable network models and explore its basic statistical properties. Several theoretical and practical features make edge exchangeable models better suited to many applications in network analysis than more common vertex-centric approaches. In particular, edge exchangeable models allow for sparse structure and power law degree distributions, both of which are widely observed empirical properties that cannot be handled naturally by more conventional approaches. Our discussion culminates in the Hollywood model, which we identify here as the canonical family of edge exchangeable distributions. The Hollywood model is computationally tractable, admits a clear interpretation, exhibits good theoretical properties, and performs reasonably well in estimation and prediction as we demonstrate on real network datasets. As a generalization of the Hollywood model, we further identify the vertex components model as a nonparametric subclass of models with a convenient stick breaking construction.

| S-EPMC6241523 | biostudies-literature

Inherited neuronal ion channelopathies: new windows on complex neurological diseases.

Project description:Studies of genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. Gain-of-function missense mutations in the brain type-I sodium channel Na(V)1.1 are a primary cause of generalized epilepsy with febrile seizures plus. Loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy of infancy, an intractable childhood epilepsy. Studies of a mouse model show that this disease is caused by selective loss of sodium current and excitability of GABAergic inhibitory interneurons, which leads to hyperexcitability, epilepsy, and ataxia. Mutations in the peripheral sodium channel Na(V)1.7 cause familial pain syndromes. Gain-of-function mutations cause erythromelalgia and paroxysmal extreme pain disorder as a result of hyperexcitability of sensory neurons, whereas loss-of-function mutations cause congenital indifference to pain because of attenuation of action potential firing. These experiments have defined correlations between genotype and phenotype in chronic pain diseases and focused attention on Na(V)1.7 as a therapeutic target. Familial hemiplegic migraine is caused by mutations in the calcium channel, Ca(V)2.1, which conducts P/Q-type calcium currents that initiate neurotransmitter release. These mutations increase activation at negative membrane potentials and increase evoked neurotransmitter release at cortical glutamatergic synapses. Studies of a mouse genetic model show that these gain-of-function effects lead to cortical spreading depression, aura, and potentially migraine. Overall, these experiments indicate that imbalance in the activity of excitatory and inhibitory neurons is an important underlying cause of these diseases.

| S-EPMC3177942 | biostudies-literature

Mathematical Modeling for Inherited Diseases.

Project description:We introduced a new nonassociative algebra, namely, left almost algebra, and discussed some of its genetic properties. We discussed the relation of this algebra with flexible algebra, Jordan algebra, and generalized Jordan algebra.

| S-EPMC5525089 | biostudies-other

Inherited complex cnv

Project description:Different clustered copy number variants in a mother and daughter are explained by unequal crossing-over during meiosis

| PRJEB26641 | ENA

Endophenotype Network Models: Common Core of Complex Diseases.

Project description:Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease's expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules.

| S-EPMC4899691 | biostudies-literature

Inherited human diseases of heterotopic bone formation.

Project description:Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extraskeletal bone formation-fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells.

| S-EPMC3551620 | biostudies-other

Golgi glycosylation and human inherited diseases.

Project description:The Golgi factory receives custom glycosylates and dispatches its cargo to the correct cellular locations. The process requires importing donor substrates, moving the cargo, and recycling machinery. Correctly glycosylated cargo reflects the Golgi's quality and efficiency. Genetic disorders in the specific equipment (enzymes), donors (nucleotide sugar transporters), or equipment recycling/reorganization components (COG, SEC, golgins) can all affect glycosylation. Dozens of human glycosylation disorders fit these categories. Many other genes, with or without familiar names, well-annotated pedigrees, or likely homologies will join the ranks of glycosylation disorders. Their broad and unpredictable case-by-case phenotypes cross the traditional medical specialty boundaries. The gene functions in patients may be elusive, but their common feature may include altered glycosylation that provide clues to Golgi function. This article focuses on a group of human disorders that affect protein or lipid glycosylation. Readers may find it useful to generalize some of these patient-based, translational observations to their own research.

| S-EPMC3181031 | biostudies-literature

Gene therapy for inherited metabolic diseases.

Project description:Over the last two decades, gene therapy has been successfully translated to many rare diseases. The number of clinical trials is rapidly expanding and some gene therapy products have now received market authorisation in the western world. Inherited metabolic diseases (IMD) are orphan diseases frequently associated with a severe debilitating phenotype with limited therapeutic perspective. Gene therapy is progressively becoming a disease-changing therapeutic option for these patients. In this review, we aim to summarise the development of this emerging field detailing the main gene therapy strategies, routes of administration, viral and non-viral vectors and gene editing tools. We discuss the respective advantages and pitfalls of these gene therapy strategies and review their application in IMD, providing examples of clinical trials with lentiviral or adeno-associated viral gene therapy vectors in rare diseases. The rapid development of the field and implementation of gene therapy as a realistic therapeutic option for various IMD in a short term also require a good knowledge and understanding of these technologies from physicians to counsel the patients at best.

| S-EPMC8518100 | biostudies-literature

Prime Editing for Inherited Retinal Diseases.

Project description:Inherited retinal diseases (IRDs) are chronic, hereditary disorders that lead to progressive degeneration of the retina. Disease etiology originates from a genetic mutation-inherited or de novo-with a majority of IRDs resulting from point mutations. Given the plethora of IRDs, to date, mutations that cause these dystrophies have been found in approximately 280 genes. However, there is currently only one FDA-approved gene augmentation therapy, Luxturna (voretigene neparvovec-rzyl), available to patients with RPE65-mediated retinitis pigmentosa (RP). Although clinical trials for other genes are underway, these techniques typically involve gene augmentation rather than genome surgery. While gene augmentation therapy delivers a healthy copy of DNA to the cells of the retina, genome surgery uses clustered regularly interspaced short palindromic repeats (CRISPR)-based technology to correct a specific genetic mutation within the endogenous genome sequence. A new technique known as prime editing (PE) applies a CRISPR-based technology that possesses the potential to correct all twelve possible transition and transversion mutations as well as small insertions and deletions. EDIT-101, a CRISPR-based therapy that is currently in clinical trials, uses double-strand breaks and nonhomologous end joining to remove the IVS26 mutation in the CEP290 gene. Preferably, PE does not cause double-strand breaks nor does it require any donor DNA repair template, highlighting its unparalleled efficiency. Instead, PE uses reverse transcriptase and Cas9 nickase to repair mutations in the genome. While this technique is still developing, with several challenges yet to be addressed, it offers promising implications for the future of IRD treatment.

| S-EPMC8656220 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data