Genetic Pleiotropy: A phenomenon in which multiple and diverse phenotypic outcomes are influenced by a single gene (or single gene product.)Polymorphism, Single Nucleotide: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.Genome-Wide Association Study: An analysis comparing the allele frequencies of all available (or a whole GENOME representative set of) polymorphic markers in unrelated patients with a specific symptom or disease condition, and those of healthy controls to identify markers associated with a specific disease or condition.Genetic Variation: Genotypic differences observed among individuals in a population.Genetic Predisposition to Disease: A latent susceptibility to disease at the genetic level, which may be activated under certain conditions.Genotype: The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone.Models, Genetic: Theoretical representations that simulate the behavior or activity of genetic processes or phenomena. They include the use of mathematical equations, computers, and other electronic equipment.Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Alleles: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.Quantitative Trait Loci: Genetic loci associated with a QUANTITATIVE TRAIT.Gene Frequency: The proportion of one particular in the total of all ALLELES for one genetic locus in a breeding POPULATION.Genetic Association Studies: The analysis of a sequence such as a region of a chromosome, a haplotype, a gene, or an allele for its involvement in controlling the phenotype of a specific trait, metabolic pathway, or disease.Genetic Loci: Specific regions that are mapped within a GENOME. Genetic loci are usually identified with a shorthand notation that indicates the chromosome number and the position of a specific band along the P or Q arm of the chromosome where they are found. For example the locus 6p21 is found within band 21 of the P-arm of CHROMOSOME 6. Many well known genetic loci are also known by common names that are associated with a genetic function or HEREDITARY DISEASE.Genome, Human: The complete genetic complement contained in the DNA of a set of CHROMOSOMES in a HUMAN. The length of the human genome is about 3 billion base pairs.Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group.Research Support, U.S. Gov't, Non-P.H.S.Research Support, U.S. Gov't, P.H.S.Research Support, Non-U.S. Gov'tLipoproteins: Lipid-protein complexes involved in the transportation and metabolism of lipids in the body. They are spherical particles consisting of a hydrophobic core of TRIGLYCERIDES and CHOLESTEROL ESTERS surrounded by a layer of hydrophilic free CHOLESTEROL; PHOSPHOLIPIDS; and APOLIPOPROTEINS. Lipoproteins are classified by their varying buoyant density and sizes.Coronary Disease: An imbalance between myocardial functional requirements and the capacity of the CORONARY VESSELS to supply sufficient blood flow. It is a form of MYOCARDIAL ISCHEMIA (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels.Research Support, U.S. GovernmentMendelian Randomization Analysis: The use of the GENETIC VARIATION of known functions or phenotypes to correlate the causal effects of those functions or phenotypes with a disease outcome.Perilla frutescens: A plant genus of the family LAMIACEAE that is an ingredient of Banxia Houpu (DRUGS, CHINESE HERBAL).Risk Factors: An aspect of personal behavior or lifestyle, environmental exposure, or inborn or inherited characteristic, which, on the basis of epidemiologic evidence, is known to be associated with a health-related condition considered important to prevent.Causality: The relating of causes to the effects they produce. Causes are termed necessary when they must always precede an effect and sufficient when they initiate or produce an effect. Any of several factors may be associated with the potential disease causation or outcome, including predisposing factors, enabling factors, precipitating factors, reinforcing factors, and risk factors.Insulin-Like Growth Factor I: A well-characterized basic peptide believed to be secreted by the liver and to circulate in the blood. It has growth-regulating, insulin-like, and mitogenic activities. This growth factor has a major, but not absolute, dependence on GROWTH HORMONE. It is believed to be mainly active in adults in contrast to INSULIN-LIKE GROWTH FACTOR II, which is a major fetal growth factor.Prostate: A gland in males that surrounds the neck of the URINARY BLADDER and the URETHRA. It secretes a substance that liquefies coagulated semen. It is situated in the pelvic cavity behind the lower part of the PUBIC SYMPHYSIS, above the deep layer of the triangular ligament, and rests upon the RECTUM.Prostatic Neoplasms: Tumors or cancer of the PROSTATE.Insulin-Like Growth Factor II: A well-characterized neutral peptide believed to be secreted by the LIVER and to circulate in the BLOOD. It has growth-regulating, insulin-like and mitogenic activities. The growth factor has a major, but not absolute, dependence on SOMATOTROPIN. It is believed to be a major fetal growth factor in contrast to INSULIN-LIKE GROWTH FACTOR I, which is a major growth factor in adults.Hyperplasia: An increase in the number of cells in a tissue or organ without tumor formation. It differs from HYPERTROPHY, which is an increase in bulk without an increase in the number of cells.Cardiomyopathies: A group of diseases in which the dominant feature is the involvement of the CARDIAC MUSCLE itself. Cardiomyopathies are classified according to their predominant pathophysiological features (DILATED CARDIOMYOPATHY; HYPERTROPHIC CARDIOMYOPATHY; RESTRICTIVE CARDIOMYOPATHY) or their etiological/pathological factors (CARDIOMYOPATHY, ALCOHOLIC; ENDOCARDIAL FIBROELASTOSIS).Myocytes, Cardiac: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).Cardiomyopathy, Hypertrophic: A form of CARDIAC MUSCLE disease, characterized by left and/or right ventricular hypertrophy (HYPERTROPHY, LEFT VENTRICULAR; HYPERTROPHY, RIGHT VENTRICULAR), frequent asymmetrical involvement of the HEART SEPTUM, and normal or reduced left ventricular volume. Risk factors include HYPERTENSION; AORTIC STENOSIS; and gene MUTATION; (FAMILIAL HYPERTROPHIC CARDIOMYOPATHY).Sarcomeres: The repeating contractile units of the MYOFIBRIL, delimited by Z bands along its length.Cardiomyopathy, Hypertrophic, Familial: An autosomal dominant inherited form of HYPERTROPHIC CARDIOMYOPATHY. It results from any of more than 50 mutations involving genes encoding contractile proteins such as VENTRICULAR MYOSINS; cardiac TROPONIN T; ALPHA-TROPOMYOSIN.Heart: The hollow, muscular organ that maintains the circulation of the blood.Glycosylation End Products, Advanced: Products derived from the nonenzymatic reaction of GLUCOSE and PROTEINS in vivo that exhibit a yellow-brown pigmentation and an ability to participate in protein-protein cross-linking. These substances are involved in biological processes relating to protein turnover and it is believed that their excessive accumulation contributes to the chronic complications of DIABETES MELLITUS.Lie Detection: Ascertaining of deception through detection of emotional disturbance as manifested by changes in physiologic processes usually using a polygraph.Receptors, Immunologic: Cell surface molecules on cells of the immune system that specifically bind surface molecules or messenger molecules and trigger changes in the behavior of cells. Although these receptors were first identified in the immune system, many have important functions elsewhere.Cross-Linking Reagents: Reagents with two reactive groups, usually at opposite ends of the molecule, that are capable of reacting with and thereby forming bridges between side chains of amino acids in proteins; the locations of naturally reactive areas within proteins can thereby be identified; may also be used for other macromolecules, like glycoproteins, nucleic acids, or other.Pyruvaldehyde: An organic compound used often as a reagent in organic synthesis, as a flavoring agent, and in tanning. It has been demonstrated as an intermediate in the metabolism of acetone and its derivatives in isolated cell preparations, in various culture media, and in vivo in certain animals.Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere.Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.Physics: The study of those aspects of energy and matter in terms of elementary principles and laws. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Selection, Genetic: Differential and non-random reproduction of different genotypes, operating to alter the gene frequencies within a population.Biological Evolution: The process of cumulative change over successive generations through which organisms acquire their distinguishing morphological and physiological characteristics.CaliforniaGenetics, Population: The discipline studying genetic composition of populations and effects of factors such as GENETIC SELECTION, population size, MUTATION, migration, and GENETIC DRIFT on the frequencies of various GENOTYPES and PHENOTYPES using a variety of GENETIC TECHNIQUES.Evolution, Molecular: The process of cumulative change at the level of DNA; RNA; and PROTEINS, over successive generations.

*Mendelian randomization

... genetic heterogeneity, pleiotropy (often detected as a genetic correlation), or population stratification. Katan MB (March 1986 ... misleading conclusions may also arise in the presence of linkage disequilibrium with unmeasured directly-causal variants, ... a causal effect from observational data in the presence of confounding factors. It uses common genetic polymorphisms with well- ... Davey Smith G, Ebrahim S, Lewis S, Hansell AL, Palmer LJ, Burton PR (2005). "Genetic epidemiology and public health: hope, hype ...

*Genotype-first approach

Common variants are filtered out, and pathogenicity is determined though predicted genetic implications. These steps allow for ... These features limit the ability of both research and clinical studies to designate causal genes or variants to the observed ... This approach contributes to studying both expressivity, pleiotropy and sporadic mutations. This approach examines highly ... Deleterious variants are found at higher frequencies within a smaller spectrum of rare variants in bottlenecked founder ...

*Genetic correlation

... the genetic influences on a trait and the genetic influences on a different trait estimating the degree of pleiotropy or causal ... trait to increase the prior probability of variants for a second trait; for example, since intelligence and years of education ... A genetic correlation of 0 implies that the genetic effects on one trait are independent of the other, while a correlation of 1 ... A genetic correlation between two traits will tend to produce phenotypic correlations - e.g. the genetic correlation between ...

*Genome-wide complex trait analysis

... there is no genetic contribution, b) the genetic contribution is entirely in the form of genetic variants not included, or c) ... are due to the same genetic traits, and in the case of diseases, can indicate shared causal pathways such as the overlap of ... "Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and ... "Common genetic variants, acting additively, are a major source of risk for autism", Klei et al 2012 "Most genetic risk for ...

*Ageing

Such a genetic effect is called the antagonistic pleiotropy effect when referring to a gene (pleiotropy signifying the gene has ... Also, it has been suggested that some of the genetic variants that increase fertility in the young increase cancer risk in the ... the authors point out however that a causal link between ageing and increased mitochondrial production of reactive oxygen ... Most known genetic interventions in C. elegans increase lifespan by 1.5 to 2.5-fold. As of 2009[update], the record for ...
TY - JOUR. T1 - Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons. AU - Rainwater, David L.. AU - Cox, Laura A.. AU - Rogers, Jeffrey. AU - VandeBerg, John L.. AU - Mahamey, Michae L.C.. PY - 2009/7/1. Y1 - 2009/7/1. N2 - We employed a novel approach to identify the key loci that harbor genes influencing lipoprotein metabolism in approximately 2,000 pedigreed baboons fed various diets differing in levels of fat and cholesterol. In this study, 126 overlapping traits related to both LDL and HDL metabolism were normalized and subjected to genome-wide linkage screening. As was expected, the traits were highly, but not completely, correlated. We exploited the information in these correlated traits by focusing on those genomic regions harboring quantitative trait loci (QTL) for multiple traits, reasoning that the more influential genes would impact a larger number of traits. This study identified five major QTL clusters (each with at least two significant logarithm of ...
A multivariate genome-wide association test is proposed for analyzing data on multivariate quantitative phenotypes collected from related subjects. The proposed method is a two-step approach. The first step models the association between the genotype and marginal phenotype using a linear mixed model. The second step uses the correlation between residuals of the linear mixed model to estimate the null distribution of the Fisher combination test statistic. The simulation results show that the proposed method controls the type I error rate and is more powerful than the marginal tests across different population structures (admixed or non-admixed) and relatedness (related or independent). The statistical analysis on the database of the Study of Addiction: Genetics and Environment (SAGE) demonstrates that applying the multivariate association test may facilitate identification of the pleiotropic genes contributing to the risk for alcohol dependence commonly expressed by four ...
The use of genome-wide single nucleotide polymorphism (SNP) data has recently proven useful in the study of human population structure. We have studied the internal genetic structure of the Swedish population using more than 350,000 SNPs from 1525 Swedes from all over the country genotyped on the Illumina HumanHap550 array. We have also compared them to 3212 worldwide reference samples, including Finns, northern Germans, British and Russians, based on the more than 29,000 SNPs that overlap between the Illumina and Affymetrix 250K Sty arrays. The Swedes - especially southern Swedes - were genetically close to the Germans and British, while their genetic distance to Finns was substantially longer. The overall structure within Sweden appeared clinal, and the substructure in the southern and middle parts was subtle. In contrast, the northern part of Sweden, Norrland, exhibited pronounced ...
Henry, RJ, Bundock, PC, Pacey-Miller, T, Kennedy, BG, Ablett, GA, Waters, DLE & Jin,QS 2003, Single nucleotide polymorphism analysis in support of plant breeding, paper presented to the 12th Australasian Plant Breeding Conference, Perth, WA, 15-20 September.. ...
The identification of copy number aberration in the human genome is an important area in cancer research. We develop a model for determining genomic copy numbers using high-density single nucleotide polymorphism genotyping microarrays. The method is based on a Bayesian spatial normal mixture model with an unknown number of components corresponding to true copy numbers. A reversible jump Markov chain Monte Carlo algorithm is used to implement the model and perform posterior inference. The performance of the algorithm is examined on both simulated and real cancer data, and it is compared with the popular CNAG algorithm for copy number detection. We demonstrate that our Bayesian mixture model performs at least as well as the hidden Markov model based CNAG algorithm and in certain cases does better. One of the added advantages of our method is the flexibility of modeling normal cell contamination in tumor samples.
Looking for online definition of Negative pleiotropy in the Medical Dictionary? Negative pleiotropy explanation free. What is Negative pleiotropy? Meaning of Negative pleiotropy medical term. What does Negative pleiotropy mean?
Early detection of karyotype abnormalities, including aneuploidy, could aid producers in identifying animals which, for example, would not be suitable candidate parents. Genome-wide genetic marker data in the form of single nucleotide polymorphisms (SNPs) are now being routinely generated on animals. The objective of the present study was to describe the statistics that could be generated from the allele intensity values from such SNP data to diagnose karyotype abnormalities; of particular interest was whether detection of aneuploidy was possible with both commonly used genotyping platforms in agricultural species, namely the Applied BiosystemsTM AxiomTM and the Illumina platform. The hypothesis was tested using a case study of a set of dizygotic X-chromosome monosomy 53,X sheep twins. Genome-wide SNP data were available from the Illumina platform (11 082 autosomal and 191 X-chromosome SNPs) on 1848 male and 8954 female sheep and available from the AxiomTM platform (11 128 ...
Read "Associations between three common single nucleotide polymorphisms (rs266729, rs2241766, and rs1501299) of ADIPOQ and cardiovascular disease: a meta-analysis, Lipids in Health and Disease" on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
Multiple genetic and environmental factors interact to determine an individuals predisposition to non-alcoholic fatty liver disease and its phenotypic characteristics. Association studies have found a number of alleles associated with the development of non-alcoholic steatohepatitis. Our aim was to investigate whether multiple risk-associated alleles may be present in affected monozygotic twins, indicating underlying genetic predisposition to non-alcoholic steatohepatitis. We determined the genotype of 14 candidate gene polymorphisms (at 11 unlinked loci) in a set of monozygotic twins with who presented with cirrhosis within 18 months of each other. Genotyping revealed multiple single nucleotide polymorphisms at 9 independent loci in genes PNPLA3, APOC3, GCKR, TRIB1, LYPLAL1, PPP1R3B, COL13A1, and EFCAB4B, previously implicated in contributing to non-alcoholic steatohepatitis pathogenesis. In conclusion, this case series illustrates the ...
Recent technological progress has permitted the efficient performance of genome-wide association studies (GWAS) to map genetic variants associated with common diseases. Here, we analyzed 2,893 single nucleotide polymorphisms (SNPs) that have been identified in 593 published GWAS as associated with a disease phenotype with respect to their genomic location. In absolute numbers, most significant SNPs are located in intergenic regions and introns. When compared to their representation on the chips, there is essentially overrepresentation of nonsynonymous coding SNPs (nsSNPs), synonymous coding SNPs, and SNPs in untranscribed regions upstream of genes among the disease associated SNPs. A Gene Ontology term analysis showed that genes putatively causing a phenotype often code for membrane associated proteins or signal transduction genes.. ...
Kim, S.-Y., Metcalfe, N. and Velando, A. (2015) A benign juvenile environment reduces the strength of antagonistic pleiotropy and genetic variation in the rate of senescence. [Data Collection] ...
One PLOS paper details a study of pleiotropy in C. Elegans, finding that 50% of genes involved in embryogenesis are pleiotropic. Whats more, these genes tend to occupy central (rather than initial or final) positions in protein pathways10. Pleiotropy, when viewed in the light of evolution, is usually discussed as a constraining factor. That is, a single mutation may be beneficial or neutral in one tissue, but harmful in another, increasing the likelihood that pleiotropic gene mutations would be selected against. The effect of pleiotropy neednt always be one of constraint, however. For example, in the case of parsimonious pleiotropy11, "knowing" that a mutation that fails to harm sperm is also unlikely to harm the brain, the sperm may relax strict mutation checking controls a tad. Note that evolutionary pressures favoring pleiotropy tend to negate the popular notion of "modularity" in gene expression ...
One PLOS paper details a study of pleiotropy in C. Elegans, finding that 50% of genes involved in embryogenesis are pleiotropic. Whats more, these genes tend to occupy central (rather than initial or final) positions in protein pathways10. Pleiotropy, when viewed in the light of evolution, is usually discussed as a constraining factor. That is, a single mutation may be beneficial or neutral in one tissue, but harmful in another, increasing the likelihood that pleiotropic gene mutations would be selected against. The effect of pleiotropy neednt always be one of constraint, however. For example, in the case of parsimonious pleiotropy11, "knowing" that a mutation that fails to harm sperm is also unlikely to harm the brain, the sperm may relax strict mutation checking controls a tad. Note that evolutionary pressures favoring pleiotropy tend to negate the popular notion of "modularity" in gene expression ...
Knowledge of genetic diversity and population structure in breeding material could be of great importance for crop improvement. Inheritance of molecular markers has been proved to be a powerful tool for verifying or discovering the parentage of cultivars in several crops. The present study aimed to undertake an extended parentage analysis using a large sample of garden asparagus (Asparagus officinalis L.) cultivars based on single nucleotide polymorphism (SNP) markers. In the past, asparagus cultivars began to be classified according to the countries and towns where they were grown. Among them, Violet Dutch is one of the oldest asparagus cultivars, considered to be the genetic stock from which several modern cultivars were derived. Starting from Violet Dutch, the breeding programs branched in two directions, yielding Argenteuil and Braunschweiger varieties in France and Germany, respectively. These lines became very important in all breeding ...
In regions where malaria is endemic, individuals are often infected with multiple distinct parasite genotypes, a situation that may impact on evolution of parasite virulence and drug resistance. Most approaches to studying genotypic diversity have involved analysis of a modest number of polymorphic loci, although whole genome sequencing enables a broader characterisation of samples. PCR-based microsatellite typing of a panel of ten loci was performed on Plasmodium falciparum in 95 clinical isolates from a highly endemic area in the Republic of Guinea, to characterize within-isolate genetic diversity. Separately, single nucleotide polymorphism (SNP) data from genome-wide short-read sequences of the same samples were used to derive within-isolate fixation indices (F ws), an inverse measure of diversity within each isolate compared to overall local genetic diversity. The latter indices were compared with the microsatellite results, and also ...
Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected by clinical teams after clinical examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also in only participants with pathological diagnosis. In the replication stage, we ...
Approach and Results-We adapted Egger regression, a technique frequently used in Mendelian randomization studies to detect genetic pleiotropy, to reanalyze the available randomized control trial data of statin therapy. For cardiovascular end points, each 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 0.77 (95% confidence interval, 0.71-0.84) with an intercept that was indistinguishable from zero (intercept, −0.0032; [95% confidence interval, −0.090 to 0.084]; P=0.94), indicating no pleiotropy. For incident diabetes mellitus, a 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 1.07 (95% confidence interval, 0.99-1.16) and an intercept nondistinguishable from zero (intercept, −0.015; [95% confidence interval, −0.30 to 0.27]; P=0.91), again indicating no pleiotropy. ...
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We questioned the significance of haplotype structure in gene regulation by testing whether individual single nucleotide polymorphisms (SNPs) within a gene promoter region [interleukin-1-beta (IL1B)] might affect promoter function and, if so, whether function was dependent on haplotype context. We sequenced genomic DNA from 25 individuals of diverse ethnicity, focusing on exons and upstream flanking regions of genes of the cluster. We identified four IL1B promoter region SNPs that were active in transient transfection reporter gene assays. To substantiate allelic differences found in reporter gene assays, we also examined nuclear protein binding to promoter sequence oligonucleotides containing different alleles of the SNPs. The effect of individual SNPs on reporter gene transcription varied according to which alleles of the three other SNPs were present in the promoter construct. The SNP patterns that influenced function reflected common haplotypes that occur in the population, suggesting ...
Genome‐wide association studies have successfullyidentified many novel genetic loci for various human complex diseases and quantitative traits
Kovacs, A, Green, F, Hansson, LO, Lundman, P, Samnegard, A, Boquist, S, Ericsson, CG, Watkins, HH, Hamsten, A and Tornvall, P (2005) A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein ...
Skol, A. D., Scott, L. J., Abecasis, G. R. and Boehnke, M. (2007), Optimal designs for two-stage genome-wide association studies. Genet. Epidemiol., 31: 776-788. doi: 10.1002/gepi.20240 ...
Analyzing a single nucleotide polymorphism in schizophrenia: a meta-analysis approach Oluwadamilare Falola,1 Victor Chukwudi Osamor,1,2 Marion Adebiyi,1,2 Ezekiel Adebiyi1,2 1Covenant University Bioinformatics Research (CUBRe), 2Department of Computer and Information Sciences, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria Background: Schizophrenia is a severe mental disorder affecting >21 million people worldwide. Some genetic studies reported that single nucleotide polymorphism (SNP) involving variant rs1344706 from the ZNF804A gene in human beings is associated with the risk of schizophrenia in several populations. Similar results tend to conflict with other reports in literature, indicating that no true significant association exists between rs1344706 and schizophrenia. We seek to determine the level of association of this SNP with schizophrenia in the Asian population using more recent genome-wide association study (GWAS) ...
TY - JOUR. T1 - A genome-wide association study reveals that variants within the HLA region are associated with risk for nonobstructive azoospermia. AU - Zhao, Han. AU - Xu, Jianfeng. AU - Zhang, Haobo. AU - Sun, Jielin. AU - Sun, Yingpu. AU - Wang, Zhong. AU - Liu, Jiayin. AU - Ding, Qiang. AU - Lu, Shaoming. AU - Shi, Rong. AU - You, Li. AU - Qin, Yingying. AU - Zhao, Xiaoming. AU - Lin, Xiaoling. AU - Li, Xiao. AU - Feng, Junjie. AU - Wang, Li. AU - Trent, Jeffrey M.. AU - Xu, Chengyan. AU - Gao, Ying. AU - Zhang, Bo. AU - Gao, Xuan. AU - Hu, Jingmei. AU - Chen, Hong. AU - Li, Guangyu. AU - Zhao, Junzhao. AU - Zou, Shuhua. AU - Jiang, Hong. AU - Hao, Cuifang. AU - Zhao, Yueran. AU - Ma, Jinglong. AU - Zheng, S. Lilly. AU - Chen, Zi Jiang. PY - 2012/5/4. Y1 - 2012/5/4. N2 - A genome-wide association study of Han Chinese subjects was conducted to identify genetic susceptibility loci for nonobstructive azoospermia (NOA). In the discovery ...
A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.s profile, publications, research topics, and co-authors
Advantages of sSNP genotyping: sSNPs afford many advantages for analysis of phylogenetic relationships among microbial strains, especially closely related clonal organisms such as the M. tuberculosis complex. Most or all sSNPs are selectively neutral and hence minimally subject to convergence, a process that can obscure or distort evolutionary relationships (Kimura 1983). Binary data are obtained, which means that the information is readily amenable to storage, retrieval, analysis by personal computers equipped with simple software, and comparison between different laboratories and studies. Importantly, the considerable biomedical interest in human SNPs (Schorket al. 2000; Dalyet al. 2001; Gut 2001; Johnsonet al. 2001) means that microbial pathogen research will benefit extensively from the ongoing development and implementation of methods to index very large numbers of SNPs efficiently, inexpensively, and automatically (Kwok 2001). Because of the many advantages of using ...
Purpose: Previous genome-wide association study (GWAS) of keratoconus in a US-based Caucasian population reported 15 potentially associated single nucleotide polymorphisms (SNPs) from 13 distinct loci. A replication study of the GWAS findings in an Australian Caucasian population showed significant association (p,0.05) in SNPs in KCND3, RAB3GAP1, UBXD2, IMMP2L, and 13q33.3 loci. In this study, we sought to replicate the GWAS findings in East Asian populations.. Methods: Six hundred and thirty-nine Japanese samples (179 keratoconus cases and 460 controls) and 419 Korean samples (190 keratoconus cases and 229 controls) were recruited. We genotyped 15 SNPs reported in the previous GWAS using TaqMan assay. Association analysis was performed in SNP & Variation Suite 8.2.1. A meta-analysis combining the Japanese and Korean populations was performed using the Mantel-Haenszel method.. Results: The significant association was observed for rs6792542 in 3q26.2 in the meta-analysis (meta-p=0.00095: p=0.0025 ...
TY - JOUR. T1 - Single nucleotide polymorphism in toll-like receptor 6 is associated with a decreased risk for ureaplasma respiratory tract colonization and bronchopulmonary dysplasia in preterm infants. AU - Winters, Alexandra H.. AU - LeVan, Tricia D. AU - Vogel, Stefanie N.. AU - Chesko, Kirsty L.. AU - Pollin, Toni I.. AU - Viscardi, Rose M.. PY - 2013/8/1. Y1 - 2013/8/1. N2 - BACKGROUND: Ureaplasma spp. respiratory tract colonization is a risk factor for bronchopulmonary dysplasia (BPD) in preterm infants, but differences in host susceptibility have not been elucidated. We hypothesized that variants in genes regulating the innate immune response are associated with altered risk for Ureaplasma spp. respiratory colonization and BPD in preterm infants. METHODS: Twenty-four tag single nucleotide polymorphisms (SNPs) from Toll-like receptor (TLR)1, TLR2, TLR4 and TLR6 were assayed in 298 infants ,33 weeks gestation who had serial respiratory cultures for Ureaplasma spp. and ...
OBJECTIVE-A recent meta-analysis demonstrated a nominal association of the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K→Q missense single nucleotide polymorphism (SNP) at position 121 with type 2 diabetes. We set out to confirm the association of ENPP1 K121Q with hyperglycemia, expand this association to insulin resistance traits, and determine whether the association stems from K121Q or another variant in linkage disequilibrium with it. RESEARCH DESIGN AND METHODS-We characterized the haplotype structure of ENPP1 and selected 39 tag SNPs that captured 96% of common variation in the region (minor allele frequency ≥5%) with an r2 value ≥0.80. We genotyped the SNPs in 2,511 Framingham Heart Study participants and used age- and sex-adjusted linear mixed effects (LME) models to test for association with quantitative metabolic traits. We also examined whether interaction between K121Q and BMI affected glycemic trait levels. RESULTS-The Q allele of K121Q (rs1044498) was ...
There is growing evidence of shared risk alleles for complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing among all individuals (whole-group pleiotropy) or a subset of individuals in a genetically heterogeneous cohort (subgroup heterogeneity). Here we describe the use of a well-powered statistic, BUHMBOX, to distinguish between those two situations using genotype data. We observed a shared genetic basis for 11 autoimmune diseases and type 1 diabetes (T1D; P , 1 x 10(-4)) and for 11 autoimmune diseases and rheumatoid arthritis (RA; P , 1 x 10(-3)). This sharing was not explained by subgroup heterogeneity (corrected P-BUHMBOX , 0.2; 6,670 T1D cases and 7,279 RA cases). Genetic sharing between seronegative and seropostive RA (P , 1 x 10(-9)) had significant evidence of subgroup heterogeneity, suggesting a subgroup of ...
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = ...
Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for ,15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving 4098 cases and 18 972 controls. Stage 1 comprised previously published GWAS analysis of 307 291 SNPs in 986 cases and 4946 controls. In Stage 2, we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1064 cases and 10 082 controls. Here, we report new genotyping of eight SNPs showing some evidence of association in combined analysis of Stage 1 and Stage 2 in an additional 2048 cases of TGCT and 3944 controls (Stage 3). Through fixed-effects meta-analysis across three stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT [per-allele odds ratio (OR) = 1.16, 95% confidence ...
Multifactor Dimensionality Reduction (MDR) Analysis to Detect Single Nucleotide Polymorphisms Associated with a Carcass Trait in a Hanwoo Population - Multifactor-dimensionality Reduction (MDR);SNP;Hanwoo;Association Study;
TY - JOUR. T1 - Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis. AU - Davis, Lisa A.. AU - Polk, Brooke. AU - Mann, Alyse. AU - Wolff, Roger K.. AU - Kerr, Gail S.. AU - Reimold, Andreas M.. AU - Cannon, Grant W.. AU - Mikuls, Ted R.. AU - Caplan, Liron. PY - 2014/1/1. Y1 - 2014/1/1. N2 - Objective: Methotrexate (MTX) is the cornerstone medication in the treatment of rheumatoid arthritis (RA). We examined whether single nucleotide polymorphisms (SNPs) in enzymes of the folic acid pathway (folylpoly-gamma-glutamate synthetase [FPGS], gamma-glutamyl hydrolase [GGH], and methylenetetrahydrofolate reductase [MTHFR]) associate with significant adverse events (SigAE). Methods: Patients (n=319) enrolled in the Veterans Affairs RA (VARA) registry taking MTX were genotyped for HLA-DRB1-SE and the following SNPs: FPGS (rs7033913, rs10760503, rs10106), GGH (12548933, rs7010484, rs4617146, ...
Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked ...
Cave animals have adapted to the challenges of life in perpetual darkness by losing their eyes and pigmentation and enhancing other sensory systems, such as taste, smell, and tactile senses. Although the sensory gains are easily explained by natural selection, the losses are more difficult to explain because they seem to have no immediate benefits. Recent studies in the Mexican cavefish (Astyanax mexicanus) show that eye degeneration is developmentally linked to adaptive gains in the gustatory system via evolutionary changes in a pleiotropic gene called sonic hedgehog. Thus, cavefish may illustrate a general phenomenon in biology in which pleiotropy and indirect selection guide the course and extent of evolution. Another benefit for cavefish living in dark caves is the absence of predators, which promotes survival by evolving an unusual suite of feeding behaviors. These behaviors would be risky in more complex, well-lit environments, such as exist on the Earths surface, illustrating the ...
Objective: To further confirm the association between two IRF6 single nucleotide polymorphisms and nonsyndromic cleft lip with or without cleft palate in a Chinese population.. Participants: A total of 106 nonsyndromic cleft lip with or without cleft palate case trios and 129 control trios.. Intervention: Two IRF6 single nucleotide polymorphisms, rs2235371 and rs642961, were genotyped for all case and control families. Case-control analysis and family-based linkage analysis were both performed for the two single nucleotide polymorphisms.. Results: The genotype and allele frequencies of rs2235371 (odds ratio(AG+AA) (vs. GG), 0.581; 95% confidence interval, 0.345 to 0.976; P < .039) and rs642961 (odds ratio(AG+AA vs. GG), 5.389; 95% confidence interval, 2.936 to 9.893; P = 5e-08) were significantly higher in nonsyndromic cleft lip with or without cleft palate patients compared with controls. There was an obvious dosage effect of allele A at rs642961. The transmission of a major allele (G) of ...
TY - JOUR. T1 - Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. AU - Rioux, John D.. AU - Xavier, Ramnik J.. AU - Taylor, Kent D.. AU - Silverberg, Mark S.. AU - Goyette, Philippe. AU - Huett, Alan. AU - Green, Todd. AU - Kuballa, Petric. AU - Barmada, M. Michael. AU - Datta, Lisa. AU - Shugart, Yin Yao. AU - Griffiths, Anne M.. AU - Targan, Stephan R.. AU - Ippoliti, Andrew F.. AU - Bernard, Edmond Jean. AU - Mei, Ling. AU - Nicolae, Dan L.. AU - Regueiro, Miguel. AU - Schumm, L. Philip. AU - Steinhart, A. Hillary. AU - Rotter, Jerome I.. AU - Duerr, Richard H.. AU - Cho, Judy H.. AU - Daly, Mark J.. AU - Brant, Steven R.. PY - 2007/5. Y1 - 2007/5. N2 - We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we ...
Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).
Pleiotropic genes can influence the course of evolution by producing correlated responses to selection and potentially hindering adaptive evolution if alternative alleles have antagonistic effects on fitness traits. Little is known about the pleiotropic effects of natural variation in any gene on fitness and the selective agents acting on this variation. In this thesis, I examined the pleiotropic effects of natural variation in the ,italic,Dopa decarboxylase,,/, (,italic,Ddc,,/,) gene of ,italic,Drosophila melanogaster,,/,. I show that natural ,italic,Ddc polymorphism,,/, associated with life span variation has pleiotropic effects on larval defenses against parasitoid wasps, larval foraging behavior, and larval feeding rates. I measured these traits because,italic, Ddc,,/, catalyzes the production of two neurotransmitters, dopamine and serotonin, which have known effects on behavior and immunity in invertebrates and vertebrates. Homozygote and heterozygote effects of two ,italic,Ddc,,/, alleles ...
Infertility affects 1 in 6 couples and approximately 1 in 25 men. Male factor infertility is a major cause of spermatogenic anomalies, the causes of which are largely unknown. Impaired repro-ductive functions in men might result from physiological, genetic, and/or environmental factors such as xenobiotics. The multi-drug re-sistance1 (MDR1) gene encodes a P-glycoprotein which has a role in the active transport of various substrates providing protection of somatic cells from potentially toxic substances, including xenobi-otics. MDR1 is highly expressed at the luminal surface of capillary endothelial cells, and is expressed in Leydig cells, testicular mac-rophages, and Sertoli cells. We performed genotype and haplotype analyses of MDR1 in 192 infertile and 102 fertile Turkish men for the genetic markers C1236T and C3435T, using polymerase chain reaction-restriction fragment length polymorphism analysis. In the overall population, correlations ...
We describe a novel method for inferring the local ancestry of admixed individuals from dense genome-wide single nucleotide polymorphism data. The method, called MULTIMIX, allows multiple source populations, models population linkage disequilibrium between markers and is applicable to datasets in which the sample and source populations are either phased or unphased. The model is based upon a hidden Markov model of switches in ancestry between consecutive windows of loci. We model the observed haplotypes within each window using a multivariate normal distribution with parameters estimated from the ancestral panels. We present three methods to fit the model-Markov chain Monte Carlo sampling, the Expectation Maximization algorithm, and a Classification Expectation Maximization algorithm. The performance of our method on individuals simulated to be admixed with European and West African ancestry shows it to be comparable to HAPMIX, the ancestry calls of the two methods agreeing at 99.26% of loci ...
Endothelin-1 (ET-1) and adrenomedullin (ADM) are circulating vasoactive peptides involved in vascular homeostasis and endothelial function. Elevated levels of plasma ET-1 and ADM, and their biologically stable surrogates, C-terminal-pro-endothelin-1 (CT-pro-ET-1) and midregional proadrenomedullin (MR-pro-ADM), are predictors of cardiac death and heart failure. We studied the association of common genetic variation with MR-pro-ADM and CT-pro-ET-1 by genome-wide association analyses in 3444 participants of European ancestry. We performed follow-up genotyping of single nucleotide polymorphisms (SNPs) that showed suggestive or significant association in the discovery stage in additional 3230 participants. The minor variants in KLKB1 (rs4253238) and F12 (rs2731672), both part of the kallikrein-kinin system, were associated with higher MR-pro-ADM (P=4.46E-52 and P=5.90E-24, respectively) and higher CT-pro-ET-1 levels (P=1.23E-122 and P=1.26E-67, ...
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P , 5 x 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be ...
The overall goal of this project is to forensically characterize 100 unknown Burkholderia isolates in the US-Australia collaboration. We will identify genome-wide single nucleotide polymorphisms (SNPs) from B. pseudomallei and near neighbor species including B. mallei, B. thailandensis and B. oklahomensis. We will design microarray probes to detect these SNP markers and analyze 100 Burkholderia genomic DNAs extracted from environmental, clinical and near neighbor isolates from Australian collaborators on the Burkholderia SNP microarray. We will analyze the microarray genotyping results to characterize the genetic diversity of these new isolates and triage the samples for whole genome sequencing. In this interim report, we described the SNP analysis and the microarray probe design for the Burkholderia SNP microarray. ...
10 µCi quantities of [2-14C]-Thymidine are available for your research. Application of [14C]Thymidine can be found in: reutilization of 14C-thymidine in the liver of young and adult mice, alkyl-fluorinated thymidine derivatives for imaging cell proliferation, changes in deoxyribonucleotide biosynthesis during carrot somatic embryogenesis, effect of arachidonic acid on proliferation, cytokines production and pleiotropic genes expression, etc.. ...
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The cold shock domain (CSD) is a nucleic acid binding domain that is widely conserved from bacteria to higher plants and animals. In Escherichia coli, cold shock proteins (CSPs) are composed solely of a CSD and function as RNA chaperones that destabilize RNA secondary structures. Cellular RNAs tend to be folded into unfavorable structures under low temperature conditions, and RNA chaperones resolve these structures, recovering functionality of the RNAs. CSP functions are associated mainly with cold adaptation, but they are also involved in other biological processes under normal growth conditions. Eukaryotic CSD proteins contain auxiliary domains in addition to the CSD and regulate many biological processes such as development and stress tolerance. In plants, it has been demonstrated that CSD proteins play essential roles in acquiring freezing tolerance. In addition, it has been suggested that some plant CSD proteins regulate embryo development, flowering time and fruit development. In this review, we
Avian pathogenic Escherichia coli strains cause extraintestinal diseases in birds, leading to substantial economic losses to the poultry industry worldwide. Bacteria that invade cells can overcome the host humoral immune response, resulting in a higher pathogenicity potential. Invasins are members of a large family of outer membrane proteins that allow pathogen invasion into host cells by interacting with specific receptors on the cell surface. An in silico analysis of the genome of a septicemic APEC strain (SEPT362) demonstrated the presence of a putative invasin homologous to the ychO gene from E. coli str. K-12 substr. MG1655. In vitro and in vivo assays comparing a mutant strain carrying a null mutation of this gene, a complemented strain, and its counterpart wild-type strain showed that ychO plays a role in the pathogenicity of APEC strain SEPT362. In vitro assays demonstrated that the mutant strain exhibited significant decreases in bacterial adhesiveness and invasiveness in chicken cells and
Antagonistic selection-where alleles at a locus have opposing effects on male and female fitness ("sexual antagonism"), or between components of fitness ("antagonistic pleiotropy")-might play an important role in maintaining population genetic variation, and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two ...
Infections occur as early as the first year of life and may impact the immune system and cancer risk. The increase in antigenic exposure, after birth through viral/bacterial infections, may be essential for newborns to switch from a Th2 biased [19] to a balanced Th1/Th2 immunity as well as to develop immunological memory [20]. Also, childhood diseases may activate specific anti-tumoral responses. For instance, mumps may lead to immune recognition of TAA present on ovarian cancer cells, resulting in an effective immunosurveillance [21]. However, childhood diseases could be associated with inflammation, and the persistence of this inflammatory process in adulthood may increase the risk of mutations in normal cells, giving an example of antagonistic pleiotropy4. In fact, individuals that have experienced major childhood illness are twice at risk to develop a cancer [22]. Leukemia is a specific example where childhood infections seem to play an ambiguous role [23]. A protective role of ...
View Notes - November 23 from BIOL 442 at UMBC. Biology 442 Developmental Biology Lecture 9 Senescence Lecture outline I. Evolutionary hypotheses of aging: antagonistic pleiotropy and disposable soma
BackgroundThe associations between nicotine dependence and specific variants in the nicotinic receptor CHRNA5-A3-B4 subunit genes are irrefutable with replications in many studies. The relationship between the newly identified genetic risk variants for nicotine dependence and comorbid psychiatric disorders is unclear.
Both chapters are about fitness landscapes. The first one explains that fitness landscapes is the third "parameter" that is needed to make predictions in evolution. The first two are the population size and the mutation rate. If all the known effects of mutations are known (which implies the fitness landscape), then it is possible to statistically say which direction an evolving population will go and where it will end up. Stochasticity is still important, but one can still make sensible predictions ...
Scientists in the life science field have long been seeking genetic variants associated with complex diseases (or traits) to advance our understanding of complex genetic disorders and to provide effective disease treatment. However, many complex diseases are driven by the combined effect of many genetic variants, each of which may have only a small effect. To identify these genetic variants, large sample sizes are required but meeting such a requirement is usually beyond the capacity of a single GWAS. Exploring the pleiotropy across multiple related diseases is a promising strategy for identifying genetic variants with small effects, thereby uncovering the mystery of biological mechanisms in ...
Dyslipidemia (DL) is closely related to osteoporosis (OP), while the exact common genetic mechanisms are still largely unknown. We proposed to use novel genetic analysis methods with pleiotropic information to identify potentially novel and/or common genes for the potential shared pathogenesis associated with OP and/or DL. We assessed the pleiotropy between plasma lipid (PL) and femoral neck bone mineral density (FNK BMD). We jointly applied the conditional false discovery rate (cFDR) method and the genetic analysis incorporating pleiotropy and annotation (GPA) method to the summary statistics provided by genome-wide association studies (GWASs) of FNK BMD (n = 49,988) and PL (n = 188,577) to identify potentially novel and/or common genes for BMD/PL ...
Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the ...
Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the ...
Perhaps the main lesson we eventually learn in school is how little we actually know. In elementary genetics, we were taught that there are two alleles for eye color, blue and brown, with brown dominant, allowing simple assessment of whether we were more likely fathered by dad or the mailman. In these simple Mendelian days, eye color was not considered to be a focus for natural selection, except perhaps in the context of an associated trait, pale skin, being favored to help accrue vitamin D in the high, dark latitudes of northern Europe. Only over the past few months has a series of publications begun to reveal the true complexities of human eye-color genetics, genomics, selection and evolution. In the context of tantalizing data linking eye color to social behavior, rather than just skin and hair color, these studies show that the metaphor of eyes as windows to souls may be more than poetic. (more…). ...
J Am Coll Cardiol. 2013 Nov 12;62(20):1906-8. doi: 10.1016/j.jacc.2013.07.085. Epub 2013 Sep 18. Comment; Letter; Research Support, Non-U.S. Govt
For the first decade after the paper was published, it was the most controversial and hotly argued idea in all of paleontology. Soon the great debate among paleontologists boiled down to just a few central points, which Gould and Eldredge (1977) nicely summarized on the fifth anniversary of the papers release. The first major discovery was that stasis was much more prevalent in the fossil record than had been previously supposed. Many paleontologists came forward and pointed out that the geological literature was one vast monument to stasis, with relatively few cases where anyone had observed gradual evolution. If species didnt appear suddenly in the fossil record and remain relatively unchanged, then biostratigraphy would never work-and yet almost two centuries of successful biostratigraphic correlations was evidence of just this kind of pattern. As Gould put it, it was the "dirty little secret" hidden in the paleontological closet. Most paleontologists were trained to focus on gradual ...
Background Inhibition of glycogen synthase kinase-3 (GSK-3) improves the efficiency of embryonic stem (ES) cell derivation from various strains of mice and rats, as well as dramatically promotes ES cell self-renewal potential. β-catenin has been reported to be involved in the maintenance of self-renewal of ES cells through TCF dependent and independent pathway. But the intrinsic difference between ES cell lines from different species and strains has not been characterized. Here, we dissect the mechanism of GSK-3 inhibition by CHIR99021 in mouse ES cells from refractory mouse strains. Methodology/Principal Findings We found that CHIR99021, a GSK-3 specific inhibitor, promotes self-renewal of ES cells from recalcitrant C57BL/6 (B6) and BALB/c mouse strains through stabilization of β-catenin and c-Myc protein levels. Stabilized β-catenin promoted ES self-renewal through two mechanisms. First, β-catenin translocated into the nucleus to maintain stem cell pluripotency in a lymphoid-enhancing factor/T
In Phenome-Wide Association Studies (PheWAS), the association between single nucleotide polymorphisms (SNPs) and an extensive range of phenotypic measurements are calculated in a high throughput, unbiased manner. The phenotypic data used in PheWAS can come from a variety of sources. One possible source is epidemiologic health surveys linked to genotypic data that include measurements of intermediate traits or biomarkers such as blood cell counts and blood pressure measurements, as well as information on case/control status for multiple clinical conditions and risk factors such as presence/absence of diabetes or hypertension. One such example is the Population Architecture Using Genomics (PAGE) network, which is a National Human Genome Research Institute (NHGRI)-supported network of four study sites and a coordinating center accessing eight extensively characterized studies for PheWAS studies in diverse populations [1, 2]. These survey-based PheWAS efforts are complimentary to on-going PheWAS ...
Title: Vitamin D and Cardiovascular Disease: A Novel Agent for Reducing Cardiovascular Risk?. VOLUME: 8 ISSUE: 5. Author(s):Panagiotis Anagnostis, Vasilios G. Athyros, Fotini Adamidou, Matilda Florentin and Asterios Karagiannis. Affiliation:Endocrinology Clinic, Hippokration Hospital, 49 Konstantinoupoleos Str., Thessaloniki, 54642, Greece.. Keywords:Vitamin D, cardiovascular disease, hypertension, diabetes mellitus, metabolic syndrome. Abstract: Vitamin D deficiency is a well-established risk factor for bone disease. Emerging data suggest a pleiotropic role of this agent in a variety of functions in humans. Epidemiological studies indicate an inverse association between vitamin D deficiency and the prevalence of cardiovascular disease (CVD), as well as individual cardiometabolic risk factors, such as hypertension, diabetes, dyslipidemia and the metabolic syndrome. Moreover, vitamin D deficiency has been implicated in the atherosclerotic process. This review considers current data regarding the ...
Macrophages play pleiotropic roles in maintaining the balance between immune tolerance and inflammatory responses in the gut. Here, we identified transcription factor RBP-J as a crucial regulator of colonic macrophage-mediated immune responses against the enteric pathogen Citrobacter rodentium . In the immune response phase, RBP-J promoted pathogen clearance by enhancing intestinal macrophage-elicited Th17 cell immune responses, which was achieved by maintenance of C/EBPβ-dependent IL-6 production by overcoming miRNA-17∼92-mediated suppressive effects. RBP-J deficiency-associated phenotypes could be genetically corrected by further deleting miRNA-17∼92 in macrophages. In the late phase, noneradicated pathogens in RBP-J KO mice recruited abundant IL-1β-expressing CD64 + Ly6C + colonic macrophages and thereby promoted persistence of ILC3-derived IL-22 to compensate for the impaired innate and adaptive immune responses, leading to ultimate clearance of pathogens. These results ...
The DHODH, or dihydroorotate dehydrogenase, gene encodes a 43-kDa enzymatic protein localized to the inner mitochondrial membrane, where it interacts with the mitochondrial respiratory chain and acts as a rate-limiting step in de novo pyrimidine biosynthesis (51-53). Mutations within DHODH have been linked with Miller Syndrome, a recessive disorder characterized by malformations of the limbs and eyes, among other symptoms (54-57). DHODH has also been investigated for a role in cancer, including melanoma (58) and acute myeloid leukemia (59), and decreased expression of DHODH was associated with breast cancer risk (60). Several other studies have examined the utility of DHODH inhibitors in cancer by inducing cell-cycle arrest and apoptosis in cancer cells (59, 61-66). Although DHODH has not been previously associated with lung cancer risk, the abundance of biological evidence for its pleiotropic role in cancer gives credibility to the association.. We identified significant associations on ...
The technical advances in mass spectrometry, particularly the development of (ultra)-high-resolution/mass accuracy measurement capabilities in combination with refinement of soft ionization techniques, have increased the application and success of lipidomics to answer biological questions in relation to lipid metabolism. Together with other omics technologies, lipidomics has become an important tool to practice systems biology as lipids comprise a very significant part of the metabolome and play pleiotropic roles in cellular functions. As an increasing number of disorders are linked to lipid metabolism, lipidomics is used to search for biomarkers, understand disease mechanism and follow the efficacy of therapeutic options. This review provides a first introduction to the major methodological strategies currently used for mass spectrometry-based lipidomics and associated data pre-processing and analysis ...
During the last few years, accumulated evidence has supported a complex and pleiotropic role for proteins of the LOX family. Apart from their classical and widely reported function as ECM remodeling factors (Csiszar, 2001; Lucero & Kagan, 2006), emerging data have demonstrated the involvement of lysyl oxidases in a plethora of intracellular and extracellular processes (Barker et al, 2012; Cano et al, 2012). Generation of loss‐of‐function mouse models for Lox and Loxl1 has shed some light on tissue‐specific functions of these two LOX family members. The prototypic Lox plays a key role in the cardiovascular system (Maki et al, 2002; Hornstra et al, 2003), and Loxl1 was shown to be critical during the elastogenesis process (Liu et al, 2004). However, in vivo data concerning other members of the LOX family remain unexplored although similar multifunctional actions have been described, in particular for LOXL2 (Cano et al, 2012). Therefore, we generated deletion and overexpression mice for Loxl2 ...
Large-conductance calcium and voltage-activated potassium channels, termed SLO-1 (or BK), are pivotal players in the regulation of cell excitability across the animal phyla. Furthermore, emerging evidence indicates that these channels are key mediators of a number of neuroactive drugs, including the most recent new anthelmintic, the cyclo-octadepsipeptide emodepside. Detailed reviews of the structure, function and pharmacology of BK channels have recently been provided (Salkoff et al. in Nat Rev Neurosci 7:921-931, 2006; Ghatta et al. in Pharmacol Ther 110:103-116, 2006) and therefore these aspects will only briefly be covered here. The purpose of this review is to discuss how SLO-1 channels might function as regulators of neural transmission and network activity. In particular, we focus on the role of SLO-1 in the regulation of Caenorhabditis elegans behaviour and highlight the role of this channel as an effector for pleiotropic actions of neuroactive drugs, including emodepside. On the premise ...
In this study, we showed that pioglitazone treatment prevented the development of hypertension and renal oxidative stress in a rat model of diet-induced obesity. Also, our results indicate that compared with vitamin E, a well-known antioxidant, pioglitazone is more efficient in reducing BP and increasing sodium excretion in obese versus lean rats, while being equally efficient in reducing urinary isoprostanes, kidney TBARS, and HNE adducts. One possible explanation for these different effects is the ability of pioglitazone, as opposed to vitamin E, to increase renal NOS expression and NOx excretion in treated OP rats. In addition, pioglitazone, but not vitamin E treatment, significantly reduced expression of p47phox and gp91phox in OP rats, suggesting that both a reduction in oxidative stress and an improvement in NO production/bioavailability are important in efficiently reducing BP in this model.. Thiazolidinediones are known to exert pleiotropic actions both in vivo and in vitro, some of ...
Rationale:. Apart from their cholesterol lowering effects, statins have cholesterol‐independent pleiotropic actions, such as upregulation of 5‐ectonucleotidase and up‐regulation of NO‐synthase that may increase tolerance against ischemia‐reperfusion injury (IR‐injury). Several animal studies have shown reduction of IR‐injury as a result of statin treatment in both the heart and the kidney. Recently the investigators have shown, using Annexin A5 targeting after voluntary ischemic exercise to assess IR‐injury, a protective effect of a 7 day oral rosuvastatin treatment. A three day treatment with atorvastatin however failed to reduce annexin targeting.. Assessment of the flow mediated dilation of the brachial artery as measure of endothelial (dys)function, is a validated model to research effects of possible protective strategies and perform mechanistic experiments on IR‐injury in humans in vivo.. The investigators hypothesize that pretreatment with statins can increase ...
With the success of the human genome project, the focus of life science research has shifted to the functional and structural analyses of proteins, such as the fields of proteomics and structural genomics. These analyses of proteins, including newly identified proteins, are expected to contribute to the identification of therapeutically applicable proteins for various diseases. Thus, pharmacoproteomic-based drug discovery and the development of protein therapies has currently attracted a great deal of attention (1, 2, 3) . However, it is clinically difficult to use most bioactive proteins, such as tumor necrosis factor-α (TNF-α), as antitumor agents because of their very low stability and pleiotropic action in vivo (4 , 5) .. TNF-α was reported to exert a strong cytotoxicity to various kinds of tumor cells but not to normal cells in vitro and to cause hemorrhagic necrosis of certain transplanted solid tumors (6) . Thus, TNF-α has been considered a promising new drug for cancer therapy. On ...
Cry-toxin genes originating from Bacillus thuringiensis are inserted into genetically modified (GM) plants, often called Bt-plants, to provide insect resistance to pests. Significant amounts of Bt-plant residues, and thus Cry-toxins, will be shed to soil and aquatic environments. We exposed Daphnia magna to purified Cry1Ab and Cry2Aa toxins for the full life-span of the animals. We used single toxins in different doses and combinations of toxins and Roundup, another potential stressor on the rise in agricultural ecosystems. Animals exposed to 4.5 mg/L (ppm) of Cry1Ab, Cry2Aa and the combination of both showed markedly higher mortality, smaller body size and very low juvenile production compared to controls. Animals exposed to 0.75 mg/L also showed a tendency towards increased mortality but with increased early fecundity compared to the controls. Roundup stimulated animals to strong early reproductive output at the cost of later rapid mortality. We conclude that i) purified ...
Title: Heterogeneous pleiotropy in whole genome selection models. Speaker: Nora Bello*; Department of Statistics, Kansas State University. Place: Rawls (RAWL) Hall 1086. Date: November 5, 2013; Tuesday. Time: 4:30pm. Abstract:. *Joint work with: JP Stebil and RJ Tempelman; Department of Animal Science, Michigan State University. The additive genetic correlation between economically relevant traits is generally considered a critical factor determining the relative advantage of multi-trait models over single-trait models for whole genome prediction of genetic merit. Yet, the additive genetic correlation between traits may be considered an aggregate summary of between-trait correlations at the level of individual quantitative trait loci, thereby defining pleiotropic mechanisms by which individual genes have simultaneous effects on multiple phenotypic traits. Pleiotropic effects, in turn, may be ...
Understanding the causal chain from genotypic to phenotypic variation is a tremendous challenge with huge implications for personalized medicine. Here we argue that linking computational physiology to genetic concepts, methodology and data provides a new framework for this endeavor. We exemplify this causally cohesive genotype-phenotype (cGP) modeling approach using a detailed mathematical model of a heart cell. In silico genetic variation is mapped to parametric variation, which propagates through the physiological model to generate multivariate phenotypes for the action potential and calcium transient under regular pacing, and ion currents under voltage clamping. The resulting genotype-to-phenotype map is characterized using standard quantitative genetic methods and novel applications of high-dimensional data analysis. These analyses reveal many well-known ...
BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis ...
In several cases, the homologous WDR proteins are highly conserved throughout the length of the proteins, and appear to operate in highly analogous mechanisms, with specificity in function conferred by changes in upstream signaling pathways and/or downstream effectors. One case is AGB1, the only clear Arabidopsis ortholog of Gβ [31] (Fig. 1). Loss of AGB1 function leads to developmental pleiotropy including shortened fruits [32] and changes in patterns of cell division in the hypocotyl and root [33]. These phenotypes are associated with the derepression of genes that are normally turned on by auxin, suggesting a role for AGB1 as a negative regulator of auxin signaling [33]. There appears to be one Gα-like protein (GPA1) and two Gγ-like proteins (AGG1 and AGG2) in the Arabidopsis proteome [31], and molecular modeling and yeast two-hybrid studies of potential interactions among AGB1, GPA1 and AGG1 are not inconsistent with the possibility that these could form a heterotrimeric protein [33, ...
[email protected],Onuralp Söylemez]]** is a postdoctoral research fellow. He obtained his PhD in biomedical sciences at Pompeu Fabra University, Spain. During his PhD, he studied the prevalence and role of allele interactions at the protein level in shaping fitness within natural populations and between species. His current research focuses on applying evolutionary and population genetics tools to gene and pathway discovery via diagnosis of patients with Mendelian disorders of unknown etiology. His primary research interests include the link between Mendelian disorders and multifactorial traits, statistical genetics of rare genetic diseases, and novel regulatory mechanisms of pleiotropy ...
Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Pagets disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid-phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly ...
The validity of the MR analysis may be compromised by (1) population stratification, where allele frequencies and disease rates differ between population subgroups; (2) pleiotropy, where genetic instruments affect the outcome through ,1 intermediate risk factor, though this is not an issue for cis-acting SNPs used as instruments for a protein biomarker; (3) linkage disequilibrium, where another polymorphism in close proximity (and in linkage disequilibrium) to the variant of interest, is causing disease through another pathway; and (4) weak instrument bias. Analysis in the WHII was restricted to whites, and principal component analysis revealed no substantial population stratification. In the IMPROVE study, although all individuals were whites, there was population stratification that reflected the geographical location from which the samples were obtained.22 However, the SNPs used to generate the GLGC genetic scores were ...
Gutiérrez V, Rego N, Naya H, García G. First complete mitochondrial genome of the South American annual fish Austrolebias charrua (Cyprinodontiformes: Rivulidae): peculiar features among cyprinodontiforms mitogenomes. BMC Genomics. 2015 Oct 28;16(1):879 - Gianola D, de los Campos G, Toro MA, Naya H, Schön CC, Sorensen D. Do Molecular Markers Inform About Pleiotropy? Genetics. 2015 Sep;201(1):23-9.- Fernandez-Calero T, Garcia-Silva R, Pena A, Robello C, Persson H, Rovira C, Naya H, Cayota A. Profiling of small RNA cargo of extracellular vesicles shed by Trypanosoma cruzi reveals a specific extracellular signature. Mol Biochem Parasitol. 2015;199(1-2):19-28.- Berná L, Iraola G, Greif G, Coitinho C, Rivas CM, Naya H, Robello C. Whole-Genome Sequencing of an Isoniazid-Resistant Clinical Isolate of Mycobacterium tuberculosis Strain MtURU-002 from Uruguay. Genome Announc. 2014;2(4)- Chiribao ML, Libisch, G, Parodi‐Talice, A, Robello, C. Early Trypanosoma cruzi ...
…but dont forget the complicating factors! Non-penetrance New mutation Adult-onset conditions Consanguinity Interaction Sex-limited/sex influenced Germline mosaicism Anticipation Heterogeniety Pleiotropy
The different cell types of the vertebrate pancreas arise asynchronously during organogenesis. Beta-cells producing insulin, alpha-cells producing glucagon, and exocrine cells secreting digestive enzymes differentiate sequentially from a common primordium. Notch signaling has been shown to be a major mechanism controlling these cell-fate choices. So far, the pleiotropy of Delta and Jagged/Serrate genes has hindered the evaluation of the roles of specific Notch ligands, as the phenotypes of knock-out mice are lethal before complete pancreas differentiation. Analyses of gene expression and experimental manipulations of zebrafish embryos allowed us to determine individual contributions of Notch ligands to pancreas development. We have found that temporally distinct phases of both endocrine and exocrine cell type specification are controlled by different delta and jagged genes. Specifically, deltaA knock-down embryos lack alpha cells, similarly to mib (Delta ubiquitin ligase) mutants and embryos ...
In the last few years there has been a growing interest towards intrinsically disordered proteins related to the understanding of the numerous and diverse functional roles they play. Our group played a pioneering role in focusing the attention of virologists on the abundance of disorder within proteins of the replicative complex of paramyxoviruses. Following these seminal reports in the early 2000s, many other studies that addressed the disordered nature of various viral proteins have been published in subsequent years, leading to revisiting the classical way structure-function relationships in viral proteins are seen. The main advantage of disorder within viral proteins has been proposed to be related to (i) mutational robustness, (ii) pleiotropy, (iii) genetic compaction and (iv) the lessening of evolutionary constraints on overlapping reading frames. In the coming years we aim at further extending these studies by assessing the disordered state of ...
Several of the pressing scientific challenges in the filed of environmental toxicology are to understand the basic mechanisms of chemically-induced toxic substances and of the design, interpretation, and extrapolation of data from non-human bioassay systems to the human situation. The objective is to offer a new paradigm, namely the idea that cytotoxic and epigenetic effects of chemicals can contribute to many toxic endpoints in human beings. We will speculate that the disruption of calcium homeostasis by a wide variety of chemicals and the conditions of their use might provide an unification of mechanisms leading to either cytotoxicity or epigenetic changes. Depending on the conditions, the effects of this disruption, a pleiotropy of diseases might result, namely, embryotoxicity, teratogenesis, tumor promotion, immune modulation, neurotoxicity, and preproductive dysfunction. In summary, there are at least three biological ...
The hypothesis that skin color is a genetic correlate of IQ was endorsed by Jensen (2006) who suggested that pleiotropy (genes having more than one effect) may underlie the relationship. Skin color became of greater theoretical interest after Ducrest, Keller, and Roulin (2008) reviewed the literature and reported that in 20 wild vertebrate species, darker individuals were more aggressive, sexually active, and resistant to stress than lighter individuals. Studied were three mammal species (African lion, soay sheep, and white-tailed deer), four fish species (mosquito fish, guppy, green swordtail, and Arctic char), four reptile species (asp viper, adder, fence lizard, and spiny lizard), one amphibian species (spadefoot toad) and 36 bird species. Darker individuals also tended to have a larger body mass and greater energy and physical activity such as grooming. Ducrest et al. (2008) confirmed the naturalistic observations using experimental studies such as the ...
The model: While Ill leave it to you to check out the full supplemental information for the details of their model, it is firmly rooted in the quantitative genetics framework of Lande land (Lande 1979; Lande and Arnold, 1983). As such, evolutionary change is measured by how selection changes the variance/covariance structure (G-matrix) of the underlying traits. The analytical model assumes a fixed G-matrix, however their simulations relax this assumption. The primary goal of the analysis is to calculate the ability of the victim/host to escape the exploiter/parasite measured as the maximum evolutionary escape rate. This evolutionary escape rate is the difference in the rates of change of the host defense traits compared to the parasite attacking trait. When the host is winning host it is said to be outrunning the parasite ...
Objective. RA patients develop autoantibodies against a spectrum of antigens but their clinical significance is unclear. Using the phenome-wide association study (PheWAS) approach, we examined the association between autoantibodies and clinical subphenotypes of RA. Methods. This study was conducted using a validated electronic medical record (EMR) RA cohort from 2 tertiary care centers. Using a published multiplex bead assay, we measured 36 autoantibodies targeting epitopes implicated in RA. We extracted all ICD-9 codes for each subject and grouped them using a published method into disease categories (PheWAS codes). We tested for the association of each autoantibody grouped by targeted protein with PheWAS codes. For significant associations (false discovery rate [FDR] ≤0.1), we reviewed 50 medical records of subjects with each PheWAS code to determine the positive predictive value (PPV). Results. We studied 1006 RA subjects, mean age 61.0 years (SD 12.9) and 79.0% female. There were 3,568 ...
There is an interesting article on evolvability which I wrote a bit more about here. It is by Massimo Pigliucci and titled, Is Evolvability Evolvable, for which the whole PDF is available online. Pigliucci discusses definitions of evolvability as well as different ideas about the origins of evolvability. Here is the abstract: In recent years,…
Effect of Mutation and Recombination on the Genotype-Phenotype Map: The effect of genetic operators other than selection, such as mutation and recombination, on
By adopting a basic interpretation of the biological processes of transcription and translation, the multilayered GA (MGA) introduces a genotype-phenotype mapping for a haploid genotype, which allows the granularity of the representation to be tuned. The paper examines the impact of altering the level of neutrality through changes in the granularity of the representation and compares the performance of a standard GA (SGA) to that of a number of multi-layered GAs, each with a different level of neutrality, over both static and changing environments. Initial results indicate that it appears advantageous to include a multi-layered, biologically motivated genotype-phenotype encoding over more difficult landscapes. The paper also introduces an interpretation of missense mutation, which operates within the genotype-phenotype map (GP-map). Results also suggest that this mutation strategy can assist in tracking the optimum over various landscapes ...
The mechanisms by which adaptive phenotypes spread within an evolving population after their emergence are understood fairly well. Much less is known about the factors that influence the evolutionary accessibility of such phenotypes, a pre-requisite for their emergence in a population. Here, we investigate the influence of environmental quality on the accessibility of adaptive phenotypes of Escherichia colis central metabolic network. We used an established flux-balance model of metabolism as the basis for a genotype-phenotype map (GPM). We quantified the effects of seven qualitatively different environments (corresponding to both carbohydrate and gluconeogenic metabolic substrates) on the structure of this GPM. We found that the GPM has a more rugged structure in qualitatively poorer environments, suggesting that adaptive phenotypes could be intrinsically less accessible in such environments. Nevertheless, on average approximately 74% of the genotype can be altered by neutral drift, in the ...
A multivariate quantitative genetic model is analyzed that is based on the assumption that the genetic variation at a locus j primarily influences an underlying physiological variable yj, while influence on the genotypic values is determined by a kind of "developmental function" which is not changed by mutations at this locus. Assuming additivity among loci the developmental function becomes a linear transformation of the underlying variables y onto the genotypic values x, x = By. In this way the pleiotropic effects become constrained by the structure of the B-matrix. The equilibrium variance under mutation-stabilizing selection balance in infinite and finite populations is derived by using the house of cards approximation. The results are compared to the predictions given by M. Turelli in 1985 for pleiotropic two-character models. It is shown that the B-matrix model gives the same results as Turellis five-allele model, suggesting that the ...
Epistasis:. 1. Epistasis refers to interaction of two or more genes. Thus it involves two or more loci. 2. Epistasis may involve both homo and heterozygotes. Hence it is fixable in homozygotes. 3. Epistasis is of several types such as dominant, recessive, duplicate, etc. 4. Epistasis modifies the normal dihybrid phenotypic ratios in F2. 5. Epistasis is also known as inter genie or inter-locus gene interaction. 6. Recessive gene can also exhibit masking effect. Dominance: ...
... typically applies to a certain allele, or version, of a gene. Epistasis depends on how the protein allele codes for actually functions. In our analogy, epistasis depends on what the workers do in our process.. Now well add epistasis to our example. Lets say a version (or allele) of a is broken so that it contains no instructions. Worker A wouldnt be able to put paint into the tray, and we would end up with a blank poster-even though workers B and C are still doing their jobs.. This broken version of a is epistatic to b and c: the final product (a blank poster) shows no evidence of what B and C have been told to do. We cant tell if Bs instructions said to add red or blue, or if Cs said to draw a circle or a square.. The important aspect of epistasis is that it doesnt just influence the phenotype, it hides the output of another gene or genes.. Now lets imagine that a is working, but c is broken. This version, or "allele," of c is epistatic to a and b: the output shows no evidence ...
The Rhine Research Center will hold a conference on March 22-24, 2007 in Myrtle Beach, SC at the Holiday Inn-West the theme of the conference will ...
The Rhino Resource Center is committed to assisting research and conservation of the rhinoceros worldwide by collecting all publications and maintaining archives.
Signal transductionRegulatory functionsDNA interactionsGTP-sensing transcriptional pleiotropic repressor CodY (TIGR02787; HMM-score: 351.8) ...

Mendelian randomization - WikipediaMendelian randomization - Wikipedia

... genetic heterogeneity, pleiotropy (often detected as a genetic correlation), or population stratification. Katan MB (March 1986 ... misleading conclusions may also arise in the presence of linkage disequilibrium with unmeasured directly-causal variants, ... a causal effect from observational data in the presence of confounding factors. It uses common genetic polymorphisms with well- ... Davey Smith G, Ebrahim S, Lewis S, Hansell AL, Palmer LJ, Burton PR (2005). "Genetic epidemiology and public health: hope, hype ...
more infohttps://en.wikipedia.org/wiki/Mendelian_randomization

Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease: a...Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease: a...

Remnant cholesterol as a causal risk factor for ischemic heart disease. [J Am Coll Cardiol. 2013] ... Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease: a ... Response: Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed/24055740

A global overview of pleiotropy and genetic architecture in complex traits | Nature GeneticsA global overview of pleiotropy and genetic architecture in complex traits | Nature Genetics

We find that potential causal variants are enriched in coding and flanking regions, as well as in regulatory elements, and show ... For a subset of well-powered GWASs on 558 traits, we provide an extensive overview of pleiotropy and genetic architecture. We ... such as the extent of pleiotropy across the genome and variation in genetic architecture across traits, are still unanswered. ... Systematic analyses of large-scale genome-wide association data provide an overview of pleiotropy and genetic architecture for ...
more infohttps://www.nature.com/articles/s41588-019-0481-0?error=cookies_not_supported&code=235e230e-4ae5-4b5d-ae42-f2da082362af

Interpreting findings from Mendelian randomization using the MR-Egger method | SpringerLinkInterpreting findings from Mendelian randomization using the MR-Egger method | SpringerLink

MR-Egger consists of three parts: (1) a test for directional pleiotropy, (2)... ... is an analysis method for Mendelian randomization using summarized genetic data. ... of the genetic variants are valid instrumental variables, and is unaffected by a few genetic variants with outlying causal ... Orientation of the genetic variants. Genetic associations are usually the per allele associations of the genetic variants with ...
more infohttps://link.springer.com/article/10.1007%2Fs10654-017-0255-x

Plus itPlus it

Mendelian randomisation is a genetic epidemiological method for assessing causal inference by exploiting genetic variants ... Completely ruling out pleiotropy (where a genetic variant is associated with more than one risk factor) or an alternative ... Genetic variants. For each modifiable risk factor, we selected genetic variants (single nucleotide polymorphisms) associated ... with other genetic variants for the same risk factor. When we encountered genetic variants in linkage disequilibrium, we chose ...
more infohttps://www.bmj.com/content/359/bmj.j5375

Genomic Prediction from Multiple-Trait Bayesian Regression Methods Using Mixture Priors | GeneticsGenomic Prediction from Multiple-Trait Bayesian Regression Methods Using Mixture Priors | Genetics

Many researchers are interested in genome-wide association studies and finding causal genes and variants. For those researchers ... is the genetic covariance matrix and and are the probabilities a marker has null effects on the first trait but not the second ... In most cases, the researcher will have little or no knowledge of the likely extent of pleiotropy of loci that influence two ... is the genetic variance, is the allele frequency for locus j, and π is the probability that a marker has a null effect (Habier ...
more infohttps://www.genetics.org/content/209/1/89?ijkey=3c1eadfb58f365f0ec2fc258bde4e4b9e501a77b&keytype2=tf_ipsecsha

Assessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians | SpringerLinkAssessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians | SpringerLink

These analyses require the assumption that the genetic variants capture the causal relationships and that the associations are ... LD between variants influencing each trait or the influence of other mechanisms such as pleiotropy. As discussed by Fall et al ... Another limitation of these analyses is that the causal variants influencing HDL-C are generally unknown and these may not be ... Fall T, Xie W, Poon W et al (2015) Using genetic variants to assess the relationship between circulating lipids and type 2 ...
more infohttps://link.springer.com/article/10.1007/s00125-015-3835-x

Serum magnesium levels and risk of coronary artery disease: Mendelian randomisation study | BMC Medicine | Full TextSerum magnesium levels and risk of coronary artery disease: Mendelian randomisation study | BMC Medicine | Full Text

A genetic predisposition to higher serum magnesium levels was inversely associated with CAD. In conventional Mendelian ... but whether this association is causal is unknown. We conducted a Mendelian randomisation study to investigate whether serum ... Causal inference from an MR study relies on the instrumental variable assumptions, which require that the genetic variant is ... The MR-Egger analysis did not provide evidence of either directional pleiotropy (intercept -0.023; P = 0.21) or a causal ...
more infohttps://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1065-z

Plus itPlus it

We calculated a weighted genetic risk score including four genetic variants previously found to be associated with circulating ... Presence of pleiotropy and the robustness of the results were assessed using MR-Egger and weighted-median analyses. Genetically ... Inverse-variance weighted analysis was used to obtain a risk ratio (RR) for the causal relation between circulating ... This study aims to investigate the causal relation between circulating phylloquinone (vitamin K1) concentrations and type 2 ...
more infohttp://diabetes.diabetesjournals.org/content/early/2018/10/16/db18-0543

Iron and hepcidin as risk factors in atherosclerosis: what do the genes say? | BMC Genetics | Full TextIron and hepcidin as risk factors in atherosclerosis: what do the genes say? | BMC Genetics | Full Text

Our results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is ... Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) ... This might indicate presence of pleiotropy, where a single genetic variant affects multiple traits independently. It can also ... the genetic variant must not directly be associated with the outcome, and 3) the genetic variant must not be associated with ...
more infohttps://bmcgenet.biomedcentral.com/articles/10.1186/s12863-015-0246-4

Frontiers | Exploring the Genetic Correlation Between Growth and Immunity Based on Summary Statistics of Genome-Wide...Frontiers | Exploring the Genetic Correlation Between Growth and Immunity Based on Summary Statistics of Genome-Wide...

... and reveal the genetic background of their correlation in the context of pleiotropy. ... Some variants, such as rs3184504 located in SH2B3, rs13107325 in SLC39A8, and rs1260326 located in GCKR, which have been ... Some variants, such as rs3184504 located in SH2B3, rs13107325 in SLC39A8, and rs1260326 located in GCKR, which have been ... In addition, pleiotropic variants and KEGG pathways were identified. As a result, we found negative correlations between ...
more infohttps://www.frontiersin.org/articles/10.3389/fgene.2018.00393/full

Studying individual risk factors for self-harm in the UK Biobank: A polygenic scoring and Mendelian randomisation studyStudying individual risk factors for self-harm in the UK Biobank: A polygenic scoring and Mendelian randomisation study

Kai Xiang Lim and co-workers use genetic instruments to investigate risk factors associated with self-harm. ... arising from the inclusion of thousands of genetic variants [20]. Unmediated pleiotropy exists when a genetic variant ... MR can more stringently address unmediated pleiotropy and further strengthen causal inference. In MR, individual genetic ... Using genetic information to help strengthen causal inference can help to identify plausibly causal risk factors for self-harm. ...
more infohttps://phgkb.cdc.gov/PHGKB/phgHome.action?action=forward&dbsource=cluster&id=34578

Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways.  - PubMed - NCBISmoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways. - PubMed - NCBI

... evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants ... By using "moloc", we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. ... We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p , 1.2 × 10-4). Replication analysis ... We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV1) in UK Biobank ...
more infohttps://phgkb.cdc.gov/PHGKB/phgHome.action?action=forward&dbsource=cluster&id=33485

Prioritizing putative influential genes in cardiovascular disease susceptibility by applying tissue-specific Mendelian...Prioritizing putative influential genes in cardiovascular disease susceptibility by applying tissue-specific Mendelian...

We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both ... Fine-mapping was performed to prioritize possible causal variants for detected associations. Two-sample Mendelian randomization ... Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. Our MR analysis ... as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future ...
more infohttps://genomemedicine.biomedcentral.com/articles/10.1186/s13073-019-0613-2

Risposta dei sistemi deposizionali continentali dellarea Alpino Dolomitica alle variazioni climatiche a scala del millennio...Risposta dei sistemi deposizionali continentali dell'area Alpino Dolomitica alle variazioni climatiche a scala del millennio...

Pleiotropy occurs when the same genetic causal element affects more than one phenotype "in parallel" and can explain the ... Among them, mediation occurs when a genetic variant is directly associated with a phenotype and that phenotype is itself causal ... It can appear at a single variant level, where a single causal variant is related to multiple phenotypes, or at a locus level, ... Many genetic loci appear to harbour variants associated with multiple phenotypes (cross-phenotype associations, CP). CP ...
more infohttp://eprints.unife.it/917/

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization:...Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization:...

Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We ... low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these ... genetic variants as instruments for circulating levels International Journal of Cancer, 139 (7). pp. 1520-1533. ... IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs ...
more infohttp://epubs.surrey.ac.uk/811728/

Profile  | College of Medicine and Health | University of ExeterProfile | College of Medicine and Health | University of Exeter

... summary data for large numbers of genetic variants. Heterogeneity among the causal estimates obtained from multiple genetic ... When additionally all genetic variants are valid instruments, the type I error rate of the MR-Egger test for pleiotropy is ... summary data for large numbers of genetic variants. Heterogeneity among the causal estimates obtained from multiple genetic ... When additionally all genetic variants are valid instruments, the type I error rate of the MR-Egger test for pleiotropy is ...
more infohttp://medicine.exeter.ac.uk/people/profile/index.php?web_id=Jack_Bowden

Frontiers | Regular Exercise, Subjective Wellbeing, and Internalizing Problems in Adolescence: Causality or Genetic Pleiotropy?...Frontiers | Regular Exercise, Subjective Wellbeing, and Internalizing Problems in Adolescence: Causality or Genetic Pleiotropy?...

The association largely reflects the effects of common genetic factors on these traits. ... The association largely reflects the effects of common genetic factors on these traits. ... because genetic confounding is excluded. Data on these phenotypes were available in a sample of 6,317 adolescent twins and ... because genetic confounding is excluded. Data on these phenotypes were available in a sample of 6,317 adolescent twins and ...
more infohttps://www.frontiersin.org/articles/10.3389/fgene.2012.00004/full

Pleiotropy of genetic variants on obesity and smoking phenotypes: Results from the Oncoarray Project of The International Lung...Pleiotropy of genetic variants on obesity and smoking phenotypes: Results from the Oncoarray Project of The International Lung...

Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking ... Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to ... Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with ... consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray ...
more infohttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185660

Body mass index as a modifiable risk factor for type 2 diabetes: Refining and understanding causal estimates using Mendelian...Body mass index as a modifiable risk factor for type 2 diabetes: Refining and understanding causal estimates using Mendelian...

We explore the potential for pleiotropic genetic variants to generate bias, revise existing estimates and illustrate value in ... This indicated the potential for pleiotropy to affect estimates and differences in performance of alternative analytical ... The availability of multiple variants associated with BMI offers a new chance to resolve the true causal effect of BMI on T2D, ... A two-sample Mendelian randomisation (MR) approach with 96 genetic variants was employed using three different analysis methods ...
more infohttp://diabetes.diabetesjournals.org/content/early/2016/07/08/db16-0418

DiVA - SøkeresultatDiVA - Søkeresultat

... this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal ... A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We ... Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the ... This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of ...
more infohttp://www.diva-portal.org/smash/resultList.jsf?af=%5B%5D&aq=%5B%5B%7B%22personId%22%3A%22authority-person%3A11080%22%7D%5D%5D&aqe=%5B%5D&aq2=%5B%5B%5D%5D&language=no&query=

DNA methylation as a marker of education | npj Science of Learning CommunityDNA methylation as a marker of education | npj Science of Learning Community

2) Genetic variants have independent effects on educational attainment, smoking and DNA methylation (genetic pleiotropy), which ... Which CpGs are related to exposure to other pollutants? Which CpGs might have a causal role in smoking behavior and educational ... genetic variants associated with gene expression and DNA methylation, respectively),and DNA methylation heritability, and will ... 1) Genetic effects on DNA methylation correlate across tissues 2) DNA methylation in these tissues respond similarly to ...
more infohttps://npjscilearncommunity.nature.com/users/85991-jenny-van-dongen/posts/31505-dna-methylation-as-a-marker-of-education

Human cardiomyopathy mutations induce myocyte hyperplasia and activate hypertrophic pathways during cardiogenesis in zebrafish ...Human cardiomyopathy mutations induce myocyte hyperplasia and activate hypertrophic pathways during cardiogenesis in zebrafish ...

The zebrafish Tnnt2 splice variant genocopies the human disease-causing TNNT2 splice variant. In order to precisely ... 2007). Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. J. Cardiovasc. Electrophysiol. 19, 104-110. ... Many of the causal genes for inherited hypertrophic cardiomyopathy (HCM) encode for proteins involved in the proper function of ... However, substantial pleiotropy is seen for many cardiomyopathy genes. Even within families harboring the same mutation there ...
more infohttp://dmm.biologists.org/content/4/3/400

Smoller J[au] - PubMed - NCBISmoller J[au] - PubMed - NCBI

Genetic risk variants for social anxiety.. Stein MB, Chen CY, Jain S, Jensen KP, He F, Heeringa SG, Kessler RC, Maihofer A, ... Polygenic pleiotropy and potential causal relationships between educational attainment, neurobiological profile, and positive ... Genetic risk variants for social anxiety.. Stein MB, Chen CY, Jain S, Jensen KP, He F, Heeringa SG, Kessler RC, Maihofer A, ... Genetic overlap between vascular pathologies and Alzheimers dementia and potential causal mechanisms. ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=Smoller+J%5Bau%5D&dispmax=50

A putative causal relationship between genetically determined female body shape and posttraumatic stress disorder | Genome...A putative causal relationship between genetically determined female body shape and posttraumatic stress disorder | Genome...

The relationship between AFB and PTSD seems to be due to a large genetic overlap (i.e. pleiotropy); WCadj appears to be ... A causal relationship between two traits should show asymmetry in the effect sizes of associated variants [41]. We observed ... This is a strategy to test cause-effect associations, in which evidence on the associations of genetic variants (i.e. ... Conversely, there was an asymmetry in the effect sizes of associated variants: WCadj-associated variants affect the risk of ...
more infohttps://genomemedicine.biomedcentral.com/articles/10.1186/s13073-017-0491-4
  • The design was first proposed in 1986 and subsequently described by Gray and Wheatley as a method for obtaining unbiased estimates of the effects of a putative causal variable without conducting a traditional randomised trial. (wikipedia.org)
  • The approach undertaken in our study can be used to elucidate mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. (biomedcentral.com)
  • There is a putative causal relationship between genetically determined female body shape and PTSD, which could be mediated by evolutionary mechanisms involved in human sexual behaviors. (biomedcentral.com)
  • However, the functional and clinical relevance for the vast majority of GWAS results are still unknown, emphasizing the importance of developing our understanding of the causal pathway from single nucleotide polymorphism (SNP) to disease. (biomedcentral.com)
  • Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. (surrey.ac.uk)
  • By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. (cdc.gov)
  • Strong support for a non-causal explanation came from the finding that in genetically identical twin pairs, the twin who exercised more did not have fewer depressive and anxious symptoms than his or her co-twin who exercised less. (frontiersin.org)
  • to incorporate marker effects from whole-genome data into genetic evaluation. (genetics.org)
  • Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies. (nih.gov)
  • 3 The most recent large-scale meta-analysis published in 2015 by CARDIoGRAMplusC4D involved genome-wide genetic data imputed to the 1000 genomes panel for the first time. (ahajournals.org)
  • The findings of genome-wide association studies to date provide important insights on the genetic architecture of CAD, the causal mechanisms at play, and the predictive power of genetics. (ahajournals.org)
  • 3) Epigenetic mechanisms that contribute to education-related physical health differences or that are a biomarker of health differences without being the causal trigger. (nature.com)
  • Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization ("moloc") framework. (cdc.gov)
  • By using "moloc", we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. (cdc.gov)
  • Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. (biomedcentral.com)
  • It uses common genetic polymorphisms with well-understood effects on exposure patterns (e.g., propensity to drink alcohol) or effects that mimic those produced by modifiable exposures (e.g., raised blood cholesterol). (wikipedia.org)
  • Under this hypothesis, prospective associations between exercise behavior and psychological wellbeing reflect the effects of common genetic factors influencing a disposition for exercise participation as well as a disposition for psychological wellbeing, a process referred to as genetic pleiotropy ( de Geus and de Moor, 2008 ). (frontiersin.org)
  • While the MR-Egger method is a worthwhile sensitivity analysis for detecting violations of the instrumental variable assumptions, there are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants. (springer.com)
  • These assumptions may be reasonable when the risk factor is a protein biomarker and the genetic variants are located in or around the coding region for that protein. (springer.com)
  • Jack has helped to develop a range of statistical methods for MR, as well as methods for sensitivity analysis that help to determine whether individual genetic variants satisfy the IV assumptions, in order for the approach to draw reliable causal conclusions. (exeter.ac.uk)
  • In such a case, causal inferences from a straightforward application of instrumental variable methods have some credibility. (springer.com)
  • Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. (cdc.gov)
  • Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). (surrey.ac.uk)
  • In this article we review IV estimation of so-called conditional causal odds ratios which express the effect of an arbitrary exposure on a dichotomous outcome conditional on the exposure level, instrumental variable and measured covariates. (exeter.ac.uk)
  • In addition, we propose IV estimators of so-called marginal causal odds ratios which express the effect of an arbitrary exposure on a dichotomous outcome at the population level, and are therefore of greater public health relevance. (exeter.ac.uk)
  • Our results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women. (biomedcentral.com)
  • Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. (nature.com)
  • Inverse-variance weighted analysis was used to obtain a risk ratio (RR) for the causal relation between circulating phylloquinone concentrations and risk of type 2 diabetes. (diabetesjournals.org)
  • In general, the conclusion that has been drawn from these studies is that increased levels of psychological wellbeing found in exercisers are the reflection of causal effects of exercise. (frontiersin.org)
  • The re-creation of a human disease-causing TNNT2 splice variant demonstrates that sarcomeric mutations can alter cardiomyocyte biology at the earliest stages of heart development with distinct effects from those observed in adult hearts despite shared transcriptional responses. (biologists.org)
  • This model not only facilitates the study of the initial developmental effects of a primary cause of hypertrophic cardiomyopathy, but also allows the systematic study of genetic and environmental modifiers before the effects of chronic myocardial remodeling supervene. (biologists.org)
  • We conclude that longevity is moderately heritable in the OOA, that the genetic effects are additive, and that genetic influences on longevity are likely to be expressed across a broad range of ages. (pinboard.in)
  • Out of these 24 risk factors, major depressive disorder, attention-deficit hyperactivity disorder and schizophrenia appeared to be the most plausible causal risk factors for self-harm. (cdc.gov)
  • Our results provide insights into how genetic variation contributes to trait variation. (nature.com)
  • In the last two decades, genetic studies of inherited forms of human cardiomyopathy have offered important insights into the fundamental biology of myocardial hypertrophy and heart failure. (biologists.org)
  • In 2014 the genotype-first approach was used to assess rare and low-frequency variants in the Finnish population. (wikipedia.org)