WorldWideScience

Sample records for simple mendelian inheritance

  1. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance.

    Science.gov (United States)

    Hernandez, Dena G; Reed, Xylena; Singleton, Andrew B

    2016-10-01

    Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special

  2. Beyond the simplicity of Mendelian inheritance.

    Science.gov (United States)

    Schacherer, Joseph

    2016-01-01

    Elucidating the underlying rules that govern the phenotypic diversity observed in natural populations is an old but still unaccomplished goal in biology. In 1865, Gregor Mendel paved the way for the dissection of the underlying genetic basis of traits by setting out to understand the principles of heredity. To date, we still lack a global overview of the spectrum and continuum existing between Mendelian and complex traits within any natural population. In this respect, we recently performed a species-wide survey of Mendelian traits across a large population of isolates using the yeast Saccharomyces cerevisiae. By analyzing the distribution and the inheritance patterns of the trait, we have clearly shown that monogenic mutations can display a significant, variable, and continuous expressivity across different genetic backgrounds. Our study also demonstrated that combining the elegancy of both classical genetics and high-throughput genomics is more than valuable to dissect the genotype-phenotype relationship in natural populations. Copyright © 2016 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  3. What Mendel did not discover: exceptions in Mendelian genetics and their role in inherited human disease.

    Science.gov (United States)

    Hern, Laura M; Bidichandani, Sanjay I

    2004-01-01

    It has been one hundred and thirty-eight years after the initial publication of Mendel's laws of inheritance. Following a couple of decades of unprecedented progress in deciphering the molecular basis of human genetic disease, we have the luxury of hindsight to revisit Mendel's original discoveries in order to recognize variations in the themes that have otherwise endured the test of time. In this article we focus on diseases inherited in a Mendelian (or near Mendelian) fashion and describe deviations from the laws of Mendelian inheritance. We discuss relevant examples of inherited human disease and the underlying molecular mechanisms for the observed variations in Mendelian laws of inheritance.

  4. Using Mendelian inheritance to improve high-throughput SNP discovery.

    Science.gov (United States)

    Chen, Nancy; Van Hout, Cristopher V; Gottipati, Srikanth; Clark, Andrew G

    2014-11-01

    Restriction site-associated DNA sequencing or genotyping-by-sequencing (GBS) approaches allow for rapid and cost-effective discovery and genotyping of thousands of single-nucleotide polymorphisms (SNPs) in multiple individuals. However, rigorous quality control practices are needed to avoid high levels of error and bias with these reduced representation methods. We developed a formal statistical framework for filtering spurious loci, using Mendelian inheritance patterns in nuclear families, that accommodates variable-quality genotype calls and missing data--both rampant issues with GBS data--and for identifying sex-linked SNPs. Simulations predict excellent performance of both the Mendelian filter and the sex-linkage assignment under a variety of conditions. We further evaluate our method by applying it to real GBS data and validating a subset of high-quality SNPs. These results demonstrate that our metric of Mendelian inheritance is a powerful quality filter for GBS loci that is complementary to standard coverage and Hardy-Weinberg filters. The described method, implemented in the software MendelChecker, will improve quality control during SNP discovery in nonmodel as well as model organisms. Copyright © 2014 by the Genetics Society of America.

  5. Unlinked Mendelian inheritance of red and black pigmentation in snakes: Implications for Batesian mimicry.

    Science.gov (United States)

    Davis Rabosky, Alison R; Cox, Christian L; Rabosky, Daniel L

    2016-04-01

    Identifying the genetic basis of mimetic signals is critical to understanding both the origin and dynamics of mimicry over time. For species not amenable to large laboratory breeding studies, widespread color polymorphism across natural populations offers a powerful way to assess the relative likelihood of different genetic systems given observed phenotypic frequencies. We classified color phenotype for 2175 ground snakes (Sonora semiannulata) across the continental United States to analyze morph ratios and test among competing hypotheses about the genetic architecture underlying red and black coloration in coral snake mimics. We found strong support for a two-locus model under simple Mendelian inheritance, with red and black pigmentation being controlled by separate loci. We found no evidence of either linkage disequilibrium between loci or sex linkage. In contrast to Batesian mimicry systems such as butterflies in which all color signal components are linked into a single "supergene," our results suggest that the mimetic signal in colubrid snakes can be disrupted through simple recombination and that color evolution is likely to involve discrete gains and losses of each signal component. Both outcomes are likely to contribute to the exponential increase in rates of color evolution seen in snake mimicry systems over insect systems. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

  6. Mendelian inheritance, linkage and genotypic disequilibrium in microsatellite loci isolated from Hymenaea courbaril (Leguminosae).

    Science.gov (United States)

    Carneiro, F S; Lacerda, A E B; Lemes, M R; Gribel, R; Kanashiro, M; Sebbenn, A M

    2012-07-19

    The Neotropical tree Hymenaea courbaril, locally known as Jatobá, is a valuable source of lumber and also produces comestible and medicinal fruit. We characterized Mendelian inheritance, linkage and genotypic disequilibrium at nine microsatellite loci isolated from H. courbaril, in order to determine if they would provide accurate estimates of population genetic parameters of this important Amazon species. The study was made on 250 open-pollinated offspring originated from 14 seed trees. Only one of nine loci presented significant deviation from the expected Mendelian segregation (1:1). Genotypic disequilibrium between pairwise loci was investigated based on samples from 55 adult and 56 juvenile trees. No genetic linkage between any paired loci was observed. After Bonferroni's corrections for multiple tests, we found no evidence of genotypic disequilibrium between pairs of loci. We conclude that this set of loci can be used for genetic diversity/ structure, mating system, gene flow, and parentage analyses in H. courbaril populations.

  7. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders.

    Science.gov (United States)

    Hamosh, Ada; Scott, Alan F; Amberger, Joanna S; Bocchini, Carol A; McKusick, Victor A

    2005-01-01

    Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative and timely knowledgebase of human genes and genetic disorders compiled to support human genetics research and education and the practice of clinical genetics. Started by Dr Victor A. McKusick as the definitive reference Mendelian Inheritance in Man, OMIM (http://www.ncbi.nlm.nih.gov/omim/) is now distributed electronically by the National Center for Biotechnology Information, where it is integrated with the Entrez suite of databases. Derived from the biomedical literature, OMIM is written and edited at Johns Hopkins University with input from scientists and physicians around the world. Each OMIM entry has a full-text summary of a genetically determined phenotype and/or gene and has numerous links to other genetic databases such as DNA and protein sequence, PubMed references, general and locus-specific mutation databases, HUGO nomenclature, MapViewer, GeneTests, patient support groups and many others. OMIM is an easy and straightforward portal to the burgeoning information in human genetics.

  8. The Application of Restriction Landmark Genome Scanning Method for Surveillance of Non-Mendelian Inheritance in F1 Hybrids

    Directory of Open Access Journals (Sweden)

    Tomoko Takamiya

    2009-01-01

    Full Text Available We analyzed inheritance of DNA methylation in reciprocal F1 hybrids (subsp. japonica cv. Nipponbare × subsp. indica cv. Kasalath of rice (Oryza sativa L. using restriction landmark genome scanning (RLGS, and detected differing RLGS spots between the parents and reciprocal F1 hybrids. MspI/HpaII restriction sites in the DNA from these different spots were suspected to be heterozygously methylated in the Nipponbare parent. These spots segregated in F1 plants, but did not segregate in selfed progeny of Nipponbare, showing non-Mendelian inheritance of the methylation status. As a result of RT-PCR and sequencing, a specific allele of the gene nearest to the methylated sites was expressed in reciprocal F1 plants, showing evidence of biased allelic expression. These results show the applicability of RLGS for scanning of non-Mendelian inheritance of DNA methylation and biased allelic expression.

  9. Systematic large-scale study of the inheritance mode of Mendelian disorders provides new insight into human diseasome.

    Science.gov (United States)

    Hao, Dapeng; Wang, Guangyu; Yin, Zuojing; Li, Chuanxing; Cui, Yan; Zhou, Meng

    2014-11-01

    One important piece of information about the human Mendelian disorders is the mode of inheritance. Recent studies of human genetic diseases on a large scale have provided many novel insights into the underlying molecular mechanisms. However, most successful analyses ignored the mode of inheritance of diseases, which severely limits our understanding of human disease mechanisms relating to the mode of inheritance at the large scale. Therefore, we here conducted a systematic large-scale study of the inheritance mode of Mendelian disorders, to bring new insight into human diseases. Our analyses include the comparison between dominant and recessive disease genes on both genomic and proteomic characteristics, Mendelian mutations, protein network properties and disease connections on both the genetic and the population levels. We found that dominant disease genes are more functionally central, topological central and more sensitive to disease outcome. On the basis of these findings, we suggested that dominant diseases should have higher genetic heterogeneity and should have more comprehensive connections with each other compared with recessive diseases, a prediction we confirm by disease network and disease comorbidity.

  10. Darbishire expands his vision of heredity from Mendelian genetics to inherited memory.

    Science.gov (United States)

    Wood, Roger J

    2015-10-01

    The British biologist A.D. Darbishire (1879-1915) responded to the rediscovery in 1900 of Mendel's theory of heredity by testing it experimentally, first in Oxford, then in Manchester and London. He summarised his conclusions in a textbook 'Breeding and the Mendelian Discovery' (1911), in which he questioned whether Mendelism alone could explain all aspects of practical breeding experience. Already he had begun to think about an alternative theory to give greater emphasis to the widely held conviction among breeders regarding the inheritance of characteristics acquired during an individual's life. Redefining heredity in terms of a germ-plasm based biological memory, he used vocabulary drawn partly from sources outside conventional science, including the metaphysical/vitalistic writings of Samuel Butler and Henri Bergson. An evolving hereditary memory fitted well with the conception of breeding as a creative art aimed at greater economic efficiency. For evolution beyond human control he proposed a self-modifying process, claiming it to surpass in efficiency the chancy mechanism of natural selection proposed by Darwin. From his writings, including early chapters of an unfinished book entitled 'An Introduction to a Biology', we consider how he reached these concepts and how they relate to later advances in understanding the genome and the genetic programme. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. The Hidden Complexity of Mendelian Traits across Natural Yeast Populations

    Directory of Open Access Journals (Sweden)

    Jing Hou

    2016-07-01

    Full Text Available Mendelian traits are considered to be at the lower end of the complexity spectrum of heritable phenotypes. However, more than a century after the rediscovery of Mendel’s law, the global landscape of monogenic variants, as well as their effects and inheritance patterns within natural populations, is still not well understood. Using the yeast Saccharomyces cerevisiae, we performed a species-wide survey of Mendelian traits across a large population of isolates. We generated offspring from 41 unique parental pairs and analyzed 1,105 cross/trait combinations. We found that 8.9% of the cases were Mendelian. Further tracing of causal variants revealed background-specific expressivity and modified inheritances, gradually transitioning from Mendelian to complex traits in 30% of the cases. In fact, when taking into account the natural population diversity, the hidden complexity of traits could be substantial, confounding phenotypic predictability even for simple Mendelian traits.

  12. Why the Rediscoverer Ended up on the Sidelines: Hugo De Vries's Theory of Inheritance and the Mendelian Laws

    Science.gov (United States)

    Stamhuis, Ida H.

    2015-01-01

    Eleven years before the `rediscovery' in 1900 of Mendel's work, Hugo De Vries published his theory of heredity. He expected his theory to become a big success, but it was not well-received. To find supporting evidence for this theory De Vries started an extensive research program. Because of the parallels of his ideas with the Mendelian laws and because of his use of statistics, he became one of the rediscoverers. However, the Mendelian laws, which soon became the foundation of a new discipline of genetics, presented a problem. De Vries was the only one of the early Mendelians who had developed his own theory of heredity. His theory could not be brought in line with the Mendelian laws. But because his original theory was still very dear to him, something important was at stake and he was unwilling to adapt his ideas to the new situation. He belittled the importance of the Mendelian laws and ended up on the sidelines.

  13. Cytosine hypomethylation at CHG and CHH sites in the pleiotropic mutants of Mendelian inheritance in Catharanthus roseus.

    Science.gov (United States)

    Kumari, Renu; Yadav, Gitanjali; Sharma, Vishakha; Sharma, Vinay; Kumar, Sushil

    2013-12-01

    The 5S and 18S rDNA sequences of Catharanthus roseus cv 'Nirmal' (wild type) and its leafless inflorescence (lli), evergreen dwarf (egd) and irregular leaf lamina (ill) single mutants and lli egd, lli ill and egd ill double mutants were characterized. The lli, egd and ill mutants of Mendelian inheritance bore the names after their most conspicuous morphological feature(s). They had been chemically induced and isolated for their salt tolerance. The double mutants were isolated as morphological segregants from crosses between single mutants. The morphological features of the two parents accompanied salt tolerance in the double mutants. All the six mutants were hypomethylated at repeat sequences, upregulated and downregulated for many genes and carried pleiotropic alterations for several traits. Here the 5S and 18S rDNAs of C. roseus were found to be relatively low in cytosine content. Cytosines were preponderantly in CG context (53%) and almost all of them were methylated (97%). The cytosines in CHH and CHG (where H = A, T or C) contexts were largely demethylated (92%) in mutants. The demethylation was attributable to reduced expression of RDR2 and DRM2 led RNA dependant DNA methylation and CMT3 led maintenance methylation pathways. Mutants had gained some cytosines by substitution of C at T sites. These perhaps arose on account of errors in DNA replication, mediated by widespread cytosine demethylation at CHG and CHH sites. It was concluded that the regulation of cytosine ethylation mechanisms was disturbed in the mutants. ILL, EGD and LLI genes were identified as the positive regulators of other genes mediating the RdDM and CMT3 pathways, for establishment and maintenance of cytosine methylation in C. roseus.

  14. The Mendelian inheritance of rare flesh and shell colour variants in the black-lipped pearl oyster (Pinctada margaritifera).

    Science.gov (United States)

    Ky, Chin-Long; Nakasai, Seiji; Pommier, Steve; Sham Koua, Manaarii; Devaux, Dominique

    2016-10-01

    Pinctada margaritifera is French Polynesia's most economically important aquaculture species. This pearl oyster has the specific ability to produce cultured pearls with a very wide range of colours, depending on the colour phenotypes of donor oysters used. Its aquaculture is still based on natural spat collection from wild stocks. We investigated three rare colour variants of P. margaritifera - orange flesh, and red and white shell colour phenotypes - in comparison with the wild-type black flesh and shell commonly found in this species. The study aimed to assess the geographic distribution and genetic basis of these colour variants. Colour frequencies were evaluated during transfer and graft processes of pearl oyster seed captured at collector stations. Among the collection locations studied, Mangareva Island showed the highest rate of the orange flesh phenotype, whereas Takaroa and Takume atolls had relatively high rates of red and white shell phenotypes respectively. Broodstocks were made of these rare colour variants, and crosses were performed to produce first- and second-generation progenies to investigate segregation. The results were consistent with Mendelian ratios and suggest a distinct model with no co-dominance: (i) a two-allele model for flesh trait, whereby the orange allele is recessive to the black fleshed type, and (ii) a three-allele model for shell trait, whereby the black wild-type allele is dominant to the red coloration, which is dominant to the white shell. Furthermore, the proposed model provides the basis for producing selected donor pearl oyster lines through hatchery propagation. © 2016 Stichting International Foundation for Animal Genetics.

  15. CGMIM: Automated text-mining of Online Mendelian Inheritance in Man (OMIM to identify genetically-associated cancers and candidate genes

    Directory of Open Access Journals (Sweden)

    Jones Steven

    2005-03-01

    Full Text Available Abstract Background Online Mendelian Inheritance in Man (OMIM is a computerized database of information about genes and heritable traits in human populations, based on information reported in the scientific literature. Our objective was to establish an automated text-mining system for OMIM that will identify genetically-related cancers and cancer-related genes. We developed the computer program CGMIM to search for entries in OMIM that are related to one or more cancer types. We performed manual searches of OMIM to verify the program results. Results In the OMIM database on September 30, 2004, CGMIM identified 1943 genes related to cancer. BRCA2 (OMIM *164757, BRAF (OMIM *164757 and CDKN2A (OMIM *600160 were each related to 14 types of cancer. There were 45 genes related to cancer of the esophagus, 121 genes related to cancer of the stomach, and 21 genes related to both. Analysis of CGMIM results indicate that fewer than three gene entries in OMIM should mention both, and the more than seven-fold discrepancy suggests cancers of the esophagus and stomach are more genetically related than current literature suggests. Conclusion CGMIM identifies genetically-related cancers and cancer-related genes. In several ways, cancers with shared genetic etiology are anticipated to lead to further etiologic hypotheses and advances regarding environmental agents. CGMIM results are posted monthly and the source code can be obtained free of charge from the BC Cancer Research Centre website http://www.bccrc.ca/ccr/CGMIM.

  16. Pleiotropic phenotypes of the salt-tolerant and cytosine hypomethylated leafless inflorescence, evergreen dwarf and irregular leaf lamina mutants of Catharanthus roseus possessing Mendelian inheritance.

    Science.gov (United States)

    Kumari, Renu; Sharma, Vishakha; Sharma, Vinay; Kumar, Sushil

    2013-12-01

    In Catharanthus roseus, three morphological cum salt-tolerant chemically induced mutants of Mendelian inheritance and their wild-type parent cv Nirmal were characterized for overall cytosine methylation at DNA repeats, expression of 119 protein coding and seven miRNA-coding genes and 50 quantitative traits. The mutants, named after their principal morphological feature(s), were leafless inflorescence (lli), evergreen dwarf (egd) and irregular leaf lamina (ill). The Southern-blot analysis of MspI digested DNAs of mutants probed with centromeric and 5S and 18S rDNA probes indicated that, in comparison to wild type, the mutants were extensively demethylated at cytosine sites. Among the 126 genes investigated for transcriptional expression, 85 were upregulated and 41 were downregulated in mutants. All of the five genes known to be stress responsive had increased expression in mutants. Several miRNA genes showed either increased or decreased expression in mutants. The C. roseus counterparts of CMT3, DRM2 and RDR2 were downregulated in mutants. Among the cell, organ and plant size, photosynthesis and metabolism related traits studied, 28 traits were similarly affected in mutants as compared to wild type. Each of the mutants also expressed some traits distinctively. The egd mutant possessed superior photosynthesis and water retention abilities. Biomass was hyperaccumulated in roots, stems, leaves and seeds of the lli mutant. The ill mutant was richest in the pharmaceutical alkaloids catharanthine, vindoline, vincristine and vinblastine. The nature of mutations, origins of mutant phenotypes and evolutionary importance of these mutants are discussed.

  17. Evaluation of nose shape as a Mendelian‑inherited trait in the ...

    African Journals Online (AJOL)

    Background: Nose shape might be environmentally influenced; however, there are evidences of it being inherited in simple Mendelian dominant‑recessive patterns. In such instance, a nose can be broad or narrow with respect to its wideness in comparison to the intercanthal bridge. Therefore, this study was aimed at ...

  18. The Mendelian colorectal cancer syndromes.

    Science.gov (United States)

    Tomlinson, Ian

    2015-11-01

    A small minority of colorectal cancers (CRCs) (≤5%) are caused by a single, inherited faulty gene. These diseases, the Mendelian colorectal cancer (CRC) syndromes, have been central to our understanding of colorectal carcinogenesis in general. Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1). Lynch syndrome (MSH2, MLH1, MSH6, PMS2), by contrast, is associated primarily with cancer risk. Major functional pathways are consistently inactivated in the Mendelian CRC syndromes: certain types of DNA repair (proofreading of DNA replication errors, mismatch repair and base excision repair) and signalling (bone morphogenetic protein (BMP), Wnt signalling and mTOR). The inheritance of the CRC syndromes also varies: most are dominant but some of the DNA repair deficiencies are recessive. Some of the Mendelian CRC genes are especially important because they play a role through somatic inactivation in sporadic CRC (APC, MLH1, SMAD4, POLE). Additional Mendelian CRC genes may remain to be discovered and searches for these genes are ongoing, especially in patients with multiple adenomas and hyperplastic polyps. © The Author(s) 2015.

  19. The pre-Mendelian, pre-Darwinian world: Shifting relations between ...

    Indian Academy of Sciences (India)

    2005-03-11

    Mar 11, 2005 ... The reliable dependence of many features of contemporary organisms on changes in gene content and activity is tied to the processes of Mendelian inheritance and Darwinian evolution. With regard to morphological characters, however, Mendelian inheritance is the exception rather than the rule, and ...

  20. Autosomal recessive inheritance of goiter in Dutch goats

    NARCIS (Netherlands)

    Kok, K.; van Dijk, J. E.; Sterk, A.; Baas, F.; van Ommen, G. J.; de Vijlder, J. J.

    1987-01-01

    The inheritance of congenital goiter due to a thyroglobulin synthesis defect in a strain of Dutch goats has been studied by Mendelian and biochemical methods. Mendelian analysis of 301 matings, resulting in 591 kids, showed an autosomal recessive mode of inheritance. A restriction fragment length

  1. A simple PCR-based method for the rapid genotyping of inherited fifth complement component (C5)-deficient mice.

    Science.gov (United States)

    Wang, Qingkai; Wang, Na; Zhang, Xin; Hu, Weiguo

    2015-01-01

    The fifth component of complement (C5) is considered to be the center of complement activation and function. However, there are no genetically engineered knockout mice for this gene, and the only commercially available inherited C5-deficient mice, in which a "TA" nucleotide deletion in the coding frame was previously identified, are in theC57BL/10Sn genetic background rather than the commonly used backgrounds C57BL/6 and BALB/c. Therefore, these mice must be backcrossed into the desired genetic background. Here, we developed an ARMS (amplification refractory mutation system) PCR method using a specific primer pair that was able to discriminate between the genotypes when the resulting product was analyzed by agarose gel electrophoresis. These results were supported by quantitative RT-PCR and semi-quantitative PCR and were consistent with the results from sequencing each backcrossed generation. Using ARMS-PCR method, we generated C5-deficient mice in the C57BL/6 background over 9 backcrossed generations and further verified the phenotype using complement-mediated hemolytic assays. In this study, we describe a simple, rapid and reliable PCR-based method for genotyping inherited C5-deficient mice that may be used to backcross C57BL/10Sn mice into other genetic backgrounds.

  2. Human Toddlers’ Attempts to Match Two Simple Behaviors Provide No Evidence for an Inherited, Dedicated Imitation Mechanism

    Science.gov (United States)

    Jones, Susan S.

    2012-01-01

    Influential theories of imitation have proposed that humans inherit a neural mechanism – an “active intermodal matching “ (AIM) mechanism or a mirror neuron system - that functions from birth to automatically match sensory input from others’ actions to motor programs for performing those same actions, and thus produces imitation. To test these proposals, 160 1- to 2½-year-old toddlers were asked to imitate two simple movements– bending the arm to make an elbow, and moving the bent elbow laterally. Both behaviors were almost certain to be in each child’s repertoire, and the lateral movement was goal-directed (used to hit a plastic cup). Thus, one or both behaviors should have been imitable by toddlers with a functioning AIM or mirror neuron system. Each child saw the two behaviors repeated 18 times, and was encouraged to imitate. Children were also asked to locate their own elbows. Almost no children below age 2 imitated either behavior. Instead, younger children gave clear evidence of a developmental progression, from reproducing only the outcome of the models’ movements (hitting the object), through trying (but failing) to reproduce the model’s arm posture and/or the arm-cup relations they had seen, to accurate imitation of arm bending by age 2 and of both movements by age 2½. Across age levels, almost all children who knew the word ‘elbow’ imitated both behaviors: very few who did not know the word imitated either behavior. The evidence is most consistent with a view of early imitation as the product of a complex system of language, cognitive, social, and motor competencies that develop in infancy. The findings do not rule out a role for an inherited neural mechanism, but they suggest that such a system would not by itself be sufficient to explain imitation at any age. PMID:23251500

  3. Human toddlers' attempts to match two simple behaviors provide no evidence for an inherited, dedicated imitation mechanism.

    Science.gov (United States)

    Jones, Susan S

    2012-01-01

    Influential theories of imitation have proposed that humans inherit a neural mechanism - an "active intermodal matching " (AIM) mechanism or a mirror neuron system - that functions from birth to automatically match sensory input from others' actions to motor programs for performing those same actions, and thus produces imitation. To test these proposals, 160 1- to 2½-year-old toddlers were asked to imitate two simple movements- bending the arm to make an elbow, and moving the bent elbow laterally. Both behaviors were almost certain to be in each child's repertoire, and the lateral movement was goal-directed (used to hit a plastic cup). Thus, one or both behaviors should have been imitable by toddlers with a functioning AIM or mirror neuron system. Each child saw the two behaviors repeated 18 times, and was encouraged to imitate. Children were also asked to locate their own elbows. Almost no children below age 2 imitated either behavior. Instead, younger children gave clear evidence of a developmental progression, from reproducing only the outcome of the models' movements (hitting the object), through trying (but failing) to reproduce the model's arm posture and/or the arm-cup relations they had seen, to accurate imitation of arm bending by age 2 and of both movements by age 2½. Across age levels, almost all children who knew the word 'elbow' imitated both behaviors: very few who did not know the word imitated either behavior. The evidence is most consistent with a view of early imitation as the product of a complex system of language, cognitive, social, and motor competencies that develop in infancy. The findings do not rule out a role for an inherited neural mechanism, but they suggest that such a system would not by itself be sufficient to explain imitation at any age.

  4. Human toddlers' attempts to match two simple behaviors provide no evidence for an inherited, dedicated imitation mechanism.

    Directory of Open Access Journals (Sweden)

    Susan S Jones

    Full Text Available Influential theories of imitation have proposed that humans inherit a neural mechanism - an "active intermodal matching " (AIM mechanism or a mirror neuron system - that functions from birth to automatically match sensory input from others' actions to motor programs for performing those same actions, and thus produces imitation. To test these proposals, 160 1- to 2½-year-old toddlers were asked to imitate two simple movements- bending the arm to make an elbow, and moving the bent elbow laterally. Both behaviors were almost certain to be in each child's repertoire, and the lateral movement was goal-directed (used to hit a plastic cup. Thus, one or both behaviors should have been imitable by toddlers with a functioning AIM or mirror neuron system. Each child saw the two behaviors repeated 18 times, and was encouraged to imitate. Children were also asked to locate their own elbows. Almost no children below age 2 imitated either behavior. Instead, younger children gave clear evidence of a developmental progression, from reproducing only the outcome of the models' movements (hitting the object, through trying (but failing to reproduce the model's arm posture and/or the arm-cup relations they had seen, to accurate imitation of arm bending by age 2 and of both movements by age 2½. Across age levels, almost all children who knew the word 'elbow' imitated both behaviors: very few who did not know the word imitated either behavior. The evidence is most consistent with a view of early imitation as the product of a complex system of language, cognitive, social, and motor competencies that develop in infancy. The findings do not rule out a role for an inherited neural mechanism, but they suggest that such a system would not by itself be sufficient to explain imitation at any age.

  5. Common variants in mendelian kidney disease genes and their association with renal function

    NARCIS (Netherlands)

    A. Parsa (Afshin); C. Fuchsberger (Christian); A. Köttgen (Anna); C.M. O'Seaghdha (Conall); C. Pattaro (Cristian); M. de Andrade (Mariza); D.I. Chasman (Daniel); A. Teumer (Alexander); K. Endlich (Karlhans); M. Olden (Matthias); M-H. Chen (Ming-Huei); A. Tin (Adrienne); Y-J. Kim (Yong-Jin); D. Taliun (Daniel); M. Li (Man); M.F. Feitosa (Mary Furlan); M. Gorski (Mathias); Q. Yang (Qiong); C. Hundertmark (Claudia); M.C. Foster (Michael); N. Glazer (Nicole); A.J. Isaacs (Aaron); M. Rao (Madhumathi); G.D. Smith; J.R. O´Connell; M.V. Struchalin (Maksim); T. Tanaka (Toshiko); G. Li (Guo); S.J. Hwang; E.J. Atkinson (Elizabeth); K. Lohman (Kurt); M. Cornelis (Marilyn); A. Johansson (Åsa); A. Tönjes (Anke); A. Dehghan (Abbas); V. Couraki (Vincent); E.G. Holliday (Elizabeth); R. Sorice; Z. Kutalik (Zoltán); T. Lehtimäki (Terho); T. Esko (Tõnu); H. Deshmukh (Harshal); S. Ulivi (Shelia); A.Y. Chu (Audrey); D. Murgia (Daniela); S. Trompet (Stella); M. Imboden (Medea); B. Kollerits (Barbara); G. Pistis (Giorgio); T.B. Harris (Tamara); L.J. Launer (Lenore); T. Aspelund (Thor); G. Eiriksdottir (Gudny); B.D. Mitchell (Braxton); E.A. Boerwinkle (Eric); H. Schmidt (Helena); E. Hofer (Edith); F.B. Hu (Frank); A. Demirkan (Ayşe); B.A. Oostra (Ben); S.T. Turner (Stephen); J. Ding (Jinhui); J.S. Andrews (Jeanette); B.I. Freedman (Barry); F. Giulianini (Franco); W. Koenig (Wolfgang); T. Illig (Thomas); A. Döring (Angela); H.E. Wichmann (Heinz Erich); L. Zgaga (Lina); T. Zemunik (Tatijana); M. Boban (Mladen); C. Minelli (Cosetta); H.E. Wheeler (Heather); W. Igl (Wilmar); G. Zaboli (Ghazal); S.H. Wild (Sarah); A.F. Wright (Alan); H. Campbell (Harry); D. Ellinghaus (David); U. Nöthlings (Ute); G. Jacobs (Gunnar); R. Biffar (Reiner); F.D.J. Ernst (Florian); G. Homuth (Georg); H.K. Kroemer (Heyo); M. Nauck (Matthias); S. Stracke (Sylvia); U. Vol̈ker (Uwe); H. Völzke (Henry); P. Kovacs (Peter); M. Stumvoll (Michael); R. Mägi (Reedik); A. Hofman (Albert); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); Y.S. Aulchenko (Yurii); O. Polasek (Ozren); N. Hastie (Nick); V. Vitart (Veronique); C. Helmer (Catherine); J.J. Wang (Jie Jin); B. Stengel (Bernd); D. Ruggiero; S.M. Bergmann (Sven); M. Kähönen (Mika); J. Viikari (Jorma); T. Nikopensius (Tiit); M.A. Province (Mike); H.M. Colhoun (H.); A.S.F. Doney (Alex); A. Robino (Antonietta); B.K. Krämer (Bernhard); L. Portas (Laura); I. Ford (Ian); B.M. Buckley (Brendan M.); M. Adam (Martin); G.-A. Thun (Gian-Andri); B. Paulweber (Bernhard); M. Haun (Margot); C. Sala (Cinzia); P. Mitchell (Paul); M. Ciullo; P. Vollenweider (Peter); O. Raitakari (Olli); A. Metspalu (Andres); C.N.A. Palmer (Colin); P. Gasparini (Paolo); M. Pirastu (Mario); J.W. Jukema (Jan Wouter); N.M. Probst-Hensch (Nicole M.); F. Kronenberg (Florian); D. Toniolo (Daniela); V. Gudnason (Vilmundur); A.R. Shuldiner (Alan); J. Coresh (Josef); R. Schmidt (Reinhold); L. Ferrucci (Luigi); C.M. van Duijn (Cornelia); I.B. Borecki (Ingrid); S.L.R. Kardia (Sharon); Y. Liu (Yongmei); G.C. Curhan (Gary); I. Rudan (Igor); U. Gyllensten (Ulf); J.F. Wilson (James); A. Franke (Andre); P.P. Pramstaller (Peter Paul); R. Rettig (Rainer); I. Prokopenko (Inga); J.C.M. Witteman (Jacqueline); C. Hayward (Caroline); P.M. Ridker (Paul); M. Bochud (Murielle); I.M. Heid (Iris); D.S. Siscovick (David); C.S. Fox (Caroline); W.H.L. Kao (Wen); C.A. Böger (Carsten)

    2013-01-01

    textabstractMany common genetic variants identified by genome-wide association studies for complex traitsmap to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with

  6. Teaching Mendelian Genetics with the Computer.

    Science.gov (United States)

    Small, James W., Jr.

    Students in general undergraduate courses in both biology and genetics seem to have great difficulty mastering the basic concepts of Mendelian Genetics and solving even simple problems. In an attempt to correct this situation, students in both courses at Rollins College were introduced to three simulation models of the genetics of the fruit…

  7. Mendelian Randomization versus Path Models: Making Causal Inferences in Genetic Epidemiology.

    Science.gov (United States)

    Ziegler, Andreas; Mwambi, Henry; König, Inke R

    2015-01-01

    The term Mendelian randomization is popular in the current literature. The first aim of this work is to describe the idea of Mendelian randomization studies and the assumptions required for drawing valid conclusions. The second aim is to contrast Mendelian randomization and path modeling when different 'omics' levels are considered jointly. We define Mendelian randomization as introduced by Katan in 1986, and review its crucial assumptions. We introduce path models as the relevant additional component to the current use of Mendelian randomization studies in 'omics'. Real data examples for the association between lipid levels and coronary artery disease illustrate the use of path models. Numerous assumptions underlie Mendelian randomization, and they are difficult to be fulfilled in applications. Path models are suitable for investigating causality, and they should not be mixed up with the term Mendelian randomization. In many applications, path modeling would be the appropriate analysis in addition to a simple Mendelian randomization analysis. Mendelian randomization and path models use different concepts for causal inference. Path modeling but not simple Mendelian randomization analysis is well suited to study causality with different levels of 'omics' data. 2015 S. Karger AG, Basel.

  8. Flower Colour Inheritance in Nicotiana alata (Solanaceae) and its ...

    African Journals Online (AJOL)

    In Nicotiana alata, flower colour inheritance has followed Mendelian inheritance with dark colours being dominant over lighter colours. Reciprocal crosses concluded the absence of the cytoplasm involvement in the determination of flower colour. The backcross confirmed the dominant nature of red as the backcross ...

  9. Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes.

    Science.gov (United States)

    Benoit, Geneviève; Machuca, Eduardo; Heidet, Laurence; Antignac, Corinne

    2010-12-01

    A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function. The identification of genes involved in congenital anomalies of the kidney and in familial forms of nephrotic syndrome significantly increased our understanding of the renal development and kidney filtration barrier physiology. This review will focus on the classical phenotype and clinical heterogeneity observed in the monogenic forms of these disorders. In addition, the role of susceptibility genes in kidney diseases with a complex inheritance will also be discussed. © 2010 New York Academy of Sciences.

  10. Using zebrafish to learn statistical analysis and Mendelian genetics.

    Science.gov (United States)

    Lindemann, Samantha; Senkler, Jon; Auchter, Elizabeth; Liang, Jennifer O

    2011-06-01

    This project was developed to promote understanding of how mathematics and statistical analysis are used as tools in genetic research. It gives students the opportunity to carry out hypothesis-driven experiments in the classroom: students generate hypotheses about Mendelian and non-Mendelian inheritance patterns, gather raw data, and test their hypotheses using chi-square statistical analysis. In the first protocol, students are challenged to analyze inheritance patterns using GloFish, brightly colored, commercially available, transgenic zebrafish that express Green, Yellow, or Red Fluorescent Protein throughout their muscles. In the second protocol, students learn about genetic screens, microscopy, and developmental biology by analyzing the inheritance patterns of mutations that cause developmental defects. The difficulty of the experiments can be adapted for middle school to upper level undergraduate students. Since the GloFish experiments use only fish and materials that can be purchased from pet stores, they should be accessible to many schools. For each protocol, we provide detailed instructions, ideas for how the experiments fit into an undergraduate curriculum, raw data, and example analyses. Our plan is to have these protocols form the basis of a growing and adaptable educational tool available on the Zebrafish in the Classroom Web site.

  11. Can we apply the Mendelian randomization methodology without considering epigenetic effects?

    Directory of Open Access Journals (Sweden)

    Karmaus Wilfried

    2009-05-01

    considerations, algebraic derivations and data simulations to question the appropriateness of Mendelian randomization methods when epigenetic modifications are present. Conclusion Given an inheritance of gene expression from parents, Mendelian randomization studies not only need to assume a random distribution of alleles in the offspring, but also a random distribution of epigenetic changes (e.g. gene expression at conception, in order for the core assumptions of the Mendelian randomization methodology to remain valid. As an increasing number of epidemiologists employ Mendelian randomization methods in their research, caution is therefore needed in drawing conclusions from these studies if these assumptions are not met.

  12. Women as Mendelians and Geneticists

    Science.gov (United States)

    Richmond, Marsha L.

    2015-01-01

    After the rediscovery of Mendel's laws of heredity in 1900, the biologists who began studying heredity, variation, and evolution using the new Mendelian methodology--performing controlled hybrid crosses and statistically analyzing progeny to note the factorial basis of characters--made great progress. By 1910, the validity of Mendelism was…

  13. Inheriting geodesic flows

    Indian Academy of Sciences (India)

    Abstract. We investigate the propagation equations for the expansion, vorticity and shear for per- fect fluid space-times which are geodesic. It is assumed that space-time admits a conformal Killing vector which is inheriting so that fluid flow lines are mapped conformally. Simple constraints on the electric and magnetic parts of ...

  14. Inheritance and identification of SCAR marker linked to bacterial wilt ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... resistance in eggplant was controlled by a single dominant gene showing Mendelian inheritance model. In addition, a 762 bp molecular marker ... solarization, to change soil pH and reduce survival and activity of plant pathogens ..... hence to better understanding of the genetic control of the resistance(s).

  15. Investigating the inheritance of prolapsed nictitating membrane glands in a large canine pedigree.

    Science.gov (United States)

    Edelmann, Michele L; Miyadera, Keiko; Iwabe, Simone; Komáromy, András M

    2013-11-01

    To investigate the inheritance of prolapsed nictitating membrane glands (PNMG) in a large pedigree of purpose-bred mongrel dogs. Two lines of purpose-bred mongrel dogs kept at a research facility with controlled environment were analyzed for frequent occurrences of PNMG. The first line (GS line) consisted of 201 dogs, derived from one German shorthaired pointer and seven mongrel dogs. The second line (M line) was established from one mongrel dog and three miniature longhaired dachshund (MLHD) dogs followed by closed breeding practice (n = 50). The two canine lines were connected by a female dog, which contributed genetically to both lines. Medical records of all dogs were reviewed retrospectively for signalment, parental data, and the presence of PNMG. Pedigrees were constructed to facilitate assessment of inheritance. The overall prevalence of PNMG in the GS line was 4.0% (8/201) over a 12-year period. The prevalence in the M line was 10.0% (5/50) over 6 years, which increased to 23.1% (3/13) when only dogs aged 2 years or older were considered. Analysis of the pedigrees ruled out simple modes of Mendelian inheritance in both canine lines. The high prevalence of PNMG in two canine lines bred and maintained under a strictly controlled environment supported the involvement of genetic risk factors. The mode of inheritance remains to be determined, but it appears to be complex and potentially multigenic. © 2012 American College of Veterinary Ophthalmologists.

  16. To inherit heritage or to inherit inheritance?

    Directory of Open Access Journals (Sweden)

    Vladimir Krivošejev

    2016-02-01

    Full Text Available The Republic of Serbia is one of the few, if not the only country in the world that, at ratification and translation of the term „baština“– heritage which appears in two significant and related international conventions of UNESCO, used different terms: „baština“– „heritage“, with regard to the Convention Concerning the Protection of the World Cultural and Natural Heritage, and „nasledje“ –inheritance in the Convention for the Safeguarding of the Intangible Cultural Heritage. One of the reasons for the subsequent rejection of the term heritage could lay in the opinion that it was the case of (end of 20th and beginning of the 21st century political bureaucratic introduction of an old, forgotten word, which also contains the notion of gender incorrectness based on pointing out the inheritance through the male line, which could be in conflict with international law. The views expressed in this paper suggest the unsustainability of these claims, as well as greater suitability of the term „baština“– heritage. Namely, the ratification of the Convention Concerning the Protection of the World Cultural and Natural Heritage was done as early as in 1974, and since then the term „baština“– heritage was used, its new introduction into use on the basis of recent daily political aspirations cannot be the case. At the same time inheritance through the male line is encountered with the use of the Latin word „patrimonium“, which is the basis for the terms used in the official translation of the UNESCO-listed conventions in French and Spanish: „patrimoine“ and „patrimonio“ (and other Roman languages so that the use of the term „baština“ –heritage cannot be a violation of international legal norms. Finally, bearing in mind the fact that, in general, use of languages is impossible to achieve complete gender purism, it is necessary to emphasize that in contrast to the term „nasledje“ – inheritance, the

  17. Inherited sodium avid states.

    Science.gov (United States)

    Achard, Jean-Michel; Hadchouel, Juliette; Faure, Sébastien; Jeunemaitre, Xavier

    2006-04-01

    Several familial forms of hypertension have been identified, in which the mendelian pattern of inheritance indicated that hypertension results from the alteration of a single gene. This short review focuses on those rare monogenic disorders characterized by a low-renin profile. This common feature reflects that the causative mutations responsible for these disorders all result in an excessive sodium reabsorption in the aldosterone-dependent nephron. Low-renin familial hypertensions with hypokalemia encompass familial hyperaldosteronisms, in which aldosterone levels are elevated, and familial pseudohyperaldosteronisms, mimicking aldosteronism despite appropriately suppressed aldosterone levels. In these disorders, the avidity of the kidney for sodium is because of dysregulated sodium reabsorption through the epithelial sodium channel ENaC and results in potassium wasting and metabolic alcalosis. Familial hypertension with hyperkalemia is a specific syndrome resulting from mutations in at least 3 different genes, among which 2 have been recently identified. These genes encode members of a new family of kinase, the WNK kinases, involved in the regulation of sodium and potassium excretion by the kidney.

  18. Mendelian and non-Mendelian regulation of gene expression in maize.

    Directory of Open Access Journals (Sweden)

    Lin Li

    Full Text Available Transcriptome variation plays an important role in affecting the phenotype of an organism. However, an understanding of the underlying mechanisms regulating transcriptome variation in segregating populations is still largely unknown. We sought to assess and map variation in transcript abundance in maize shoot apices in the intermated B73 × Mo17 recombinant inbred line population. RNA-based sequencing (RNA-seq allowed for the detection and quantification of the transcript abundance derived from 28,603 genes. For a majority of these genes, the population mean, coefficient of variation, and segregation patterns could be predicted by the parental expression levels. Expression quantitative trait loci (eQTL mapping identified 30,774 eQTL including 96 trans-eQTL "hotspots," each of which regulates the expression of a large number of genes. Interestingly, genes regulated by a trans-eQTL hotspot tend to be enriched for a specific function or act in the same genetic pathway. Also, genomic structural variation appeared to contribute to cis-regulation of gene expression. Besides genes showing Mendelian inheritance in the RIL population, we also found genes whose expression level and variation in the progeny could not be predicted based on parental difference, indicating that non-Mendelian factors also contribute to expression variation. Specifically, we found 145 genes that show patterns of expression reminiscent of paramutation such that all the progeny had expression levels similar to one of the two parents. Furthermore, we identified another 210 genes that exhibited unexpected patterns of transcript presence/absence. Many of these genes are likely to be gene fragments resulting from transposition, and the presence/absence of their transcripts could influence expression levels of their ancestral syntenic genes. Overall, our results contribute to the identification of novel expression patterns and broaden the understanding of transcriptional variation in

  19. Mendelian and Non-Mendelian Regulation of Gene Expression in Maize

    Science.gov (United States)

    Li, Lin; Petsch, Katherine; Shimizu, Rena; Liu, Sanzhen; Xu, Wayne Wenzhong; Ying, Kai; Yu, Jianming; Scanlon, Michael J.; Schnable, Patrick S.; Timmermans, Marja C. P.; Springer, Nathan M.; Muehlbauer, Gary J.

    2013-01-01

    Transcriptome variation plays an important role in affecting the phenotype of an organism. However, an understanding of the underlying mechanisms regulating transcriptome variation in segregating populations is still largely unknown. We sought to assess and map variation in transcript abundance in maize shoot apices in the intermated B73×Mo17 recombinant inbred line population. RNA–based sequencing (RNA–seq) allowed for the detection and quantification of the transcript abundance derived from 28,603 genes. For a majority of these genes, the population mean, coefficient of variation, and segregation patterns could be predicted by the parental expression levels. Expression quantitative trait loci (eQTL) mapping identified 30,774 eQTL including 96 trans-eQTL “hotspots,” each of which regulates the expression of a large number of genes. Interestingly, genes regulated by a trans-eQTL hotspot tend to be enriched for a specific function or act in the same genetic pathway. Also, genomic structural variation appeared to contribute to cis-regulation of gene expression. Besides genes showing Mendelian inheritance in the RIL population, we also found genes whose expression level and variation in the progeny could not be predicted based on parental difference, indicating that non-Mendelian factors also contribute to expression variation. Specifically, we found 145 genes that show patterns of expression reminiscent of paramutation such that all the progeny had expression levels similar to one of the two parents. Furthermore, we identified another 210 genes that exhibited unexpected patterns of transcript presence/absence. Many of these genes are likely to be gene fragments resulting from transposition, and the presence/absence of their transcripts could influence expression levels of their ancestral syntenic genes. Overall, our results contribute to the identification of novel expression patterns and broaden the understanding of transcriptional variation in plants. PMID

  20. Segregation analysis suggests that keratoconus is a complex non-mendelian disease.

    Science.gov (United States)

    Kriszt, Agnes; Losonczy, Gergely; Berta, András; Vereb, György; Takács, Lili

    2014-11-01

    Complex segregation analysis of 60 unrelated sporadic keratoconus (KC) families was performed to reveal the presumed mode of inheritance in our dataset. Sixty probands, 212 family members and 212 age and gender matched healthy controls underwent clinical and videokeratographic examination. Family aggregation and distribution of videokeratography parameters were examined. Segregation of KSI, KISA and 6mm Fourier asymmetry alone or in covariate analysis with gender or the presence of Fleischer ring, exploring mendelian and non-mendelian models of inheritance was tested using complex segregation analysis with the S.A.G.E. program package. In 145 relatives of probands, the estimated prevalence of manifest KC was 7.6% (95% CI: 3.3-11.9) based on KISA index, indicating strong familial aggregation. All examined videokeratography indices were able to differentiate between KC and non-KC family members as well as normal controls (anova p 0.1) for all indices indicated the presence of a non-mendelian major gene effect (MG). Inclusion of Fleischer ring as covariate improved the fit of MG models. Mendelian, Sporadic and polygenic models were consistently rejected. Complex segregation analysis indicates a strong genetic contribution to the transmission of keratoconus. Inheritance is most probably due to a non-mendelian major gene effect. Low genotype-phenotype correlation in sporadic KC families can make linkage studies difficult, thus genome wide association studies, epigenetic and pathway analyses may provide more information on disease pathogenesis in non-familial keratoconus. © 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  1. Randomly amplified DNA polymorphisms in dogs are reproducible and display Mendelian transmission.

    Science.gov (United States)

    Rothuizen, J; Van Wolferen, M

    1994-02-01

    Many inherited diseases occur in pure-bred dogs, but diagnosis at the level of DNA is impossible because the canine genome is largely unknown. Random amplification of polymorphic DNA (RAPD) provides many polymorphisms, but the reproducibility and Mendelian inheritance are not beyond doubt. An optimized polymerase chain reaction (PCR) was developed for canine DNA with respect to the annealing temperature and the concentrations of MgCl2, template DNA and primers. RAPD amplification products were in the range of 100-1500 base pairs. With six primers, 21 different reactions with different electrophoretic patterns were obtained, yielding 9-29 products per reaction. In DNA from dogs of 16 different breeds, 14% of the products were polymorphic; when only beagles were included the rate of polymorphism was 10%. All of the reaction products were completely reproducible in 16 DNA samples. Mendelian transmission was analysed in six beagle families (42 dogs). The segregation of polymorphic amplification products in 21 reactions performed on DNA from all beagles was nearly complete; in only two of the 630 reactions was there a product that could not be traced back to either of the parents. The reproducibility and Mendelian behaviour of polymorphisms generated by RAPD in dogs makes this tool very suitable for development of DNA markers of canine inherited diseases.

  2. Discovery of mutations for Mendelian disorders.

    Science.gov (United States)

    Alkuraya, Fowzan S

    2016-06-01

    Mendelian mutations are the most medically actionable variants in the human genome and have always played a central role in its functional annotation. Despite the relative ease with which Mendelian mutations are identified compared to other classes of variants, the pace of their discovery has until recently been slow. However, recent technological advances in genomic sequencing have made the prospect of identifying all genes that can harbor Mendelian mutations an achievable near-term goal. The many lessons learned from previous discoveries of Mendelian mutations should inform future studies as I will discuss in this review. Also discussed are some of the challenges that will gain more prominence as we approach the last phase of the effort to map all Mendelian genes.

  3. Women as Mendelians and Geneticists

    Science.gov (United States)

    Richmond, Marsha L.

    2015-01-01

    After the rediscovery of Mendel's laws of heredity in 1900, the biologists who began studying heredity, variation, and evolution using the new Mendelian methodology—performing controlled hybrid crosses and statistically analyzing progeny to note the factorial basis of characters—made great progress. By 1910, the validity of Mendelism was widely recognized and the field William Bateson christened `genetics' was complemented by the chromosome theory of heredity of T. H. Morgan and his group in the United States. Historians, however, have largely overlooked an important factor in the early establishment of Mendelism and genetics: the large number of women who contributed to the various research groups. This article examines the social, economic, and disciplinary context behind this new wave of women's participation in science and describes the work of women Mendelians and geneticists employed at three leading experimental research institutes, 1900-1940. It argues that the key to more women working in science was the access to higher education and the receptivity of emerging interdisciplinary fields such as genetics to utilize the expertise of women workers, which not only advanced the discipline but also provided new opportunities for women's employment in science.

  4. The Centers for Mendelian Genomics: a new large-scale initiative to identify the genes underlying rare Mendelian conditions

    OpenAIRE

    Bamshad, Michael J.; Shendure, Jay A.; Rieder, Mark J.; Valle, David; Hamosh, Ada; James R Lupski; Gibbs, Richard A.; Boerwinkle, Eric; Lifton, Rick P.; Gerstein, Mark; Gunel, Murat; Mane, Shrikant; Nickersonon, Deborah A.

    2012-01-01

    Next generation exome sequencing (ES) and whole genome sequencing (WGS) are new powerful tools for discovering the gene(s) that underlie Mendelian disorders. To accelerate these discoveries, the National Institutes of Health has established three Centers for Mendelian Genomics (CMGs): the Center for Mendelian Genomics at the University of Washington; the Center for Mendelian Disorders at Yale University; and the Baylor-Johns Hopkins Center for Mendelian Genomics at Baylor College of Medicine ...

  5. The Mathematical Basis of Mendelian Genetics

    Science.gov (United States)

    Dudley, B.

    1972-01-01

    Applies set theory to the mono- and dihybrid Mendelian genetic crosses, multiple allelism, sex linkage, and linkage to show the application of mathematics to biology teaching (and of biology examples to mathematics instruction). (AL)

  6. Introducing Mendelian Genetics Through a Learning Cycle.

    Science.gov (United States)

    Lawson, Anton E.

    1996-01-01

    Presents activities that use the learning cycle to engage students in meaningful inquiries in the study of Mendelian genetics. Includes content-related background and teaching tips for each phase of the learning cycle. (JRH)

  7. DETECTION OF MENDELIAN AND GENOTYPE FREQUENCY OF GROWTH HORMONE GENE IN ONGOLE CROSSBRED CATTLE MATED BY THE ARTIFICIAL INSEMINATION TECHNIQUE

    Directory of Open Access Journals (Sweden)

    U. Paputungan

    2012-06-01

    Full Text Available The objectives of this study were to detect the Mendelian mode inheritance of growth hormone (GH and to establish genotype frequency of GH gene in Ongole-crossbred cattle mated by the artificial insemination (AI technique. Total of 76 blood samples were collected from Ongole-crossbred cows and bulls (G0, and their progenies (G1 at the Tumaratas AI service center in North Sulawesi province, Indonesia. All blood samples were screened for the presence of GH locus using a PCR-RFLP method involving restricted enzyme Msp1 on 1.2 % of agarose gel. Data were analyzed using statistical program function in Excel XP. The results showed that GH locus using alleles of Msp1+ and Msp1- enzyme restriction in Ongole-crossbred cows and bulls was inherited to their Ongole-crossbred progenies following the Mendelian mode inheritance. This Mendelian inheritance generated by AI technique was not under genetic equilibrium for the Msp1 genotype frequencies in groups of G0 and G1. The breeding program using genotypes of bulls and cows (G0 for generating the genotype of GH Msp1 enzyme restriction by AI technique should be maintained to increase these various allele dispersion rates for breeding under genetic equilibrium of the Ongole-crossbred cattle population.

  8. Mendelian and non-mendelian mutations affecting surface antigen expression in Paramecium tetraurelia

    Energy Technology Data Exchange (ETDEWEB)

    Epstein, L.M.; Forney, J.D.

    1984-08-01

    A screening procedure was devised for the isolation of X-ray-induced mutations affecting the expression of the A immobilization antigen (i-antigen) in Paramecium tetraurelia. Two of the mutations isolated by this procedure proved to be in modifier genes. The two genes are unlinked to each other and unlinked to the structural A i-antigen gene. These are the first modifier genes identified in a Paramecium sp. that affect surface antigen expression. Another mutation was found to be a deletion of sequences just downstream from the A i-antigen gene. In cells carrying this mutation, the A i-antigen gene lies in close proximity to the end of a macronuclear chromosome. The expression of the A i-antigen is not affected in these cells, demonstrating that downstream sequences are not important for the regulation and expression of the A i-antigen gene. A stable cell line was also recovered which shows non-Mendelian inheritance of a macronuclear deletion of the A i-antigen gene. This mutant does not contain the gene in its macronucleus, but contains a complete copy of the gene in its micronucleus. In the cytoplasm of wild-type animals, the micronuclear gene is included in the developing macronucleus; in the cytoplasm of the mutant, the incorporation of the A i-antigen gene into the macronucleus is inhibited. This is the first evidence that a mechanism is available in ciliates to control the expression of a gene by regulating its incorporation into developing macronuclei.

  9. Mendelian and non-mendelian mutations affecting surface antigen expression in Paramecium tetraurelia.

    Science.gov (United States)

    Epstein, L M; Forney, J D

    1984-08-01

    A screening procedure was devised for the isolation of X-ray-induced mutations affecting the expression of the A immobilization antigen (i-antigen) in Paramecium tetraurelia. Two of the mutations isolated by this procedure proved to be in modifier genes. The two genes are unlinked to each other and unlinked to the structural A i-antigen gene. These are the first modifier genes identified in a Paramecium sp. that affect surface antigen expression. Another mutation was found to be a deletion of sequences just downstream from the A i-antigen gene. In cells carrying this mutation, the A i-antigen gene lies in close proximity to the end of a macronuclear chromosome. The expression of the A i-antigen is not affected in these cells, demonstrating that downstream sequences are not important for the regulation and expression of the A i-antigen gene. A stable cell line was also recovered which shows non-Mendelian inheritance of a macronuclear deletion of the A i-antigen gene. This mutant does not contain the gene in its macronucleus, but contains a complete copy of the gene in its micronucleus. In the cytoplasm of wild-type animals, the micronuclear gene is included in the developing macronucleus; in the cytoplasm of the mutant, the incorporation of the A i-antigen gene into the macronucleus is inhibited. This is the first evidence that a mechanism is available in ciliates to control the expression of a gene by regulating its incorporation into developing macronuclei.

  10. Cootie Genetics: Simulating Mendel's Experiments to Understand the Laws of Inheritance

    Science.gov (United States)

    Galloway, Katelyn; Anderson, Nadja

    2014-01-01

    "Cootie Genetics" is a hands-on, inquiry-based activity that enables students to learn the Mendelian laws of inheritance and gain an understanding of genetics principles and terminology. The activity begins with two true-breeding Cooties of the same species that exhibit five observable trait differences. Students observe the retention or…

  11. Inheritance of most X-linked traits is not dominant or recessive, just X-linked

    NARCIS (Netherlands)

    Dobyns, WB; Filauro, A; Tomson, BN; Chan, AS; Ho, AW; Ting, NT; Oosterwijk, JC; Ober, C

    2004-01-01

    The existence of X-linked disorders in humans has been recognized for many centuries, based on lessons in religious texts and observations of specific human families (e.g., color blindness or Daltonism). Our modern concepts of Mendelian (including X-linked) inheritance originated just after the turn

  12. The Centers for Mendelian Genomics: a new large-scale initiative to identify the genes underlying rare Mendelian conditions.

    Science.gov (United States)

    Bamshad, Michael J; Shendure, Jay A; Valle, David; Hamosh, Ada; Lupski, James R; Gibbs, Richard A; Boerwinkle, Eric; Lifton, Richard P; Gerstein, Mark; Gunel, Murat; Mane, Shrikant; Nickerson, Deborah A

    2012-07-01

    Next generation exome sequencing (ES) and whole genome sequencing (WGS) are new powerful tools for discovering the gene(s) that underlie Mendelian disorders. To accelerate these discoveries, the National Institutes of Health has established three Centers for Mendelian Genomics (CMGs): the Center for Mendelian Genomics at the University of Washington; the Center for Mendelian Genomics at Yale University; and the Baylor-Johns Hopkins Center for Mendelian Genomics at Baylor College of Medicine and Johns Hopkins University. The CMGs will provide ES/WGS and extensive analysis expertise at no cost to collaborating investigators where the causal gene(s) for a Mendelian phenotype has yet to be uncovered. Over the next few years and in collaboration with the global human genetics community, the CMGs hope to facilitate the identification of the genes underlying a very large fraction of all Mendelian disorders; see http://mendelian.org. Copyright © 2012 Wiley Periodicals, Inc.

  13. Sickle cell disease resulting from uniparental disomy in a child who inherited sickle cell trait.

    Science.gov (United States)

    Swensen, Jeffrey J; Agarwal, Archana M; Esquilin, Jose M; Swierczek, Sabina; Perumbeti, Ajay; Hussey, Dottie; Lee, Margaret; Joiner, Clinton H; Pont-Kingdon, Genevieve; Lyon, Elaine; Prchal, Josef T

    2010-10-14

    Sickle cell disease (SCD) is a classic example of a disorder with recessive Mendelian inheritance, in which each parent contributes one mutant allele to an affected offspring. However, there are exceptions to that rule. We describe here the first reported case of conversion of inherited sickle cell trait to SCD by uniparental disomy (UPD) resulting in mosaicism for SS and AS erythrocytes. A 14-year-old boy presented with splenomegaly and hemolysis. Although his father has sickle cell trait, his mother has no abnormal hemoglobin (Hb). DNA sequencing, performed to rule out Hb S/β-thalassemia, detected homozygous Hb SS. Further studies revealed mosaic UPD of the β-globin locus, more SS erythroid progenitors than AS, but a reverse ratio of erythrocytes resulting from the survival advantage of AS erythrocytes. This report exemplifies non-Mendelian genetics wherein a patient who inherited sickle cell trait has mild SCD resulting from postzygotic mitotic recombination leading to UPD.

  14. Genes that bias Mendelian segregation.

    Directory of Open Access Journals (Sweden)

    Pierre Grognet

    Full Text Available Mendel laws of inheritance can be cheated by Meiotic Drive Elements (MDs, complex nuclear genetic loci found in various eukaryotic genomes and distorting segregation in their favor. Here, we identify and characterize in the model fungus Podospora anserina Spok1 and Spok2, two MDs known as Spore Killers. We show that they are related genes with both spore-killing distorter and spore-protecting responder activities carried out by the same allele. These alleles act as autonomous elements, exert their effects independently of their location in the genome and can act as MDs in other fungi. Additionally, Spok1 acts as a resistance factor to Spok2 killing. Genetical data and cytological analysis of Spok1 and Spok2 localization during the killing process suggest a complex mode of action for Spok proteins. Spok1 and Spok2 belong to a multigene family prevalent in the genomes of many ascomycetes. As they have no obvious cellular role, Spok1 and Spok2 Spore Killer genes represent a novel kind of selfish genetic elements prevalent in fungal genome that proliferate through meiotic distortion.

  15. Genes that bias Mendelian segregation.

    Science.gov (United States)

    Grognet, Pierre; Lalucque, Hervé; Malagnac, Fabienne; Silar, Philippe

    2014-01-01

    Mendel laws of inheritance can be cheated by Meiotic Drive Elements (MDs), complex nuclear genetic loci found in various eukaryotic genomes and distorting segregation in their favor. Here, we identify and characterize in the model fungus Podospora anserina Spok1 and Spok2, two MDs known as Spore Killers. We show that they are related genes with both spore-killing distorter and spore-protecting responder activities carried out by the same allele. These alleles act as autonomous elements, exert their effects independently of their location in the genome and can act as MDs in other fungi. Additionally, Spok1 acts as a resistance factor to Spok2 killing. Genetical data and cytological analysis of Spok1 and Spok2 localization during the killing process suggest a complex mode of action for Spok proteins. Spok1 and Spok2 belong to a multigene family prevalent in the genomes of many ascomycetes. As they have no obvious cellular role, Spok1 and Spok2 Spore Killer genes represent a novel kind of selfish genetic elements prevalent in fungal genome that proliferate through meiotic distortion.

  16. Statistical guidance for experimental design and data analysis of mutation detection in rare monogenic mendelian diseases by exome sequencing.

    Directory of Open Access Journals (Sweden)

    Degui Zhi

    Full Text Available Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying rare Mendelian disease genes, we propose that a viable approach is to combine, sequence, and analyze patients with the same disease together, leveraging the statistical framework presented in this work.

  17. The struggle to find reliable results in exome sequencing data: Filtering out Mendelian errors

    Directory of Open Access Journals (Sweden)

    Zubin Hasmukh Patel

    2014-02-01

    Full Text Available Next Generation Sequencing studies generate a large quantity of genetic data in a relatively cost and time efficient manner and provide an unprecedented opportunity to identify candidate causative variants that lead to disease phenotypes. A challenge to these studies is the generation of sequencing artifacts by current technologies. To identify and characterize the properties that distinguish false positive variants from true variants, we sequenced a child and both parents (trio using DNA isolated from three sources (blood, buccal cells, and saliva. The trio strategy allowed us to identify variants in the proband that could not have been inherited from the parents (Mendelian errors and would most likely indicate sequencing artifacts. Quality control measurements were examined and three measurements were found to identify the greatest number of Mendelian errors. These included read depth, genotype quality score, and alternate allele ratio. Filtering the variants on these measurements removed ~95% of the Mendelian errors while retaining 80% of the called variants. These filters were applied independently. After filtering, the concordance between identical samples isolated from different sources was 99.99% as compared to 87% before filtering. This high concordance suggests that different sources of DNA can be used in trio studies without affecting the ability to identify causative polymorphisms. To facilitate analysis of next generation sequencing data, we developed the Cincinnati Analytical Suite for Sequencing Informatics (CASSI to store sequencing files, metadata (e.g. relatedness information, file versioning, data filtering, variant annotation, and identify candidate causative polymorphisms that follow either de novo, rare recessive homozygous or compound heterozygous inheritance models. We conclude the data cleaning process improves the signal to noise ratio in terms of variants and facilitates the identification of candidate disease causative

  18. Microsatellite marker development and Mendelian analysis in the Matschie's tree kangaroo (Dendrolagus matschiei).

    Science.gov (United States)

    McGreevy, Thomas J; Dabek, Lisa; Husband, Thomas P

    2010-01-01

    Matschie's tree kangaroo (Dendrolagus matschiei) is an endangered arboreal macropodid endemic to the Huon Peninsula, Papua New Guinea (PNG). We developed 5 microsatellite markers for D. matschiei, which are the first markers developed for Dendrolagus. We screened 17 additional markers that were developed for other marsupial taxa and identified 3 that were polymorphic in D. matschiei. We estimated allelic and genetic diversity with the set of 8 markers by analyzing 22 D. matschiei from Wasaunon on the Huon Peninsula, PNG. The number of alleles ranged from 2 to 9 and expected heterozygosity ranged from 0.440 to 0.794. We tested for null alleles and Mendelian inheritance by analyzing 19 pairs of D. matschiei parents and offspring from Association of Zoos and Aquariums institutions. Null alleles were not detected and Mendelian inheritance was followed for all 8 markers. We also evaluated the reliability of using the markers to amplify DNA extracted from D. matschiei fecal samples and the ability of the markers to amplify DNA samples from Goodfellow's tree kangaroo (Dendrolagus goodfellowi ssp.), Doria's tree kangaroo (Dendrolagus dorianus ssp.), and Grizzled tree kangaroo (Dendrolagus inustus ssp.). Microsatellite markers can be used to inform management decisions to conserve D. matschiei in captivity and the wild.

  19. MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data.

    Science.gov (United States)

    Yavorska, Olena O; Burgess, Stephen

    2017-12-01

    MendelianRandomization is a software package for the R open-source software environment that performs Mendelian randomization analyses using summarized data. The core functionality is to implement the inverse-variance weighted, MR-Egger and weighted median methods for multiple genetic variants. Several options are available to the user, such as the use of robust regression, fixed- or random-effects models and the penalization of weights for genetic variants with heterogeneous causal estimates. Extensions to these methods, such as allowing for variants to be correlated, can be chosen if appropriate. Graphical commands allow summarized data to be displayed in an interactive graph, or the plotting of causal estimates from multiple methods, for comparison. Although the main method of data entry is directly by the user, there is also an option for allowing summarized data to be incorporated from the PhenoScanner database of genotype-phenotype associations. We hope to develop this feature in future versions of the package. The R software environment is available for download from [https://www.r-project.org/]. The MendelianRandomization package can be downloaded from the Comprehensive R Archive Network (CRAN) within R, or directly from [https://cran.r-project.org/web/packages/MendelianRandomization/]. Both R and the MendelianRandomization package are released under GNU General Public Licenses (GPL-2|GPL-3). © The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association.

  20. Direct power comparisons between simple LOD scores and NPL scores for linkage analysis in complex diseases.

    Science.gov (United States)

    Abreu, P C; Greenberg, D A; Hodge, S E

    1999-09-01

    Several methods have been proposed for linkage analysis of complex traits with unknown mode of inheritance. These methods include the LOD score maximized over disease models (MMLS) and the "nonparametric" linkage (NPL) statistic. In previous work, we evaluated the increase of type I error when maximizing over two or more genetic models, and we compared the power of MMLS to detect linkage, in a number of complex modes of inheritance, with analysis assuming the true model. In the present study, we compare MMLS and NPL directly. We simulated 100 data sets with 20 families each, using 26 generating models: (1) 4 intermediate models (penetrance of heterozygote between that of the two homozygotes); (2) 6 two-locus additive models; and (3) 16 two-locus heterogeneity models (admixture alpha = 1.0,.7,.5, and.3; alpha = 1.0 replicates simple Mendelian models). For LOD scores, we assumed dominant and recessive inheritance with 50% penetrance. We took the higher of the two maximum LOD scores and subtracted 0.3 to correct for multiple tests (MMLS-C). We compared expected maximum LOD scores and power, using MMLS-C and NPL as well as the true model. Since NPL uses only the affected family members, we also performed an affecteds-only analysis using MMLS-C. The MMLS-C was both uniformly more powerful than NPL for most cases we examined, except when linkage information was low, and close to the results for the true model under locus heterogeneity. We still found better power for the MMLS-C compared with NPL in affecteds-only analysis. The results show that use of two simple modes of inheritance at a fixed penetrance can have more power than NPL when the trait mode of inheritance is complex and when there is heterogeneity in the data set.

  1. [Mendelian randomisation - a genetic approach to an epidemiological method].

    Science.gov (United States)

    Stensrud, Mats Julius

    2016-06-01

    BACKGROUND Genetic information is becoming more easily available, and rapid progress is being made in developing methods of illuminating issues of interest. Mendelian randomisation makes it possible to study causes of disease using observational data. The name refers to the random distribution of gene variants in meiosis. The methodology makes use of genes that influence a risk factor for a disease, without influencing the disease itself. In this review article I explain the principles behind Mendelian randomisation and present the areas of application for this methodology.MATERIAL AND METHOD Methodology articles describing Mendelian randomisation were reviewed. The articles were found through a search in PubMed with the combination «mendelian randomization» OR «mendelian randomisation», and a search in McMaster Plus with the combination «mendelian randomization». A total of 15 methodology articles were read in full text. Methodology articles were supplemented by clinical studies found in the PubMed search.RESULTS In contrast to traditional observational studies, Mendelian randomisation studies are not affected by two important sources of error: conventional confounding variables and reverse causation. Mendelian randomisation is therefore a promising tool for studying causality. Mendelian randomisation studies have already provided valuable knowledge on the risk factors for a wide range of diseases. It is nevertheless important to be aware of the limitations of the methodology. As a result of the rapid developments in genetics research, Mendelian randomisation will probably be widely used in future years.INTERPRETATION If Mendelian randomisation studies are conducted correctly, they may help to reveal both modifiable and non-modifiable causes of disease.

  2. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

    Science.gov (United States)

    Chong, Jessica X; Buckingham, Kati J; Jhangiani, Shalini N; Boehm, Corinne; Sobreira, Nara; Smith, Joshua D; Harrell, Tanya M; McMillin, Margaret J; Wiszniewski, Wojciech; Gambin, Tomasz; Coban Akdemir, Zeynep H; Doheny, Kimberly; Scott, Alan F; Avramopoulos, Dimitri; Chakravarti, Aravinda; Hoover-Fong, Julie; Mathews, Debra; Witmer, P Dane; Ling, Hua; Hetrick, Kurt; Watkins, Lee; Patterson, Karynne E; Reinier, Frederic; Blue, Elizabeth; Muzny, Donna; Kircher, Martin; Bilguvar, Kaya; López-Giráldez, Francesc; Sutton, V Reid; Tabor, Holly K; Leal, Suzanne M; Gunel, Murat; Mane, Shrikant; Gibbs, Richard A; Boerwinkle, Eric; Hamosh, Ada; Shendure, Jay; Lupski, James R; Lifton, Richard P; Valle, David; Nickerson, Deborah A; Bamshad, Michael J

    2015-08-06

    Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  3. Relaxing Behavioural Inheritance

    Directory of Open Access Journals (Sweden)

    Nuno Amálio

    2013-05-01

    Full Text Available Object-oriented (OO inheritance allows the definition of families of classes in a hierarchical way. In behavioural inheritance, a strong version, it should be possible to substitute an object of a subclass for an object of its superclass without any observable effect on the system. Behavioural inheritance is related to formal refinement, but, as observed in the literature, the refinement constraints are too restrictive, ruling out many useful OO subclassings. This paper studies behavioural inheritance in the context of ZOO, an object-oriented style for Z. To overcome refinement's restrictions, this paper proposes relaxations to the behavioural inheritance refinement rules. The work is presented for Z, but the results are applicable to any OO language that supports design-by-contract.

  4. Genetic control of flowering time in rice: integration of Mendelian genetics and genomics.

    Science.gov (United States)

    Hori, Kiyosumi; Matsubara, Kazuki; Yano, Masahiro

    2016-12-01

    Integration of previous Mendelian genetic analyses and recent molecular genomics approaches, such as linkage mapping and QTL cloning, dramatically strengthened our current understanding of genetic control of rice flowering time. Flowering time is one of the most important agronomic traits for seed production in rice (Oryza sativa L.). It is controlled mainly by genes associated with photoperiod sensitivity, particularly in short-day plants such as rice. Since the early twentieth century, rice breeders and researchers have been interested in elucidating the genetic basis of flowering time because its modification is important for regional adaptation and yield optimization. Although flowering time is a complex trait controlled by many quantitative trait loci (QTLs), classical genetic studies have shown that many associated genes are inherited in accordance with Mendelian laws. Decoding the rice genome sequence opened a new era in understanding the genetic control of flowering time on the basis of genome-wide mapping and gene cloning. Heading date 1 (Hd1) was the first flowering time QTL to be isolated using natural variation in rice. Recent accumulation of information on rice genome has facilitated the cloning of other QTLs, including those with minor effects on flowering time. This information has allowed us to rediscover some of the flowering genes that were identified by classical Mendelian genetics. The genes characterized so far, including Hd1, have been assigned to specific photoperiod pathways. In this review, we provide an overview of the studies that led to an in-depth understanding of the genetic control of flowering time in rice, and of the current state of improving and fine-tuning this trait for rice breeding.

  5. The FG syndromes (Online Mendelian Inheritance in Man 305450): perspective in 2008.

    Science.gov (United States)

    Opitz, John M; Smith, James F; Santoro, Lucia

    2008-01-01

    Rarely in the history of medicine has an X-linked mental retardation syndrome so thoroughly entered every branch of medicine, at least of pediatrics, but also of internal medicine, on account of its protean manifestations. In such countries as Zambia, malaria, tuberculosis, HIV, and other infections diseases, and many environmental and nutritional disorders still top the list of childhood morbidity and mortality. However, in the more developed nations of the Old and New Worlds, prematurity, birth defects, and genetic conditions constitute the major burden of infant mortality adn chronic childhood handicaps. One of the most pervasive of these is the group of FG syndromes seen in every pediatric clinic and mental health service. Thus, in our experience FGS emerges as the most common yet the least known developmental disabilities condition in our society. FGS imposes a tremendous burden of morbidity, and to some extent also of mortality, on society and families. After successful neonatal adaptation, such recurring problems as otitis, reactive airway disease, and constipation can be routinely treated symptomatically. However, the neurodevelopmental burden represents the greatest challenge that FGS presents for families and to society. Under the best of circumstances, motor and speech development catch up. However, virtually all FGS children, boys and girls, have difficulties in psychologic development, school performance, and ultimate emotional adaptation to adult life and social integration. The many such cases added to those with outright psychiatric disturbances are overwhelming social, psychologic, and psychiatric services and, above all, public and private school systems, which are understaffed, under-funded, beyond formulating individual educational plans, and helpless to deal with the enormous burden of special service needs of these children. It's time that handicapped children receive care according to needs and not according to diagnosis. However, the near absence of information on FGS available to these professionals is a handicap in arriving at a specific diagnosis (allowing state and federal support for special services) and in understanding the prognosis, natural history, and such complications as "autism," seizures, and tethered cord that affect the child's success at home, in school, and out in society. The FGS parent support group has been of enormous help in informing families about all of these "issues," and to this day remains the greatest repository of knowledge on FGS. As they say in baseball, it is time at long last for the professionals "to step up to the plate."

  6. Triallelic Inheritance in Bardet-Biedl Syndrome, a Mendelian Recessive Disorder

    National Research Council Canada - National Science Library

    Nicholas Katsanis; Stephen J. Ansley; Jose L. Badano; Erica R. Eichers; Richard Alan Lewis; Bethan E. Hoskins; Peter J. Scambler; William S. Davidson; Philip L. Beales; James R. Lupski

    2001-01-01

    Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by multiple clinical features that include pigmentary retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects...

  7. [Polymorphism and inheritance of seed storage protein in sunflower].

    Science.gov (United States)

    Anisimova, I N; Gavrilova, V A; Loskutov, A V; Rozhkova, V T; Tolmachev, V V

    2004-09-01

    The data on polymorphism and inheritance of the seed storage protein helianthinin are presented. The results of hybrid analysis indicate that in the annual sunflower Helianthus annuus, helianthinin synthesis is controlled by at least three loci: HelA, HelB, HelB, and HelC. Codominant alleles controlling different electrophoretic variants of polypeptides were identified at each of the loci. The HelA locus was inherited independently of HelB and HelC in a series of dihybrid crosses. The frequencies of recombination between loci HelB and HelC estimated in F2 and BC of two crossing combinations were respectively 21.8 and 19.0%. Segregation of the Hel-C-controlled variants in the progenies from the crosses of cultured sunflower with annual wild species and forms corresponded to that theoretically expected for Mendelian inheritance. The maternal type of helianthinin inheritance was observed in the progenies from the crosses of inbred H. annuus lines with perennial diploid and polyploid Helianthus species. Altered expression of the HelC locus was detected in some hybrid combinations. These alterations appeared in early (F1, F2) hybrid generations and were similar in different hybrid combinations. They did not depend on the perennial paternal species being more influenced by the maternal genotype and by the mode of obtaining hybrids (in an embryo culture or in the field). These results are explained by "genomic shock" generated by hybridization of genetically incompatible species.

  8. Prerequisites for acquisition of inheritance

    OpenAIRE

    Večeřová, Marta

    2016-01-01

    Title: Prerequisites for Acquisition of Inheritance Keywords: deceased, inheritance, heir Type of paper: Thesis Author: Mgr. Daniela Bendová Supervisor: prof. JUDr. Jan Dvořák, CSc. Faculty of Law of Charles University Department of Civil Law The thesis addresses rudimentary prerequisites for acquisition of inheritance in the Czech Republic. These prerequisites include death of a person, that is necessary for application of inheritance rights, existence of inheritance, in particular ownership...

  9. Organs as inheritable property?

    Science.gov (United States)

    Voo, Teck Chuan; Holm, Soren

    2014-01-01

    It has been argued that organs should be treated as individual tradable property like other material possessions and assets, on the basis that this would promote individual freedom and increase efficiency in addressing the shortage of organs for transplantation. If organs are to be treated as property, should they be inheritable? This paper seeks to contribute to the idea of organs as inheritable property by providing a defence of a default of the family of a dead person as inheritors of transplantable organs. In the course of discussion, various succession rules for organs and their justifications will be suggested. We then consider two objections to organs as inheritable property. Our intention here is to provoke further thought on whether ownership of one's body parts should be assimilated to property ownership.

  10. The Knowledge Structure of Mendelian Genetics.

    Science.gov (United States)

    Collins, Angelo; Stewart, James H.

    1989-01-01

    Examines the content knowledge of genetics as it is organized for solving effect-to-cause problems. Reviews proposed reasons explaining why students find genetics difficult to learn. Explains dominant and codominant inheritance patterns, multiple alleles, and X-linkage. (RT)

  11. [Inherited aplastic anemias].

    Science.gov (United States)

    Esteves, A C; Freitas, O; Almeida, T; Rosado, L

    2010-08-01

    The inherited aplastic anaemias are a heterogeneous group of disorders characterized by bone marrow failure, frequent association with one or more somatic anomalies and increased risk of cancer. They are rare disorders, usually diagnosed at paediatric age, and have significant premature mortality. The authors report 11 cases of inherited aplastic anaemias, 8 of Fanconi's anaemia and 3 of Dyskeratosis congenita. These cases were diagnosed in the last 14 years in the Dona Estefânia Hospital. 2009 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  12. Comprehensive genotyping in dyslipidemia: mendelian dyslipidemias caused by rare variants and Mendelian randomization studies using common variants.

    Science.gov (United States)

    Tada, Hayato; Kawashiri, Masa-Aki; Yamagishi, Masakazu

    2017-04-01

    Dyslipidemias, especially hyper-low-density lipoprotein cholesterolemia and hypertriglyceridemia, are important causal risk factors for coronary artery disease. Comprehensive genotyping using the 'next-generation sequencing' technique has facilitated the investigation of Mendelian dyslipidemias, in addition to Mendelian randomization studies using common genetic variants associated with plasma lipids and coronary artery disease. The beneficial effects of low-density lipoprotein cholesterol-lowering therapies on coronary artery disease have been verified by many randomized controlled trials over the years, and subsequent genetic studies have supported these findings. More recently, Mendelian randomization studies have preceded randomized controlled trials. When the on-target/off-target effects of rare variants and common variants exhibit the same direction, novel drugs targeting molecules identified by investigations of rare Mendelian lipid disorders could be promising. Such a strategy could aid in the search for drug discovery seeds other than those for dyslipidemias.

  13. A rational treatment of Mendelian genetics

    Directory of Open Access Journals (Sweden)

    Porteous John W

    2004-08-01

    Full Text Available Abstract Background The key to a rational treatment of elementary Mendelian genetics, specifically to an understanding of the origin of dominant and recessive traits, lies in the facts that: (1 alleles of genes encode polypeptides; (2 most polypeptides are catalysts, i.e. enzymes or translocators; (3 the molecular components of all traits in all cells are the products of systems of enzymes, i.e. of fluxing metabolic pathways; (4 any flux to the molecular components of a trait responds non-linearly (non-additively to graded mutations in the activity of any one of the enzymes at a catalytic locus in a metabolic system; (5 as the flux responds to graded changes in the activity of an enzyme, the concentrations of the molecular components of a trait also change. Conclusions It is then possible to account rationally, and without misrepresenting Mendel, for: the origin of dominant and recessive traits; the occurrence of Mendel's 3(dominant:1(recessive trait ratio; deviations from this ratio; the absence of dominant and recessive traits in some circumstances, the occurrence of a blending of traits in others; the frequent occurrence of pleiotropy and epistasis.

  14. Mendelian controversies: a botanical and historical review.

    Science.gov (United States)

    Fairbanks, D J; Rytting, B

    2001-05-01

    Gregor Mendel was a 19(th) century priest and botanist who developed the fundamental laws of inheritance. The year 2000 marked a century since the rediscovery of those laws and the beginning of genetics. Although Mendel is now recognized as the founder of genetics, significant controversy ensued about his work throughout the 20(th) century. In this paper, we review five of the most contentious issues by looking at the historical record through the lens of current botanical science: (1) Are Mendel's data too good to be true? (2) Is Mendel's description of his experiments fictitious? (3) Did Mendel articulate the laws of inheritance attributed to him? (4) Did Mendel detect but not mention linkage? (5) Did Mendel support or oppose Darwin?A synthesis of botanical and historical evidence supports our conclusions: Mendel did not fabricate his data, his description of his experiments is literal, he articulated the laws of inheritance attributed to him insofar as was possible given the information he had, he did not detect linkage, and he neither strongly supported nor opposed Darwin.

  15. The Brugada syndrome: a rare arrhythmia disorder with complex inheritance

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste eGourraud

    2016-04-01

    Full Text Available For the last ten years, applying new sequencing technologies to thousands of whole exomes has revealed the high variability of the human genome. Extreme caution should thus be taken to avoid misinterpretation when associating rare genetic variants to disease susceptibility. The Brugada syndrome (Brs is a rare inherited arrhythmia disease associated with high risk of sudden cardiac death (SCD in the young adult. Familial inheritance has long been described as Mendelian, with autosomal dominant mode of transmission and incomplete penetrance. However, all except one of the 23 genes previously associated with the disease have been identified through a candidate gene approach. To date, only rare coding variants in the SCN5A gene have been significantly associated with the syndrome. However, the genotype/phenotype studies conducted in families with SCN5A mutations illustrate the complex mode of inheritance of Brs. This genetic complexity has recently been confirmed by the identification of common polymorphic alleles strongly associated with disease risk.The implication of both rare and common variants in Brs susceptibility implies that one should first define a proper genetic model for Brs predisposition prior to applying molecular diagnosis. Although long remains the way to personalized medicine against Brs, the high phenotype variability encountered in familial forms of the disease may partly find an explanation into this specific genetic architecture.

  16. The importance of cultural inheritance.

    Science.gov (United States)

    Peedicayil, J

    2001-02-01

    Cultural inheritance refers to the storage and transmission of information by communication, imitation, teaching and learning. It is transmitted by the brain rather than by genes. However, it does have a genetic basis, the genes involved determining the structure of the brain. Cultural inheritance is considered to be the latest stage in the evolution of heredity. It is thought to have evolved by epigenetic mechanisms from genetic inheritance. This article proposes that cultural inheritance underlies normal behaviour and mental disorders.

  17. Mendelian randomisation in cardiovascular research: an introduction for clinicians.

    Science.gov (United States)

    Bennett, Derrick A; Holmes, Michael V

    2017-09-01

    Understanding the causal role of biomarkers in cardiovascular and other diseases is crucial in order to find effective approaches (including pharmacological therapies) for disease treatment and prevention. Classical observational studies provide naïve estimates of the likely role of biomarkers in disease development; however, such studies are prone to bias. This has direct relevance for drug development as if drug targets track to non-causal biomarkers, this can lead to expensive failure of these drugs in phase III randomised controlled trials. In an effort to provide a more reliable indication of the likely causal role of a biomarker in the development of disease, Mendelian randomisation studies are increasingly used, and this is facilitated by the availability of large-scale genetic data. We conducted a narrative review in order to provide a description of the utility of Mendelian randomisation for clinicians engaged in cardiovascular research. We describe the rationale and provide a basic description of the methods and potential limitations of Mendelian randomisation. We give examples from the literature where Mendelian randomisation has provided pivotal information for drug discovery including predicting efficacy, informing on target-mediated adverse effects and providing potential new evidence for drug repurposing. The variety of the examples presented illustrates the importance of Mendelian randomisation in order to prioritise drug targets for cardiovascular research. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  18. Relevance of the Human Genome Project to inherited metabolic disease.

    Science.gov (United States)

    Burn, J

    1994-01-01

    The Human Genome Project is an international effort to identify the complete structure of the human genome. HUGO, the Human Genome Organization, facilitates international cooperation and exchange of information while the Genome Data Base will act as the on-line information retrieval and storage system for the huge amount of information being accumulated. The clinical register MIM (Mendelian Inheritance in Man) established by Victor McKusick is now an on-line resource that will allow biochemists working with inborn errors of metabolism to access the rapidly expanding body of knowledge. Biochemical and molecular genetics are complementary and should draw together to find solutions to the academic and clinical problems posed by inborn errors of metabolism.

  19. Epigenetic inheritance in ciliates.

    Science.gov (United States)

    Nowacki, Mariusz; Landweber, Laura F

    2009-12-01

    2009 marks not only the 200th anniversary of Darwin's birth but also publication of the first scientific evolutionary theory, Lamarck's Philosophie Zoologique. While Lamarck embraced the notion of the inheritance of acquired characters, he did not invent it (Burkhardt, 1984). New phenomena discovered recently offer molecular pathways for the transmission of several acquired characters. Ciliates have long provided model systems to study phenomena that bypass traditional modes of inheritance. RNA, normally thought of as a conduit in gene expression, displays a novel mode of action in ciliated protozoa. For example, maternal RNA templates provide both an organizing guide for DNA rearrangements in Oxytricha and a template that can transmit spontaneous mutations that may arise during somatic growth to the next generation, providing two such mechanisms of so-called Lamarckian inheritance. This suggests that the somatic ciliate genome is really an 'epigenome', formed through templates and signals arising from the previous generation. This review will discuss these new biological roles for RNA, including non-coding 'template' RNA molecules. The evolutionary consequences of viable mechanisms in ciliates to transmit acquired characters may create an additional store of heritable variation that contributes to the cosmopolitan success of this diverse lineage of microbial eukaryotes.

  20. Inheritance of cancer.

    Science.gov (United States)

    Frank, Steven A

    2004-12-01

    Extract: A single inherited mutant gene may be enough to cause a very high cancer risk. Single-mutation cases have provided much insight into the genetic basis of carcinogenesis, but they are relatively rare and account for only a small fraction of all cancers. Examples include mutation to the APC gene, causing early onset colon cancer in the syndrome familial adenomatous polyposis (tumorous polyp-tissue in the colon); mutation to either the BRCA1 or BRCA2 genes, causing an increased risk of breast cancer; and mutation to the TP53 gene, causing Li-Fraumeni syndrome with various early onset cancers such as bone or soft tissue sarcoma. Cancers sometimes cluster in families, but do not follow the rigid inheritance pattern characteristic of a mutation to a single gene. Males with a brother or father who has suffered prostate cancer are more likely to develop the disease. Similarly, females with a sister or mother who has suffered breast cancer are more likely to get a breast tumor. Some of the clustering may arise from the common diet and environment shared by families. Recently, however, researchers have begun to assign a significant fraction of cancer risk to the particular genetic variants that individuals inherit.

  1. On the origins of the Mendelian laws.

    Science.gov (United States)

    Monaghan, F; Corcos, A

    1984-01-01

    The two laws usually attributed to Mendel were not considered as laws by him. The first law, the law of independent segregation occurs in Mendel's paper as an assumption or hypothesis. Hugo de Vries refers to this as a law discovered by Mendel. This appears to be the first use of an expression equivalent to Mendel's law. In his paper de Vries did not associate the observable characters with structures having a causitive role. That was done by Correns, who transformed the law of segregation of characters into a law of the segregation of anlagen. The second law, the law of independent assortment, is present in embryonic form in Mendel's paper. Here the independent assortment of characters appears as a secondary conclusion to a series of experiments involving several pairs of traits. Mendel repeats the primary conclusion later in the paper but not the secondary one. This leads us to believe that he considered the secondary conclusion as of lesser importance. We note in this context that the 9:3:3:1 ratio commonly associated with the idea of independent assortment, and attributed to Mendel, also does not occur in his paper. A careful reading of the papers of his discoverers shows it was Correns who first drew attention to this ratio. However, he did not formulate the second Mendelian law even though it was clearly implied. Neither was it stated by de Vries. Indeed, the first clear separation of the two laws and the naming of the second law was by T. H. Morgan some 13 years later.

  2. Exploring prospective secondary science teachers' understandings of scientific inquiry and Mendelian genetics concepts using computer simulation

    Science.gov (United States)

    Cakir, Mustafa

    The primary objective of this case study was to examine prospective secondary science teachers' developing understanding of scientific inquiry and Mendelian genetics. A computer simulation of basic Mendelian inheritance processes (Catlab) was used in combination with small-group discussions and other instructional scaffolds to enhance prospective science teachers' understandings. The theoretical background for this research is derived from a social constructivist perspective. Structuring scientific inquiry as investigation to develop explanations presents meaningful context for the enhancement of inquiry abilities and understanding of the science content. The context of the study was a teaching and learning course focused on inquiry and technology. Twelve prospective science teachers participated in this study. Multiple data sources included pre- and post-module questionnaires of participants' view of scientific inquiry, pre-posttests of understandings of Mendelian concepts, inquiry project reports, class presentations, process videotapes of participants interacting with the simulation, and semi-structured interviews. Seven selected prospective science teachers participated in in-depth interviews. Findings suggest that while studying important concepts in science, carefully designed inquiry experiences can help prospective science teachers to develop an understanding about the types of questions scientists in that field ask, the methodological and epistemological issues that constrain their pursuit of answers to those questions, and the ways in which they construct and share their explanations. Key findings included prospective teachers' initial limited abilities to create evidence-based arguments, their hesitancy to include inquiry in their future teaching, and the impact of collaboration on thinking. Prior to this experience the prospective teachers held uninformed views of scientific inquiry. After the module, participants demonstrated extended expertise in

  3. [Mating types in the ciliate Dileptus anser. Inheritance and genetic determination].

    Science.gov (United States)

    Iudin, A L; Uspenskaia, Z I

    2006-01-01

    Hybridological analysis of mating types (MTs) has been first made for the lower ciliate Dileptus anser. Clones of an initially unknown genotype belonging to three MTs (MT I, MT II and MT III), characteristic of D. anser, were isolated from natural reservoirs and further used for crosses. In one group crosses, synclonal inheritance and typical Mendelian behaviour of the character were observed over sexual generations of ciliates. The results suggest that MTs in D. anser may be directly controlled by a single mat locus with three alleles showing peck-order dominance (mat1 > mat2 > mat3). In other words, cells with mat1/mat1, mat1/mat2 and mat1/mat3 genotypes belong to MT I, those with mat2/mat2 and mat2/mat3, and the mat3/mat3 belong to MT II and MT III, respectively. Sexually mature exconjugant clones stably retain their MTs corresponding to their genotypes on vegetative reproduction. The progeny of other group crosses showed various deviations from typical Mendelian behaviour of the character. In some cases, standard Mendelian ratios were more or less violated. Most typical was instability of differentiation for MT in maturing exconjugant clones. Shortly after their maturation, the majority of clones change their MT, rather frequently more than once, although the finally established MT is stably inherited afterwards, during vegetative reproduction. When unstable, exconjugant clones can successively express two or even three MTs characteristic of this species, including MTs that should not have been expected on the basis of parental genotypes available in a given cross. It looks likely that the mat locus in D. anser is complex and multipotential; it is inherited as a whole providing for expression of any MT characteristic of the species (in this respect bearing similarity with Tetrahymena thermophila). Other mechanisms, epigenetic in particular (Nanney, 1958), determine the final expression of one of the three MT potentialities by a given exconjugant clone. Stable

  4. Inheritance and wealth composition.

    Science.gov (United States)

    Perelman, S; Pestieau, P

    1992-11-01

    "This paper studies the effects of variables pertaining to alternative bequest motives on the composition of households' portfolio. It relies on a 1986 survey on the assets structure of 5,600 French households. The main conclusion is that bequest motives indeed influence the composition of households' wealth.... In general, however, for lack of data but also because households have mixed bequest motives, one cannot establish a clear relation between specific models of inheritance on the one hand and wealth pattern on the other hand." excerpt

  5. Mendelian randomization studies in coronary artery disease.

    Science.gov (United States)

    Jansen, Henning; Samani, Nilesh J; Schunkert, Heribert

    2014-08-01

    Epidemiological research over the last 50 years has discovered a plethora of biomarkers (including molecules, traits or other diseases) that associate with coronary artery disease (CAD) risk. Even the strongest association detected in such observational research precludes drawing conclusions about the causality underlying the relationship between biomarker and disease. Mendelian randomization (MR) studies can shed light on the causality of associations, i.e whether, on the one hand, the biomarker contributes to the development of disease or, on the other hand, the observed association is confounded by unrecognized exogenous factors or due to reverse causation, i.e. due to the fact that prevalent disease affects the level of the biomarker. However, conclusions from a MR study are based on a number of important assumptions. A prerequisite for such studies is that the genetic variant employed affects significantly the biomarker under investigation but has no effect on other phenotypes that might confound the association between the biomarker and disease. If this biomarker is a true causal risk factor for CAD, genotypes of the variant should associate with CAD risk in the direction predicted by the association of the biomarker with CAD. Given a random distribution of exogenous factors in individuals carrying respective genotypes, groups represented by the genotypes are highly similar except for the biomarker of interest. Thus, the genetic variant converts into an unconfounded surrogate of the respective biomarker. This scenario is nicely exemplified for LDL cholesterol. Almost every genotype found to increase LDL cholesterol level by a sufficient amount has also been found to increase CAD risk. Pending a number of conditions that needed to be fulfilled by the genetic variant under investigation (e.g. no pleiotropic effects) and the experimental set-up of the study, LDL cholesterol can be assumed to act as the functional component that links genotypes and CAD risk and

  6. The Number of Candidate Variants in Exome Sequencing for Mendelian Disease under No Genetic Heterogeneity

    Directory of Open Access Journals (Sweden)

    Jo Nishino

    2013-01-01

    Full Text Available There has been recent success in identifying disease-causing variants in Mendelian disorders by exome sequencing followed by simple filtering techniques. Studies generally assume complete or high penetrance. However, there are likely many failed and unpublished studies due in part to incomplete penetrance or phenocopy. In this study, the expected number of candidate single-nucleotide variants (SNVs in exome data for autosomal dominant or recessive Mendelian disorders was investigated under the assumption of “no genetic heterogeneity.” All variants were assumed to be under the “null model,” and sample allele frequencies were modeled using a standard population genetics theory. To investigate the properties of pedigree data, full-sibs were considered in addition to unrelated individuals. In both cases, particularly regarding full-sibs, the number of SNVs remained very high without controls. The high efficacy of controls was also confirmed. When controls were used with a relatively large total sample size (e.g., N=20, 50, filtering incorporating of incomplete penetrance and phenocopy efficiently reduced the number of candidate SNVs. This suggests that filtering is useful when an assumption of no “genetic heterogeneity” is appropriate and could provide general guidelines for sample size determination.

  7. The number of candidate variants in exome sequencing for Mendelian disease under no genetic heterogeneity.

    Science.gov (United States)

    Nishino, Jo; Mano, Shuhei

    2013-01-01

    There has been recent success in identifying disease-causing variants in Mendelian disorders by exome sequencing followed by simple filtering techniques. Studies generally assume complete or high penetrance. However, there are likely many failed and unpublished studies due in part to incomplete penetrance or phenocopy. In this study, the expected number of candidate single-nucleotide variants (SNVs) in exome data for autosomal dominant or recessive Mendelian disorders was investigated under the assumption of "no genetic heterogeneity." All variants were assumed to be under the "null model," and sample allele frequencies were modeled using a standard population genetics theory. To investigate the properties of pedigree data, full-sibs were considered in addition to unrelated individuals. In both cases, particularly regarding full-sibs, the number of SNVs remained very high without controls. The high efficacy of controls was also confirmed. When controls were used with a relatively large total sample size (e.g., N = 20, 50), filtering incorporating of incomplete penetrance and phenocopy efficiently reduced the number of candidate SNVs. This suggests that filtering is useful when an assumption of no "genetic heterogeneity" is appropriate and could provide general guidelines for sample size determination.

  8. Inherited epilepsy in dogs.

    Science.gov (United States)

    Ekenstedt, Kari J; Oberbauer, Anita M

    2013-05-01

    Epilepsy is the most common neurologic disease in dogs and many forms are considered to have a genetic basis. In contrast, some seizure disorders are also heritable, but are not technically defined as epilepsy. Investigation of true canine epilepsies has uncovered genetic associations in some cases, however, many remain unexplained. Gene mutations have been described for 2 forms of canine epilepsy: primary epilepsy (PE) and progressive myoclonic epilepsies. To date, 9 genes have been described to underlie progressive myoclonic epilepsies in several dog breeds. Investigations into genetic PE have been less successful, with only 1 causative gene described. Genetic testing as an aid to diagnosis, prognosis, and breeding decisions is available for these 10 forms. Additional studies utilizing genome-wide tools have identified PE loci of interest; however, specific genetic tests are not yet developed. Many studies of dog breeds with PE have failed to identify genes or loci of interest, suggesting that, similar to what is seen in many human genetic epilepsies, inheritance is likely complex, involving several or many genes, and reflective of environmental interactions. An individual dog's response to therapeutic intervention for epilepsy may also be genetically complex. Although the field of inherited epilepsy has faced challenges, particularly with PE, newer technologies contribute to further advances. © 2013 Elsevier Inc. All rights reserved.

  9. Was I Right? Testing Observations against Predictions in Mendelian Genetics.

    Science.gov (United States)

    Hursch, Thomas Mercer

    1979-01-01

    Two statistical tools, the Chi-square and standard error approaches, are compared for use in Mendelian genetics experiments. Although the Chi-square technique is more often used, the standard error approach is to be preferred for both research investigations and student experiments. (BB)

  10. Was Mendelian genetics taught during the Lysenkoist period in Poland?

    OpenAIRE

    Köhler, Piotr

    2014-01-01

    The content of Polish textbooks of botany, zoology and rudiments of evolutionism of Lysenkoist times was analysed, along with a methodological manual for biology and a set of guidelines. On this basis, and taking into account the memories of eyewitnesses, it can be stated that Mendelian genetics was not taught in schools in Poland during the Lysenkoist period.

  11. Can Using Human Examples Facilitate Learning Mendelian Genetics Concepts?

    Science.gov (United States)

    Moore, John M.; And Others

    1992-01-01

    Reports an experimental study of 80 ninth grade biology students randomly assigned to treatment and control groups to determine whether the use of human examples in instructional strategies on Mendelian genetics increases acquisition and retention of genetics concepts. Results indicate that use of human examples in contrast to traditional examples…

  12. Linguistic Challenges in Mendelian Genetics: Teachers' Talk in Action

    Science.gov (United States)

    Thörne, Karin; Gericke, Niklas M.; Hagberg, Mariana

    2013-01-01

    This study investigates Swedish teachers' use of language when teaching Mendelian genetics in compulsory school. The primary objective of the study is to explore how teachers use the related concepts "gene," "allele," and "anlag" (a Swedish variant of the German word "anlage") and how these are related to…

  13. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.

    Science.gov (United States)

    Blair, David R; Lyttle, Christopher S; Mortensen, Jonathan M; Bearden, Charles F; Jensen, Anders Boeck; Khiabanian, Hossein; Melamed, Rachel; Rabadan, Raul; Bernstam, Elmer V; Brunak, Søren; Jensen, Lars Juhl; Nicolae, Dan; Shah, Nigam H; Grossman, Robert L; Cox, Nancy J; White, Kevin P; Rzhetsky, Andrey

    2013-09-26

    Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. A Nondegenerate Code of Deleterious Variants in Mendelian Loci Contributes to Complex Disease Risk

    DEFF Research Database (Denmark)

    Blair, David R.; Lyttle, Christopher S.; Mortensen, Jonathan M.

    2013-01-01

    with complex diseases are enriched in the genes indicated by this ‘‘Mendelian code.’’ Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset......Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes...... to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated...

  15. Segregation analysis of Alzheimer pedigrees: Rare Mendelian dominant mutation(s) explain a minority of early-onset cases

    Energy Technology Data Exchange (ETDEWEB)

    Martinez, M.; Campion, D.; Babron, M.C.; Darpoux, F.C. [INSERM, Paris (France)] [and others

    1996-02-16

    Segregation analysis of Alzheimer disease (AD) in 92 families ascertained through early-onset ({le}age 60 years) AD (EOAD) probands has been carried out, allowing for a mixture in AD inheritance among probands. The goal was to quantify the proportion of probands that could be explained by autosomal inheritance of a rare disease allele {open_quotes}a{close_quotes} at a Mendelian dominant gene (MDG). Our data provide strong evidence for a mixture of two distributions; AD transmission is fully explained by MDG inheritance in <20% of probands. Male and female age-of-onset distributions are significantly different for {open_quotes}AA{close_quote} but not for {open_quotes}aA{close_quote} subjects. For {open_quotes}aA{close_quote} subjects the estimated penetrance value was close to 1 by age 60. For {open_quotes}AA{close_quotes} subjects, it reaches, by age 90, 10% (males) and 30% (females). We show a clear cutoff in the posterior probability of being an MDG case. 10 refs., 1 tab.

  16. Inheritance Patterns of Infantile Hemangioma

    National Research Council Canada - National Science Library

    Eeva Castrén; Päivi Salminen; Miikka Vikkula; Anne Pitkäranta; Tuomas Klockars

    2016-01-01

      BACKGROUND AND OBJECTIVE: Infantile hemangioma (IH) includes, among its other risk factors, familial clustering, but a definitive understanding of IH's inheritance model and genetic basis is lacking...

  17. Mendelian analysis of a metastasis-prone substrain of BALB/c nude mice using a subcutaneously inoculated human tumour

    DEFF Research Database (Denmark)

    Schou, M; Brünner, N; Spang-Thomsen, M

    2006-01-01

    Most nude mice do not allow the formation of metastases after heterotransplantation of human malignant tumours. Here we describe a substrain of BALB/c nude mice (BALB/c/AnNCr) that reproducibly allows some human cancers to metastasize. By Mendelian analysis of hybrids between this substrain and C57......BL/6J +/+ mice we found that the ability to allow a human tumour (MDA-MB-435 BAG) to express its metastatic phenotype is determined by a recessively inheritable trait in the mouse host. We are presently working to identify the genetics responsible for development of metastases. The study also...... includes immunohistochemical and electron microscopic analysis of the test tumour, originally assumed to be a human mammary carcinoma, but shown to possess characteristics of a malignant melanoma (1). The ultimate aim of our ongoing study is to establish a substrain of nude mice that will allow metastasis...

  18. Inheritance as a change of ownership rights

    OpenAIRE

    Velín, Aleš

    2009-01-01

    This bachelor dissertation is committed to inheritance, inheritance law and inheritance as a change of the rights of ownership. The goal of this work is to give enough information so that even the unknowing reader will know what is connected with inheritance, what are the basic terms from this area of law and also the questions of inheritance's inter-family relations because inheritance will be a subject everyone deals with eventually. The subject of this dissertation is inheritance from hist...

  19. Bladder Cancer: A Simple Model Becomes Complex

    Science.gov (United States)

    Pierro, Giovanni Battista Di; Gulia, Caterina; Cristini, Cristiano; Fraietta, Giorgio; Marini, Lorenzo; Grande, Pietro; Gentile, Vincenzo; Piergentili, Roberto

    2012-01-01

    Bladder cancer is one of the most frequent malignancies in developed countries and it is also characterized by a high number of recurrences. Despite this, several authors in the past reported that only two altered molecular pathways may genetically explain all cases of bladder cancer: one involving the FGFR3 gene, and the other involving the TP53 gene. Mutations in any of these two genes are usually predictive of the malignancy final outcome. This cancer may also be further classified as low-grade tumors, which is always papillary and in most cases superficial, and high-grade tumors, not necessarily papillary and often invasive. This simple way of considering this pathology has strongly changed in the last few years, with the development of genome-wide studies on expression profiling and the discovery of small non-coding RNA affecting gene expression. An easy search in the OMIM (On-line Mendelian Inheritance in Man) database using “bladder cancer” as a query reveals that genes in some way connected to this pathology are approximately 150, and some authors report that altered gene expression (up- or down-regulation) in this disease may involve up to 500 coding sequences for low-grade tumors and up to 2300 for high-grade tumors. In many clinical cases, mutations inside the coding sequences of the above mentioned two genes were not found, but their expression changed; this indicates that also epigenetic modifications may play an important role in its development. Indeed, several reports were published about genome-wide methylation in these neoplastic tissues, and an increasing number of small non-coding RNA are either up- or down-regulated in bladder cancer, indicating that impaired gene expression may also pass through these metabolic pathways. Taken together, these data reveal that bladder cancer is far to be considered a simple model of malignancy. In the present review, we summarize recent progress in the genome-wide analysis of bladder cancer, and analyse non

  20. Inheritance of the 8.1 ancestral haplotype in recurrent pregnancy loss

    DEFF Research Database (Denmark)

    Kolte, Astrid M; Nielsen, Henriette S; Steffensen, Rudi

    2015-01-01

    pleiotropy. It has also been proposed that the survival of long, conserved haplotypes may be due to gestational drive, i.e. selective miscarriage of fetuses who have not inherited the haplotype from a heterozygous mother. Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses....... The objective was to test the gestational drive theory for the 8.1AH in women with RPL and their live born children. METHODOLOGY: We investigated the inheritance of the 8.1AH from 82 heterozygous RPL women to 110 live born children. All participants were genotyped for HLA-A, -B and -DRB1 in DNA from EDTA......-treated blood or buccal swaps. Inheritance was compared with a Mendelian inheritance of 50% using a two-sided exact binomial test. RESULTS: We found that 55% of the live born children had inherited the 8.1AH, which was not significantly higher than the expected 50% (P = 0.29). Interestingly, we found a non...

  1. Simple Machines Made Simple.

    Science.gov (United States)

    St. Andre, Ralph E.

    Simple machines have become a lost point of study in elementary schools as teachers continue to have more material to cover. This manual provides hands-on, cooperative learning activities for grades three through eight concerning the six simple machines: wheel and axle, inclined plane, screw, pulley, wedge, and lever. Most activities can be…

  2. Dopamine receptor DRD3 codes for trait aggression as Mendelian recessive.

    Science.gov (United States)

    Benis, A M; Hobgood, D K

    2011-12-01

    The dopamine receptor gene DRD3 and in particular the single nucleotide polymorphism Ser9Gly has been extensively investigated and found to have potential association with a wide variety of conditions. These include essential tremor, unipolar and bipolar depression, as well as a loose association with schizophrenia. Evaluation of (1) these known associations with DRD3, (2) the recent finding of Costas and colleagues that a haplotype containing Ser-9 is associated with protection from schizophrenia, and (3) an extant trait model of personality, leads to the hypothesis that an allele DRD3/Ser codes for trait aggression by Mendelian recessive inheritance. The implications of this hypothesis are that (1) DRD3 is a pleiotropic gene having allelic polymorphism related to both behavior and disease, and (2) models of personality based on genetic traits hold promise. In the area of schizophrenia, the hypothesis implies that schizophrenic patients can be divided into two broad classes: those having genotype DRD3/Ser/Ser and those who lack this homozygosity. The hypothesis of the association of DRD3 with trait aggression could be readily evaluated by testing groups of healthy individuals by personality inventory focused on aggression and by biochemical assay of neurotransmitter levels. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Compiler generation based on grammar inheritance

    NARCIS (Netherlands)

    Aksit, Mehmet; Mostert, Rene; Haverkort, Boudewijn R.H.M.

    1990-01-01

    The concept of grammar inheritance is introduced. Grammar inheritance is a structural organization of grammar rules by which a grammar inherits rules from ancestor grammars or may have its own rules inherited by descendant grammars. Grammar inheritance supports reusability and extensibility of

  4. Inherited epidermolysis bullosa

    Directory of Open Access Journals (Sweden)

    Fine Jo-David

    2010-05-01

    Full Text Available Abstract Inherited epidermolysis bullosa (EB encompasses a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues. All types and subtypes of EB are rare; the overall incidence and prevalence of the disease within the United States is approximately 19 per one million live births and 8 per one million population, respectively. Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs. Each EB subtype is known to arise from mutations within the genes encoding for several different proteins, each of which is intimately involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the underlying dermis. EB is best diagnosed and subclassified by the collective findings obtained via detailed personal and family history, in concert with the results of immunofluorescence antigenic mapping, transmission electron microscopy, and in some cases, by DNA analysis. Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct whenever possible the extracutaneous complications. Prognosis varies considerably and is based on both EB subtype and the overall health of the patient.

  5. Mendelian randomization studies of biomarkers and type 2 diabetes.

    Science.gov (United States)

    Abbasi, Ali

    2015-12-01

    Many biomarkers are associated with type 2 diabetes (T2D) risk in epidemiological observations. The aim of this study was to identify and summarize current evidence for causal effects of biomarkers on T2D. A systematic literature search in PubMed and EMBASE (until April 2015) was done to identify Mendelian randomization studies that examined potential causal effects of biomarkers on T2D. To replicate the findings of identified studies, data from two large-scale, genome-wide association studies (GWAS) were used: DIAbetes Genetics Replication And Meta-analysis (DIAGRAMv3) for T2D and the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for glycaemic traits. GWAS summary statistics were extracted for the same genetic variants (or proxy variants), which were used in the original Mendelian randomization studies. Of the 21 biomarkers (from 28 studies), ten have been reported to be causally associated with T2D in Mendelian randomization. Most biomarkers were investigated in a single cohort study or population. Of the ten biomarkers that were identified, nominally significant associations with T2D or glycaemic traits were reached for those genetic variants related to bilirubin, pro-B-type natriuretic peptide, delta-6 desaturase and dimethylglycine based on the summary data from DIAGRAMv3 or MAGIC. Several Mendelian randomization studies investigated the nature of associations of biomarkers with T2D. However, there were only a few biomarkers that may have causal effects on T2D. Further research is needed to broadly evaluate the causal effects of multiple biomarkers on T2D and glycaemic traits using data from large-scale cohorts or GWAS including many different genetic variants. © 2015 The authors.

  6. Age at menarche and lung function: a Mendelian randomization study

    OpenAIRE

    Gill, Dipender; Sheehan, Nuala A; Wielscher, Matthias; Shrine, Nick; Amaral, Andre F. S.; Thompson, John R.; Granell, Raquel; Leynaert, Bénédicte; Real, Francisco Gómez; Hall, Ian P.; Tobin, Martin D; Auvinen, Juha; Ring, Susan M.; Jarvelin, Marjo-Riitta; Wain, Louise V

    2017-01-01

    A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age a...

  7. Inherited disorders of GABA metabolism

    OpenAIRE

    Pearl, Phillip L; Hartka, Thomas R; Cabalza, Jessica L; Taylor, Jacob; Gibson, Michael K

    2006-01-01

    The inherited disorders of γ-amino butyric acid (GABA) metabolism require an increased index of clinical suspicion. The known genetic disorders are GABA-transaminase deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency and homocarnosinosis. A recent link has also been made between impaired GABA synthesis and nonsyndromic cleft lip, with or without cleft palate. SSADH deficiency is the most commonly occurring of the inherited disorders of neurotransmitters. The disorder has a non...

  8. The salvage/turnover/repair (STOR) model for uniparental inheritance in Chlamydomonas: DNA as a source of sustenance.

    Science.gov (United States)

    Sears, B B; VanWinkle-Swift, K

    1994-01-01

    The non-Mendelian inheritance of chloroplast genes in Chlamydomonas has engaged researchers for decades and has prompted numerous debates regarding molecular mechanisms and evolutionary significance. The hallmarks of chloroplast inheritance in Chlamydomonas are reviewed here, including observations on vegetative haploid cells, somatic hybrids, meiotic zygospores, and vegetative zygotes resulting from sexual reproduction. Models invoked to explain the typical uniparental maternal inheritance of chloroplast genes, and which center upon the presumed existence of sex-specific protectors and destroyers of chloroplast genomes, are briefly discussed. In an effort to bring together the diverse observations on chloroplast gene inheritance in somatic as well as sexual cells, a model is proposed that focuses on organelle DNA turnover as a source of sustenance for the cell during periods of starvation. The salvage/turnover/repair (STOR) model for chloroplast inheritance in Chlamydomonas proposes that as a consequence of the high ploidy of the chloroplast genome, many copies are dispensable; their degradation would provide nucleotides for recombination, repair, RNA synthesis and cell metabolism. The STOR model offers an alternative view of uniparental inheritance as a phenomenon of direct selective benefit to the organism rather than simply being of selfish benefit to the chloroplast genome. These concepts may also have application to other lower eukaryotes that have sexual reproduction coupled with an extended dormancy.

  9. The Battle Between the Biometricians and the Mendelians: How Sir Francis Galton's Work Caused his Disciples to Reach Conflicting Conclusions About the Hereditary Mechanism

    Science.gov (United States)

    Gillham, Nicholas W.

    2015-01-01

    Francis Galton, Charles Darwin's cousin, had wide and varied interests. They ranged from exploration and travel writing to fingerprinting and the weather. After reading Darwin's On the Origin of Species, Galton reached the conclusion that it should be possible to improve the human stock through selective breeding, as was the case for domestic animals and cultivated plants. Much of the latter half of Galton's career was devoted to trying to devise methods to distinguish men of good stock and then to show that these qualities were inherited. But along the way he invented two important statistical methods: regression and correlation. He also discovered regression to the mean. This led Galton to believe that evolution could not proceed by the small steps envisioned by Darwin, but must proceed by discontinuous changes. Galton's book Natural Inheritance (1889) served as the inspiration for Karl Pearson, W.F.R. Weldon and William Bateson. Pearson and Weldon were interested in continuously varying characters and the application of statistical techniques to their study. Bateson was fascinated by discontinuities and the role they might play in evolution. Galton proposed his Law of Ancestral Heredity in the last decade of the nineteenth century. At first this seemed to work well as an explanation for continuously varying traits of the type that interested Pearson and Weldon. In contrast, Bateson had published a book on discontinuously varying traits so he was in a position to understand and embrace Mendel's principles of inheritance when they were rediscovered in 1900. The subsequent battle between Weldon and Pearson, the biometricians, and Bateson, the Mendelian, went on acrimoniously for several years at the beginning of the twentieth century before Mendelian theory finally won out.

  10. Clinical approach to inherited metabolic diseases in the neonatal period: a 20-year survey

    NARCIS (Netherlands)

    Saudubray, J. M.; Ogier, H.; Bonnefont, J. P.; Munnich, A.; Lombes, A.; Hervé, F.; Mitchel, G.; Poll The, B.; Specola, N.; Parvy, P.

    1989-01-01

    Every newborn with unexplained neurological deterioration, ketosis, metabolic acidosis or hypoglycaemia should be suspected of having an inherited error of intermediary metabolism. Many of these conditions can be diagnosed clinically with the aid of simple laboratory investigations. Since a

  11. INHERITANCE OF RESISTANCE TO PStV IN TRANSGENIC PEANUTS CONTAINING cp PStV GENE

    Directory of Open Access Journals (Sweden)

    Dwi Hapsoro, Hajrial Aswidinnoor, Rusmilah Suseno, Jumanto, dan Sudarsono .

    2011-11-01

    Full Text Available Inheritance of Resistance to PStV in Transgenic Peanuts Containing cp PStV Gene. We have obtained transgenic peanut lines containing coat protein gene of PStV. To get maximal use of the transgenic character in a breeding program, it is necessary that the transgene is also stably inherited and expressed.  This experiment was conducted from June 2002 – January 2005 at Plant Molecular Biology Laboratory, Bogor Agricultural University, and Queensland Agricultural Biotechnology Center, The University of Queensland, Australia. The research aimed (1 to test whether PStV cp transgene was functional in progenies derived from crosses between transgenic peaanut plants containing PStV cp gene and non-transgenic ones and (2 to determine pattern of inheritance of resistance to PStV as a result of PStV  cp gene action. Several crosses were made between trangenic peanut cv.Gajah resistant to PStV (T4 generation and non-transgenic peanut line WS susceptible to PStV. The F1 and F2 populations were mechanically inoculated with PStV two weeks after planting. The experiment showed that all plants in the F1 population were less susceptible to PStV, suggesting that the transgene was partially dominant.  Phenotipic segregation in F2 population was not Mendelian with the appearance of quick and slow recovery plants and the number of resistant plants being more than expected. However, the proportion of transgenic and non-transgenic plants followed 3:1 ratio, which was Mendelian.

  12. Mendelian randomization analysis with multiple genetic variants using summarized data.

    Science.gov (United States)

    Burgess, Stephen; Butterworth, Adam; Thompson, Simon G

    2013-11-01

    Genome-wide association studies, which typically report regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for Mendelian randomization investigations. We demonstrate how such coefficients from multiple variants can be combined in a Mendelian randomization analysis to estimate the causal effect of a risk factor on an outcome. The bias and efficiency of estimates based on summarized data are compared to those based on individual-level data in simulation studies. We investigate the impact of gene-gene interactions, linkage disequilibrium, and 'weak instruments' on these estimates. Both an inverse-variance weighted average of variant-specific associations and a likelihood-based approach for summarized data give similar estimates and precision to the two-stage least squares method for individual-level data, even when there are gene-gene interactions. However, these summarized data methods overstate precision when variants are in linkage disequilibrium. If the P-value in a linear regression of the risk factor for each variant is less than 1×10⁻⁵, then weak instrument bias will be small. We use these methods to estimate the causal association of low-density lipoprotein cholesterol (LDL-C) on coronary artery disease using published data on five genetic variants. A 30% reduction in LDL-C is estimated to reduce coronary artery disease risk by 67% (95% CI: 54% to 76%). We conclude that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual-level data, although the necessary assumptions cannot be so fully assessed. © 2013 WILEY PERIODICALS, INC.

  13. Does higher education protect against obesity? Evidence using Mendelian randomization.

    Science.gov (United States)

    Böckerman, Petri; Viinikainen, Jutta; Pulkki-Råback, Laura; Hakulinen, Christian; Pitkänen, Niina; Lehtimäki, Terho; Pehkonen, Jaakko; Raitakari, Olli T

    2017-08-01

    The aim of this explorative study was to examine the effect of education on obesity using Mendelian randomization. Participants (N=2011) were from the on-going nationally representative Young Finns Study (YFS) that began in 1980 when six cohorts (aged 30, 33, 36, 39, 42 and 45 in 2007) were recruited. The average value of BMI (kg/m 2 ) measurements in 2007 and 2011 and genetic information were linked to comprehensive register-based information on the years of education in 2007. We first used a linear regression (Ordinary Least Squares, OLS) to estimate the relationship between education and BMI. To identify a causal relationship, we exploited Mendelian randomization and used a genetic score as an instrument for education. The genetic score was based on 74 genetic variants that genome-wide association studies (GWASs) have found to be associated with the years of education. Because the genotypes are randomly assigned at conception, the instrument causes exogenous variation in the years of education and thus enables identification of causal effects. The years of education in 2007 were associated with lower BMI in 2007/2011 (regression coefficient (b)=-0.22; 95% Confidence Intervals [CI]=-0.29, -0.14) according to the linear regression results. The results based on Mendelian randomization suggests that there may be a negative causal effect of education on BMI (b=-0.84; 95% CI=-1.77, 0.09). The findings indicate that education could be a protective factor against obesity in advanced countries. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Improved Student Linkage of Mendelian and Molecular Genetic Concepts through a Yeast-Based Laboratory Module

    Science.gov (United States)

    Wolyniak, Michael J.

    2013-01-01

    A study of modern genetics requires students to successfully unite the principles of Mendelian genetics with the functions of DNA. Traditional means of teaching genetics are often successful in teaching Mendelian and molecular ideas but not in allowing students to see how the two subjects relate. The laboratory module presented here attempts to…

  15. Alcohol consumption and cognitive performance: a Mendelian randomization study.

    Science.gov (United States)

    Kumari, Meena; Holmes, Michael V; Dale, Caroline E; Hubacek, Jaroslav A; Palmer, Tom M; Pikhart, Hynek; Peasey, Anne; Britton, Annie; Horvat, Pia; Kubinova, Ruzena; Malyutina, Sofia; Pajak, Andrzej; Tamosiunas, Abdonas; Shankar, Aparna; Singh-Manoux, Archana; Voevoda, Mikhail; Kivimaki, Mika; Hingorani, Aroon D; Marmot, Michael G; Casas, Juan P; Bobak, Martin

    2014-09-01

    To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function. Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance. Europe. More than 34 000 adults. Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed. Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI) = 0.15, 0.20] for immediate recall, 0.17 SD (95% CI = 0.14, 0.19) for delayed recall, 0.17 SD (95% CI = 0.14, 0.19) for verbal fluency and 0.12 SD (95% CI = 0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio = 0.87; 95% CI = 0.80, 0.95; P = 0.001; R(2)  = 0.1%; F-statistic = 47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: -0.74 SD (95% CI = -1.88, 0.41) for immediate recall, -1.09 SD (95% CI = -2.38, 0.21) for delayed recall, -0.63 SD (95% CI = -1.78, 0.53) for verbal fluency and -0.16 SD (95% CI = -1.29, 0.97) for processing speed. The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability. © 2014 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

  16. Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes.

    Science.gov (United States)

    Melamed, Rachel D; Emmett, Kevin J; Madubata, Chioma; Rzhetsky, Andrey; Rabadan, Raul

    2015-04-30

    Despite large-scale cancer genomics studies, key somatic mutations driving cancer, and their functional roles, remain elusive. Here, we propose that analysis of comorbidities of Mendelian diseases with cancers provides a novel, systematic way to discover new cancer genes. If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbour cancer-associated somatic variation. Compilations of clinical records spanning over 100 million patients provide an unprecedented opportunity to assess clinical associations between Mendelian diseases and cancers. We systematically compare these comorbidities against recurrent somatic mutations from more than 5,000 patients across many cancers. Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity. This result provides a basis to identify candidate drivers in cancers including melanoma and glioblastoma. Some Mendelian diseases demonstrate 'pan-cancer' comorbidity and shared genetics across cancers.

  17. [Inherited primitive and secondary polycythemia].

    Science.gov (United States)

    Barba, T; Boileau, J-C; Pasquet, F; Hot, A; Pavic, M

    2016-07-01

    Myeloproliferative disorders and secondary polycythemia cover most of the polycythemia cases encountered in daily practice. Inherited polycythemias are rare entities that have to be suspected when the classical causes of acquired polycythemia have been ruled out. Recent advances were made in the understanding of these pathologies, which are still little known to the physicians. This review reports the state of knowledge and proposes an algorithm to follow when confronted to a possible case of inherited polycythemia. Copyright © 2015 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  18. Inheritance of porcine stress syndrome.

    Science.gov (United States)

    Mabry, J W; Christian, L L; Kuhlers, D L

    1981-01-01

    A total of 66 litters were farrowed in a Yorkshire herd of pigs selected for porcine stress syndrome (PSS) susceptibility. These litters included all possible combinations of matings between stress-susceptible, stress-carrier, and stress-resistant animals. When the data were analyzed by within-litter chi-square analysis, the null hypothesis of recessive inheritance could not be rejected (P less than 0.05). In addition, when the data were analyzed across litters, the null hypothesis of autosomal recessive inheritance could not be rejected (P less than 0.05).

  19. The inheritance of groin hernia

    DEFF Research Database (Denmark)

    Burcharth, J; Pommergaard, H C; Rosenberg, Jacob

    2013-01-01

    Groin hernia has been proposed to be hereditary; however, a clear hereditary pattern has not been established yet. The purpose of this review was to analyze studies evaluating family history and inheritance patterns and to investigate the possible heredity of groin hernias.......Groin hernia has been proposed to be hereditary; however, a clear hereditary pattern has not been established yet. The purpose of this review was to analyze studies evaluating family history and inheritance patterns and to investigate the possible heredity of groin hernias....

  20. Ernst Rüdin's Unpublished 1922-1925 Study "Inheritance of Manic-Depressive Insanity": Genetic Research Findings Subordinated to Eugenic Ideology.

    Directory of Open Access Journals (Sweden)

    Gundula Kösters

    2015-11-01

    Full Text Available In the early 20th century, there were few therapeutic options for mental illness and asylum numbers were rising. This pessimistic outlook favoured the rise of the eugenics movement. Heredity was assumed to be the principal cause of mental illness. Politicians, scientists and clinicians in North America and Europe called for compulsory sterilisation of the mentally ill. Psychiatric genetic research aimed to prove a Mendelian mode of inheritance as a scientific justification for these measures. Ernst Rüdin's seminal 1916 epidemiological study on inheritance of dementia praecox featured large, systematically ascertained samples and statistical analyses. Rüdin's 1922-1925 study on the inheritance of "manic-depressive insanity" was completed in manuscript form, but never published. It failed to prove a pattern of Mendelian inheritance, counter to the tenets of eugenics of which Rüdin was a prominent proponent. It appears he withheld the study from publication, unable to reconcile this contradiction, thus subordinating his carefully derived scientific findings to his ideological preoccupations. Instead, Rüdin continued to promote prevention of assumed hereditary mental illnesses by prohibition of marriage or sterilisation and was influential in the introduction by the National Socialist regime of the 1933 "Law for the Prevention of Hereditarily Diseased Offspring" (Gesetz zur Verhütung erbkranken Nachwuchses.

  1. Informing a Learning Progression in Genetics: Which Should Be Taught First, Mendelian Inheritance or the Central Dogma of Molecular Biology?

    Science.gov (United States)

    Duncan, Ravit Golan; Castro-Faix, Moraima; Choi, Jinnie

    2016-01-01

    The Framework for Science Education and the Next Generation Science Standards in the USA emphasize learning progressions (LPs) that support conceptual coherence and the gradual building of knowledge over time. In the domain of genetics there are two independently developed alternative LPs. In essence, the difference between the two progressions…

  2. The nucleoside diphosphate kinase gene Nme3 acts as quantitative trait locus promoting non-Mendelian inheritance.

    Directory of Open Access Journals (Sweden)

    Hermann Bauer

    Full Text Available The t-haplotype, a variant form of the t-complex region on mouse chromosome 17, acts as selfish genetic element and is transmitted at high frequencies (> 95% from heterozygous (t/+ males to their offspring. This phenotype is termed transmission ratio distortion (TRD and is caused by the interaction of the t-complex responder (Tcr with several quantitative trait loci (QTL, the t-complex distorters (Tcd1 to Tcd4, all located within the t-haplotype region. Current data suggest that the distorters collectively impair motility of all sperm derived from t/+ males; t-sperm is rescued by the responder, whereas (+-sperm remains partially dysfunctional. Recently we have identified two distorters as regulators of RHO small G proteins. Here we show that the nucleoside diphosphate kinase gene Nme3 acts as a QTL on TRD. Reduction of the Nme3 dosage by gene targeting of the wild-type allele enhanced the transmission rate of the t-haplotype and phenocopied distorter function. Genetic and biochemical analysis showed that the t-allele of Nme3 harbors a mutation (P89S that compromises enzymatic activity of the protein and genetically acts as a hypomorph. Transgenic overexpression of the Nme3 t-allele reduced t-haplotype transmission, proving it to be a distorter. We propose that the NME3 protein interacts with RHO signaling cascades to impair sperm motility through hyperactivation of SMOK, the wild-type form of the responder. This deleterious effect of the distorters is counter-balanced by the responder, SMOK(Tcr, a dominant-negative protein kinase exclusively expressed in t-sperm, thus permitting selfish behaviour and preferential transmission of the t-haplotype. In addition, the previously reported association of NME family members with RHO signaling in somatic cell motility and metastasis, in conjunction with our data involving RHO signaling in sperm motility, suggests a functional conservation between mechanisms for motility control in somatic cells and spermatozoa.

  3. A review of instrumental variable estimators for Mendelian randomization.

    Science.gov (United States)

    Burgess, Stephen; Small, Dylan S; Thompson, Simon G

    2017-10-01

    Instrumental variable analysis is an approach for obtaining causal inferences on the effect of an exposure (risk factor) on an outcome from observational data. It has gained in popularity over the past decade with the use of genetic variants as instrumental variables, known as Mendelian randomization. An instrumental variable is associated with the exposure, but not associated with any confounder of the exposure-outcome association, nor is there any causal pathway from the instrumental variable to the outcome other than via the exposure. Under the assumption that a single instrumental variable or a set of instrumental variables for the exposure is available, the causal effect of the exposure on the outcome can be estimated. There are several methods available for instrumental variable estimation; we consider the ratio method, two-stage methods, likelihood-based methods, and semi-parametric methods. Techniques for obtaining statistical inferences and confidence intervals are presented. The statistical properties of estimates from these methods are compared, and practical advice is given about choosing a suitable analysis method. In particular, bias and coverage properties of estimators are considered, especially with weak instruments. Settings particularly relevant to Mendelian randomization are prioritized in the paper, notably the scenario of a continuous exposure and a continuous or binary outcome.

  4. Digital Inheritance in the Netherlands

    NARCIS (Netherlands)

    Berlee, A.

    2017-01-01

    Our accumulation of assets is increasingly digital. What happens to these digital assets upon our death? In this Country Report, the topic of a digital inheritance is discussed in the context of Dutch law. It includes general rules on succession and their application to digital assets, which

  5. Transgenerational epigenetic inheritance in plants☆

    Science.gov (United States)

    Hauser, Marie-Theres; Aufsatz, Werner; Jonak, Claudia; Luschnig, Christian

    2015-01-01

    Interest in transgenerational epigenetic inheritance has intensified with the boosting of knowledge on epigenetic mechanisms regulating gene expression during development and in response to internal and external signals such as biotic and abiotic stresses. Starting with an historical background of scantily documented anecdotes and their consequences, we recapitulate the information gathered during the last 60 years on naturally occurring and induced epialleles and paramutations in plants. We present the major players of epigenetic regulation and their importance in controlling stress responses. The effect of diverse stressors on the epigenetic status and its transgenerational inheritance is summarized from a mechanistic viewpoint. The consequences of transgenerational epigenetic inheritance are presented, focusing on the knowledge about its stability, and in relation to genetically fixed mutations, recombination, and genomic rearrangement. We conclude with an outlook on the importance of transgenerational inheritance for adaptation to changing environments and for practical applications. This article is part of a Special Issue entitled “Epigenetic control of cellular and developmental processes in plants”. PMID:21515434

  6. Transgenerational epigenetic inheritance in plants.

    Science.gov (United States)

    Hauser, Marie-Theres; Aufsatz, Werner; Jonak, Claudia; Luschnig, Christian

    2011-08-01

    Interest in transgenerational epigenetic inheritance has intensified with the boosting of knowledge on epigenetic mechanisms regulating gene expression during development and in response to internal and external signals such as biotic and abiotic stresses. Starting with an historical background of scantily documented anecdotes and their consequences, we recapitulate the information gathered during the last 60 years on naturally occurring and induced epialleles and paramutations in plants. We present the major players of epigenetic regulation and their importance in controlling stress responses. The effect of diverse stressors on the epigenetic status and its transgenerational inheritance is summarized from a mechanistic viewpoint. The consequences of transgenerational epigenetic inheritance are presented, focusing on the knowledge about its stability, and in relation to genetically fixed mutations, recombination, and genomic rearrangement. We conclude with an outlook on the importance of transgenerational inheritance for adaptation to changing environments and for practical applications. This article is part of a Special Issue entitled "Epigenetic control of cellular and developmental processes in plants". Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Inherited polyneuropathy in Leonberger dogs.

    Science.gov (United States)

    Hultin Jäderlund, K; Baranowska Körberg, I; Nødtvedt, A

    2011-01-01

    Although reporting the same clinical phenotype, inherited polyneuropathy in Leonberger dogs (ILPN) has been attributed to various modes of inheritance. The ILPN is one disease with a major risk factor on chromosome X. Dogs affected by ILPN (n = 104). Pedigree analyses were performed by means of a case-control approach. Data were retrieved either from medical records of cases diagnosed by the first author (n = 13), from breeders (n = 18) or from different registries publishing data on affected dogs (n = 73). A comparison was made between the X-chromosome ancestry of fathers of affected male dogs and the ancestry of the X-chromosomes of mothers of affected dogs of either sex. A systematic random sample, obtained from an international database of registered Leonberger dogs, served as a reference population regarding ancestry. Having one particular female, born 1943, in the X-chromosomal lineage is a major risk factor for developing ILPN. Sex distribution among affected dogs is in favor of a risk factor on the X-chromosome and contradicts a monogenic autosomal or mitochondrial inheritance. The ILPN is considered most likely to be one disease, and the inheritance of ILPN is best explained by an underlying X-linked mode of transmission for the phenotype. However, age at onset and severity of signs might be determined by contributing loci. This has consequences in molecular genetic studies and for breeding strategies aimed at eliminating this disease. Copyright © 2011 by the American College of Veterinary Internal Medicine.

  8. Family Inheritances: Transfusion or Transformation

    Directory of Open Access Journals (Sweden)

    Catarina Bray Pinheiro

    2013-12-01

    Full Text Available This article reflects the theme of family inheritances under a psychoanalytic perspective. Concepts of three authors are highlighted: psychic transmission (R. Kaes, telescoping of generations (H. Faimberg, and transgenerational object (A. Eiguer. Clinical perspectives on filiation are questioned, particularly those that result from a practice with the institution, the individual, the family and the group.

  9. Transgenerational inheritance of metabolic disease.

    Science.gov (United States)

    Stegemann, Rachel; Buchner, David A

    2015-07-01

    Metabolic disease encompasses several disorders including obesity, type 2 diabetes, and dyslipidemia. Recently, the incidence of metabolic disease has drastically increased, driven primarily by a worldwide obesity epidemic. Transgenerational inheritance remains controversial, but has been proposed to contribute to human metabolic disease risk based on a growing number of proof-of-principle studies in model organisms ranging from Caenorhabditis elegans to Mus musculus to Sus scrofa. Collectively, these studies demonstrate that heritable risk is epigenetically transmitted from parent to offspring over multiple generations in the absence of a continued exposure to the triggering stimuli. A diverse assortment of initial triggers can induce transgenerational inheritance including high-fat or high-sugar diets, low-protein diets, various toxins, and ancestral genetic variants. Although the mechanistic basis underlying the transgenerational inheritance of disease risk remains largely unknown, putative molecules mediating transmission include small RNAs, histone modifications, and DNA methylation. Due to the considerable impact of metabolic disease on human health, it is critical to better understand the role of transgenerational inheritance of metabolic disease risk to open new avenues for therapeutic intervention and improve upon the current methods for clinical diagnoses and treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Mendelian genes for Parkinson's disease contribute to the sporadic forms of the disease.

    Science.gov (United States)

    Spataro, Nino; Calafell, Francesc; Cervera-Carles, Laura; Casals, Ferran; Pagonabarraga, Javier; Pascual-Sedano, Berta; Campolongo, Antònia; Kulisevsky, Jaime; Lleó, Alberto; Navarro, Arcadi; Clarimón, Jordi; Bosch, Elena

    2015-04-01

    Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Toyama Kametaro and Vernon Kellogg: silkworm inheritance experiments in Japan, Siam, and the United States, 1900-1912.

    Science.gov (United States)

    Onaga, Lisa

    2010-01-01

    Japanese agricultural scientist Toyama Kametaro's report about the Mendelian inheritance of silkworm cocoon color in Studies on the Hybridology of Insects (1906) spurred changes in Japanese silk production and thrust Toyama and his work into a scholarly exchange with American entomologist Vernon Kellogg. Toyama's work, based on research conducted in Japan and Siam, came under international scrutiny at a time when analyses of inheritance flourished after the "rediscovery" of Mendel's laws of heredity in 1900. The hybrid silkworm studies in Asia attracted the attention of Kellogg, who was concerned with how experimental biology would be used to study the causes of natural selection. He challenged Toyama's conclusions that Mendelism alone could explain the inheritance patterns of silkworm characters such as cocoon color because they had been subject to hundreds of years of artificial selection, or breeding. This examination of the intersection of Japanese sericulture and American entomology probes how practical differences in scientific interests, societal responsibilities, and silkworm materiality were negotiated throughout the processes of legitimating Mendelian genetics on opposite sides of the Pacific. The ways in which Toyama and Kellogg assigned importance to certain silkworm properties show how conflicting intellectual orientations arose in studies of the same organism. Contestation about Mendelism took place not just on a theoretical level, but the debate was fashioned through each scientist's rationale about the categorization of silkworm breeds and races and what counted as "natural". This further mediated the acceptability of the silkworm not as an experimental organism, but as an appropriately "natural" insect with which to demonstrate laws of inheritance. All these shed light on the challenges that came along with the use of agricultural animals to convincingly articulate new biological principles.

  12. Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study.

    Science.gov (United States)

    van der Laan, Sander W; Fall, Tove; Soumaré, Aicha; Teumer, Alexander; Sedaghat, Sanaz; Baumert, Jens; Zabaneh, Delilah; van Setten, Jessica; Isgum, Ivana; Galesloot, Tessel E; Arpegård, Johannes; Amouyel, Philippe; Trompet, Stella; Waldenberger, Melanie; Dörr, Marcus; Magnusson, Patrik K; Giedraitis, Vilmantas; Larsson, Anders; Morris, Andrew P; Felix, Janine F; Morrison, Alanna C; Franceschini, Nora; Bis, Joshua C; Kavousi, Maryam; O'Donnell, Christopher; Drenos, Fotios; Tragante, Vinicius; Munroe, Patricia B; Malik, Rainer; Dichgans, Martin; Worrall, Bradford B; Erdmann, Jeanette; Nelson, Christopher P; Samani, Nilesh J; Schunkert, Heribert; Marchini, Jonathan; Patel, Riyaz S; Hingorani, Aroon D; Lind, Lars; Pedersen, Nancy L; de Graaf, Jacqueline; Kiemeney, Lambertus A L M; Baumeister, Sebastian E; Franco, Oscar H; Hofman, Albert; Uitterlinden, André G; Koenig, Wolfgang; Meisinger, Christa; Peters, Annette; Thorand, Barbara; Jukema, J Wouter; Eriksen, Bjørn Odvar; Toft, Ingrid; Wilsgaard, Tom; Onland-Moret, N Charlotte; van der Schouw, Yvonne T; Debette, Stéphanie; Kumari, Meena; Svensson, Per; van der Harst, Pim; Kivimaki, Mika; Keating, Brendan J; Sattar, Naveed; Dehghan, Abbas; Reiner, Alex P; Ingelsson, Erik; den Ruijter, Hester M; de Bakker, Paul I W; Pasterkamp, Gerard; Ärnlöv, Johan; Holmes, Michael V; Asselbergs, Folkert W

    2016-08-30

    Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Education and coronary heart disease: mendelian randomisation study.

    Science.gov (United States)

    Tillmann, Taavi; Vaucher, Julien; Okbay, Aysu; Pikhart, Hynek; Peasey, Anne; Kubinova, Ruzena; Pajak, Andrzej; Tamosiunas, Abdonas; Malyutina, Sofia; Hartwig, Fernando Pires; Fischer, Krista; Veronesi, Giovanni; Palmer, Tom; Bowden, Jack; Davey Smith, George; Bobak, Martin; Holmes, Michael V

    2017-08-30

    Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease.Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding.Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors.Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin.Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education.Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D).Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10-8). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile.Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the

  14. Microelements and inherited metabolic diseases.

    Science.gov (United States)

    Marklová, Eliska

    2002-01-01

    In addition to the main groups of inherited metabolic diseases, including mitochondrial, peroxisomal and lysosomal defects, organic acidurias, porphyrias, defects of amino acids, saccharides and fatty acids metabolism, disorders of transport and utilisation of microelements have also been recognized. Recent findings concerning hereditary hemochromatosis (iron), Wilson and Menkes diseases (copper), molybdenum cofactor deficiency (molybdenum), defects of cobalamine synthesis (cobalt) and acrodermatitis enteropathica (zinc) are reviewed.

  15. [Maternally Inherited Diabetes and Deafness].

    Science.gov (United States)

    Sampedro, A; Barbón, J J; Alvarez, J A; Andrés, M A; Baldó, C

    2009-07-01

    We described the follow up of a patient with diabetes mellitus type 2 who had a macular pattern dystrophy and bilateral neurosensory hearing loss. Electrophysiological studies revealed abnormal pattern electroretinography and impaired electro-oculogram responses. Maternally Inherited Diabetes, neurosensory Deafness and generally macular pattern distrophy (MIDD syndrome), is a rare mitochondrial disease, responsible for approximately 0.5 to 2.8% of diabetes mellitus.

  16. Utilizing inheritance in requirements engineering

    Science.gov (United States)

    Kaindl, Hermann

    1994-01-01

    The scope of this paper is the utilization of inheritance for requirements specification, i.e., the tasks of analyzing and modeling the domain, as well as forming and defining requirements. Our approach and the tool supporting it are named RETH (Requirements Engineering Through Hypertext). Actually, RETH uses a combination of various technologies, including object-oriented approaches and artificial intelligence (in particular frames). We do not attempt to exclude or replace formal representations, but try to complement and provide means for gradually developing them. Among others, RETH has been applied in the CERN (Conseil Europeen pour la Rechereche Nucleaire) Cortex project. While it would be impossible to explain this project in detail here, it should be sufficient to know that it deals with a generic distributed control system. Since this project is not finished yet, it is difficult to state its size precisely. In order to give an idea, its final goal is to substitute the many existing similar control systems at CERN by this generic approach. Currently, RETH is also tested using real-world requirements for the Pastel Mission Planning System at ESOC in Darmstadt. First, we outline how hypertext is integrated into a frame system in our approach. Moreover, the usefulness of inheritance is demonstrated as performed by the tool RETH. We then summarize our experiences of utilizing inheritance in the Cortex project. Lastly, RETH will be related to existing work.

  17. How-to-Do-It: Hands-on Activities that Relate Mendelian Genetics to Cell Division.

    Science.gov (United States)

    McKean, Heather R.; Gibson, Linda S.

    1989-01-01

    Presented is an activity designed to connect Mendelian laws with the physical processes of cell division. Included are materials production, procedures and worksheets for the meiosis-mitosis game and a genetics game. (CW)

  18. A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease.

    Science.gov (United States)

    Smedley, Damian; Schubach, Max; Jacobsen, Julius O B; Köhler, Sebastian; Zemojtel, Tomasz; Spielmann, Malte; Jäger, Marten; Hochheiser, Harry; Washington, Nicole L; McMurry, Julie A; Haendel, Melissa A; Mungall, Christopher J; Lewis, Suzanna E; Groza, Tudor; Valentini, Giorgio; Robinson, Peter N

    2016-09-01

    The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  19. Few Mendelian genes underlie the quantitative response of a forest tree, Eucalyptus globulus, to a natural fungal epidemic.

    Science.gov (United States)

    Freeman, Jules S; Potts, Brad M; Vaillancourt, René E

    2008-01-01

    Foliar fungal pathogens from the genus Mycosphaerella affect eucalyptus in natural forests and plantations worldwide. QTL analysis was conducted to dissect the genetic control of resistance in Eucalyptus globulus to a natural infection by Mycosphaerella leaf disease, using a clonally replicated outbred F2 family (112 genotypes) planted in a field trial. Two major QTL, with high LOD support (20.2 and 10.9) and high genomewide significance, explained a large proportion (52%) of the phenotypic variance in the severity of damage by Mycosphaerella cryptica, which may be indicative of oligogenic control. Both QTL were validated in a second F2 family and one was validated in a third F2 family. The mean values of different genotype classes at both major QTL argue for Mendelian inheritance with resistance dominant over susceptibility. There were strong correlations between the levels of Mycosphaerella damage in related genetic material planted in three widely separated locations in Tasmania. These findings together provide evidence that the genes controlling resistance to Mycosphaerella damage are stable in different genetic backgrounds and across different environments.

  20. Inherited susceptibility and radiation exposure

    Energy Technology Data Exchange (ETDEWEB)

    Little, J.B. [Harvard School of Public Health, Boston, MA (United States)

    1997-03-01

    There is continuing concern that some people in the general population may have genetic makeups that place them at particularly high risk for radiation-induced cancer. The existence of such a susceptible subpopulation would have obvious implications for the estimation of risks of radiation exposure. Although it has been long known that familial aggregations of cancer do sometimes occur, recent evidence suggests that a general genetic predisposition to cancer does not exist; most cancers occur sporadically. On the other hand, nearly 10% of the known Mendelian genetic disorders are associated with cancer. A number of these involve a familial predisposition to cancer, and some are characterized by an enhanced susceptibility to the induction of cancer by various physical and chemical carcinogens, including ionizing radiation. Such increased susceptibility will depend on several factors including the frequency of the susceptibility gene in the population and its penetrance, the strength of the predisposition, and the degree to which the cancer incidence in susceptible individuals may be increased by the carcinogen. It is now known that these cancer-predisposing genes may be responsible not only for rare familial cancer syndromes, but also for a proportion of the common cancers. Although the currently known disorders can account for only a small fraction of all cancers, they serve as models for genetic predisposition to carcinogen-induced cancer in the general population. In the present report, the author describes current knowledge of those specific disorders that are associated with an enhanced predisposition to radiation-induced cancer, and discusses how this knowledge may bear on the susceptibility to radiation-induced cancer in the general population and estimates of the risk of radiation exposure.

  1. Clinical characteristics and inheritance of idiopathic epilepsy in Vizslas.

    Science.gov (United States)

    Patterson, Edward E; Mickelson, James R; Da, Yang; Roberts, Monica C; McVey, Alistair S; O'Brien, Dennis P; Johnson, Gary S; Armstrong, P Jane

    2003-01-01

    Medical record, seizure survey, and telephone interview information was obtained for 29 Vizslas with idiopathic epilepsy (IE), 74 unaffected siblings, and 41 parents to determine the common clinical characteristics and most likely mode of inheritance. IE was diagnosed on the basis of the age of seizure onset, laboratory results, and neurologic examination findings. Computerized tomography (CT) or magnetic resonance imaging (MRI) scan with cerebrospinal fluid (CSF) analysis was required for the inclusion of dogs with an age of seizure onset of 5 years. Simple segregation analysis was performed with an ascertainment correction and chi-square analysis. IE appeared to be familial in these pedigrees, with 79% of affected Vizslas exhibiting partial onset seizures. Partial seizure signs included a combination of limb tremors, staring, pupillary dilatation, or salivation without loss of consciousness in > 50% of the dogs with partial signs. The estimated segregation frequency of P = .22 (95% CI, P = .08 to .36) was consistent with autosomal recessive inheritance; however, polygenic inheritance could not be excluded as a possibility. Simulated linkage with FASTSLINK estimated that the average logarithm of odds (LOD) score would be 3.23 with a 10-centimorgan (cM) whole-genome scan for these families, indicating that these families would be useful for a whole-genome scan to potentially find the chromosomal segment(s) containing the epilepsy gene or genes. We conclude that IE in Vizslas appears to be primarily a partial onset seizure disorder that may be inherited as an autosomal recessive trait.

  2. Plate tectonics, damage and inheritance.

    Science.gov (United States)

    Bercovici, David; Ricard, Yanick

    2014-04-24

    The initiation of plate tectonics on Earth is a critical event in our planet's history. The time lag between the first proto-subduction (about 4 billion years ago) and global tectonics (approximately 3 billion years ago) suggests that plates and plate boundaries became widespread over a period of 1 billion years. The reason for this time lag is unknown but fundamental to understanding the origin of plate tectonics. Here we suggest that when sufficient lithospheric damage (which promotes shear localization and long-lived weak zones) combines with transient mantle flow and migrating proto-subduction, it leads to the accumulation of weak plate boundaries and eventually to fully formed tectonic plates driven by subduction alone. We simulate this process using a grain evolution and damage mechanism with a composite rheology (which is compatible with field and laboratory observations of polycrystalline rocks), coupled to an idealized model of pressure-driven lithospheric flow in which a low-pressure zone is equivalent to the suction of convective downwellings. In the simplest case, for Earth-like conditions, a few successive rotations of the driving pressure field yield relic damaged weak zones that are inherited by the lithospheric flow to form a nearly perfect plate, with passive spreading and strike-slip margins that persist and localize further, even though flow is driven only by subduction. But for hotter surface conditions, such as those on Venus, accumulation and inheritance of damage is negligible; hence only subduction zones survive and plate tectonics does not spread, which corresponds to observations. After plates have developed, continued changes in driving forces, combined with inherited damage and weak zones, promote increased tectonic complexity, such as oblique subduction, strike-slip boundaries that are subparallel to plate motion, and spalling of minor plates.

  3. Simple machines

    CERN Document Server

    Graybill, George

    2007-01-01

    Just how simple are simple machines? With our ready-to-use resource, they are simple to teach and easy to learn! Chocked full of information and activities, we begin with a look at force, motion and work, and examples of simple machines in daily life are given. With this background, we move on to different kinds of simple machines including: Levers, Inclined Planes, Wedges, Screws, Pulleys, and Wheels and Axles. An exploration of some compound machines follows, such as the can opener. Our resource is a real time-saver as all the reading passages, student activities are provided. Presented in s

  4. Atypical mitochondrial inheritance patterns in eukaryotes.

    Science.gov (United States)

    Breton, Sophie; Stewart, Donald T

    2015-10-01

    Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance (SMI) of mtDNA have been described, but the evolutionary forces responsible for its predominance in eukaryotes remain to be elucidated. Exceptions to SMI have been reported in diverse eukaryotic taxa, leading to the prediction that several distinct molecular mechanisms controlling mtDNA transmission are present among the eukaryotes. We propose that these mechanisms will be better understood by studying the deviations from the predominating pattern of SMI. This minireview summarizes studies on eukaryote species with unusual or rare mitochondrial inheritance patterns, i.e., other than the predominant SMI pattern, such as maternal inheritance of stable heteroplasmy, paternal leakage of mtDNA, biparental and strictly paternal inheritance, and doubly uniparental inheritance of mtDNA. The potential genes and mechanisms involved in controlling mitochondrial inheritance in these organisms are discussed. The linkage between mitochondrial inheritance and sex determination is also discussed, given that the atypical systems of mtDNA inheritance examined in this minireview are frequently found in organisms with uncommon sexual systems such as gynodioecy, monoecy, or andromonoecy. The potential of deviations from SMI for facilitating a better understanding of a number of fundamental questions in biology, such as the evolution of mtDNA inheritance, the coevolution of nuclear and mitochondrial genomes, and, perhaps, the role of mitochondria in sex determination, is considerable.

  5. The RNAi Inheritance Machinery of Caenorhabditis elegans.

    Science.gov (United States)

    Spracklin, George; Fields, Brandon; Wan, Gang; Becker, Diveena; Wallig, Ashley; Shukla, Aditi; Kennedy, Scott

    2017-07-01

    Gene silencing mediated by dsRNA (RNAi) can persist for multiple generations in Caenorhabditis elegans (termed RNAi inheritance). Here we describe the results of a forward genetic screen in C. elegans that has identified six factors required for RNAi inheritance: GLH-1/VASA, PUP-1/CDE-1, MORC-1, SET-32, and two novel nematode-specific factors that we term here (heritable RNAi defective) HRDE-2 and HRDE-4 The new RNAi inheritance factors exhibit mortal germline (Mrt) phenotypes, which we show is likely caused by epigenetic deregulation in germ cells. We also show that HRDE-2 contributes to RNAi inheritance by facilitating the binding of small RNAs to the inheritance Argonaute (Ago) HRDE-1 Together, our results identify additional components of the RNAi inheritance machinery whose conservation provides insights into the molecular mechanism of RNAi inheritance, further our understanding of how the RNAi inheritance machinery promotes germline immortality, and show that HRDE-2 couples the inheritance Ago HRDE-1 with the small RNAs it needs to direct RNAi inheritance and germline immortality. Copyright © 2017 by the Genetics Society of America.

  6. Potential roles for prions and protein-only inheritance in cancer

    Science.gov (United States)

    Antony, H; Wiegmans, AP; Wei, MQ; Chernoff, YO; Khanna, KK; Munn, AL

    2011-01-01

    Inherited mutations are known to cause familial cancers. However, the cause of sporadic cancers, which likely represent the majority of cancers, is yet to be elucidated. Sporadic cancers contain somatic mutations (including oncogenic mutations), however, the origin of these mutations is unclear. An intriguing possibility is that a stable alteration occurs in somatic cells prior to oncogenic mutations and promotes the subsequent accumulation of oncogenic mutations. This review explores the possible role of prions and protein-only inheritance in cancer. Genetic studies using lower eukaryotes, primarily yeast, have identified a large number of proteins as prions that confer dominant phenotypes with cytoplasmic (non-Mendelian) inheritance. Many of these have mammalian functional homologs. The human prion protein (PrP) is known to cause neurodegenerative diseases and has now been found to be up-regulated in multiple cancers. PrP expression in cancer cells contributes to cancer progression and resistance to various cancer therapies. Epigenetic changes in gene expression and hyper-activation of MAP kinase (MAPK) signalling, processes that in lower eukaryotes are affected by prions, play important roles in oncogenesis in humans. Prion phenomena in yeast appear to be influenced by stresses and there is considerable evidence for association of some amyloids with biologically positive functions. This suggests that if protein-only somatic inheritance exists in mammalian cells, it might contribute to cancer phenotypes. Here we highlight evidence in the literature for an involvement of prion or prion-like mechanisms in cancer and how they may in the future be viewed as diagnostic markers and potential therapeutic targets. PMID:22138778

  7. Mendelian randomization of blood lipids for coronary heart disease.

    Science.gov (United States)

    Holmes, Michael V; Asselbergs, Folkert W; Palmer, Tom M; Drenos, Fotios; Lanktree, Matthew B; Nelson, Christopher P; Dale, Caroline E; Padmanabhan, Sandosh; Finan, Chris; Swerdlow, Daniel I; Tragante, Vinicius; van Iperen, Erik P A; Sivapalaratnam, Suthesh; Shah, Sonia; Elbers, Clara C; Shah, Tina; Engmann, Jorgen; Giambartolomei, Claudia; White, Jon; Zabaneh, Delilah; Sofat, Reecha; McLachlan, Stela; Doevendans, Pieter A; Balmforth, Anthony J; Hall, Alistair S; North, Kari E; Almoguera, Berta; Hoogeveen, Ron C; Cushman, Mary; Fornage, Myriam; Patel, Sanjay R; Redline, Susan; Siscovick, David S; Tsai, Michael Y; Karczewski, Konrad J; Hofker, Marten H; Verschuren, W Monique; Bots, Michiel L; van der Schouw, Yvonne T; Melander, Olle; Dominiczak, Anna F; Morris, Richard; Ben-Shlomo, Yoav; Price, Jackie; Kumari, Meena; Baumert, Jens; Peters, Annette; Thorand, Barbara; Koenig, Wolfgang; Gaunt, Tom R; Humphries, Steve E; Clarke, Robert; Watkins, Hugh; Farrall, Martin; Wilson, James G; Rich, Stephen S; de Bakker, Paul I W; Lange, Leslie A; Davey Smith, George; Reiner, Alex P; Talmud, Philippa J; Kivimäki, Mika; Lawlor, Debbie A; Dudbridge, Frank; Samani, Nilesh J; Keating, Brendan J; Hingorani, Aroon D; Casas, Juan P

    2015-03-01

    To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

  8. Mendelian randomization of blood lipids for coronary heart disease

    Science.gov (United States)

    Holmes, Michael V.; Asselbergs, Folkert W.; Palmer, Tom M.; Drenos, Fotios; Lanktree, Matthew B.; Nelson, Christopher P.; Dale, Caroline E.; Padmanabhan, Sandosh; Finan, Chris; Swerdlow, Daniel I.; Tragante, Vinicius; van Iperen, Erik P.A.; Sivapalaratnam, Suthesh; Shah, Sonia; Elbers, Clara C.; Shah, Tina; Engmann, Jorgen; Giambartolomei, Claudia; White, Jon; Zabaneh, Delilah; Sofat, Reecha; McLachlan, Stela; Doevendans, Pieter A.; Balmforth, Anthony J.; Hall, Alistair S.; North, Kari E.; Almoguera, Berta; Hoogeveen, Ron C.; Cushman, Mary; Fornage, Myriam; Patel, Sanjay R.; Redline, Susan; Siscovick, David S.; Tsai, Michael Y.; Karczewski, Konrad J.; Hofker, Marten H.; Verschuren, W. Monique; Bots, Michiel L.; van der Schouw, Yvonne T.; Melander, Olle; Dominiczak, Anna F.; Morris, Richard; Ben-Shlomo, Yoav; Price, Jackie; Kumari, Meena; Baumert, Jens; Peters, Annette; Thorand, Barbara; Koenig, Wolfgang; Gaunt, Tom R.; Humphries, Steve E.; Clarke, Robert; Watkins, Hugh; Farrall, Martin; Wilson, James G.; Rich, Stephen S.; de Bakker, Paul I.W.; Lange, Leslie A.; Davey Smith, George; Reiner, Alex P.; Talmud, Philippa J.; Kivimäki, Mika; Lawlor, Debbie A.; Dudbridge, Frank; Samani, Nilesh J.; Keating, Brendan J.; Hingorani, Aroon D.; Casas, Juan P.

    2015-01-01

    Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10−6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain. PMID:24474739

  9. Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.

    Directory of Open Access Journals (Sweden)

    Søren D Østergaard

    2015-06-01

    Full Text Available Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR.We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49, fasting glucose (NSNPs = 36, insulin resistance (NSNPs = 10, body mass index (BMI, NSNPs = 32, total cholesterol (NSNPs = 73, HDL-cholesterol (NSNPs = 71, LDL-cholesterol (NSNPs = 57, triglycerides (NSNPs = 39, systolic blood pressure (SBP, NSNPs = 24, smoking initiation (NSNPs = 1, smoking quantity (NSNPs = 3, university completion (NSNPs = 2, and years of education (NSNPs = 1. We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3. Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8. Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3, although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28. We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1. Potential limitations of this study

  10. Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.

    Science.gov (United States)

    Østergaard, Søren D; Mukherjee, Shubhabrata; Sharp, Stephen J; Proitsi, Petroula; Lotta, Luca A; Day, Felix; Perry, John R B; Boehme, Kevin L; Walter, Stefan; Kauwe, John S; Gibbons, Laura E; Larson, Eric B; Powell, John F; Langenberg, Claudia; Crane, Paul K; Wareham, Nicholas J; Scott, Robert A

    2015-06-01

    Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this

  11. Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease.

    Science.gov (United States)

    Fernández, Maria Victoria; Kim, Jong Hun; Budde, John P; Black, Kathleen; Medvedeva, Alexandra; Saef, Ben; Deming, Yuetiva; Del-Aguila, Jorge; Ibañez, Laura; Dube, Umber; Harari, Oscar; Norton, Joanne; Chasse, Rachel; Morris, John C; Goate, Alison; Cruchaga, Carlos

    2017-11-01

    Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations.

  12. Imprinting Disorders: Non-Mendelian Mechanisms Affecting Growth

    Science.gov (United States)

    Butler, Merlin G.

    2016-01-01

    Most autosomal genes are expressed from both maternal and paternal alleles. However, imprinted genes are an example of non-Mendelian genetics, in which only one member of the gene pair is expressed and expression is determined by the parent of origin. Imprinted genes may account for 0.1–1% of all mammalian genes. At least 50 imprinted genes have been identified in humans, and imprinted genes frequently cluster under the control of an imprinting center. Many imprinted genes contribute to growth, either as growth factors, such as insulin-like growth factors (IGF2 in Beckwith-Wiedemann syndrome), or as growth inhibitors, such as the GRB10 gene in Russell-Silver syndrome. Imprinted genes have evolved over time in mammals to fine-tune the growth of the fetus. Paternally expressed genes generally enhance growth, whereas maternally expressed genes appear to suppress growth. In addition, normal and abnormal genomic imprinting and loss of heterozygosity contribute to a wide range of malignancies. A common process for controlling gene activity is methylation, which can be changed during male or female gametogenesis. Examples of classic human disorders related to genomic imprinting are Beckwith-Wiedemann syndrome (chromosome 11), Prader-Willi/Angelman syndromes (chromosome 15), Russell-Silver syndrome (chromosome 7), and Albright hereditary osteodystrophy (chromosome 20). Several of these disorders are discussed and illustrated. PMID:12510981

  13. Mapping Mendelian Factors Underlying Quantitative Traits Using RFLP Linkage Maps

    Science.gov (United States)

    Lander, E. S.; Botstein, D.

    1989-01-01

    The advent of complete genetic linkage maps consisting of codominant DNA markers [typically restriction fragment length polymorphisms (RFLPs)] has stimulated interest in the systematic genetic dissection of discrete Mendelian factors underlying quantitative traits in experimental organisms. We describe here a set of analytical methods that modify and extend the classical theory for mapping such quantitative trait loci (QTLs). These include: (i) a method of identifying promising crosses for QTL mapping by exploiting a classical formula of SEWALL WRIGHT; (ii) a method (interval mapping) for exploiting the full power of RFLP linkage maps by adapting the approach of LOD score analysis used in human genetics, to obtain accurate estimates of the genetic location and phenotypic effect of QTLs; and (iii) a method (selective genotyping) that allows a substantial reduction in the number of progeny that need to be scored with the DNA markers. In addition to the exposition of the methods, explicit graphs are provided that allow experimental geneticists to estimate, in any particular case, the number of progeny required to map QTLs underlying a quantitative trait. PMID:2563713

  14. Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.

    Science.gov (United States)

    Benitez, Bruno A; Davis, Albert A; Jin, Sheng Chih; Ibanez, Laura; Ortega-Cubero, Sara; Pastor, Pau; Choi, Jiyoon; Cooper, Breanna; Perlmutter, Joel S; Cruchaga, Carlos

    2016-04-19

    Most sequencing studies in Parkinson's disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815). Disease-causing variants in the SNCA, LRRK2 and PARK2 genes were found in 2% of PD patients. The LRRK2, p.G2019S mutation was found in 0.6 % of sporadic PD and 4.8 % of familial PD cases. Gene-based analysis suggests that additional variants in the LRRK2 gene also contribute to PD risk. The SNCA duplication was found in 0.8 % of familial PD patients. Novel variants were found in 0.8% of PD cases and 0.6 % of controls. Heterozygous Gaucher disease-causing mutations in the GBA gene were found in 7.1 % of PD patients. Here, we established that the GBA variant (p.T408M) is associated with PD risk and age at onset. Additionally, gene-based and single-variant analyses demostrated that GBA gene variants (p.L483P, p.R83C, p.N409S, p.H294Q and p.E365K) increase PD risk. Our data suggest that the impact of additional untested coding variants in the GBA and LRRK2 genes is higher than previously estimated. Our data also provide compelling evidence of the existence of additional untested variants in the primary Mendelian and PD GWAS genes that contribute to the genetic etiology of sporadic PD.

  15. Social inheritance can explain the structure of animal social networks

    Science.gov (United States)

    Ilany, Amiyaal; Akçay, Erol

    2016-01-01

    The social network structure of animal populations has major implications for survival, reproductive success, sexual selection and pathogen transmission of individuals. But as of yet, no general theory of social network structure exists that can explain the diversity of social networks observed in nature, and serve as a null model for detecting species and population-specific factors. Here we propose a simple and generally applicable model of social network structure. We consider the emergence of network structure as a result of social inheritance, in which newborns are likely to bond with maternal contacts, and via forming bonds randomly. We compare model output with data from several species, showing that it can generate networks with properties such as those observed in real social systems. Our model demonstrates that important observed properties of social networks, including heritability of network position or assortative associations, can be understood as consequences of social inheritance. PMID:27352101

  16. Social inheritance can explain the structure of animal social networks.

    Science.gov (United States)

    Ilany, Amiyaal; Akçay, Erol

    2016-06-28

    The social network structure of animal populations has major implications for survival, reproductive success, sexual selection and pathogen transmission of individuals. But as of yet, no general theory of social network structure exists that can explain the diversity of social networks observed in nature, and serve as a null model for detecting species and population-specific factors. Here we propose a simple and generally applicable model of social network structure. We consider the emergence of network structure as a result of social inheritance, in which newborns are likely to bond with maternal contacts, and via forming bonds randomly. We compare model output with data from several species, showing that it can generate networks with properties such as those observed in real social systems. Our model demonstrates that important observed properties of social networks, including heritability of network position or assortative associations, can be understood as consequences of social inheritance.

  17. Genetics of spike-wave discharges in the electroencephalogram (EEG) of the WAG/Rij inbred rat strain: a classical mendelian crossbreeding study.

    Science.gov (United States)

    Peeters, B W; Kerbusch, J M; Coenen, A M; Vossen, J M; van Luijtelaar, E L

    1992-05-01

    The WAG inbred strain might be an animal model for human absence epilepsy. To study the inheritance pattern of absence epilepsy, WAG rats were crossbred, in a classical Mendelian way, with inbred ACI rats which show no signs of epilepsy. In the parental strains, reciprocal F1 hybrids, F2, B1, and B2 generations, the number and duration of spike-wave discharges were determined. One hundred percent of the F1 animals showed spike-wave discharges, while the percentages for the F2, B1, and B2 generations were 79, 95, and 37%, respectively. These results suggest that the occurrence of spike-wave discharges is determined by one gene with a dominant mode of inheritance. Cavalli's least-squares fitting procedure suggested different genetic models for the two parameters (number and duration) during the two periods (dark and light). These results confirm our previous findings (Peeters et al., Behav. Genet. 20, 453-460, 1990) that a number of genes are involved in absence epilepsy. One dominant gene appears to determine the occurrence, however, while others manipulate the number and duration of epileptic phenomena during the two periods dark and light.

  18. Inheritance of epigenetic chromatin silencing.

    Science.gov (United States)

    David-Rus, Diana; Mukhopadhyay, Swagatam; Lebowitz, Joel L; Sengupta, Anirvan M

    2009-05-07

    Maintenance of alternative chromatin states through cell divisions pose some fundamental constraints on the dynamics of histone modifications. In this paper, we study the systems biology of epigenetic inheritance by defining and analyzing general classes of mathematical models. We discuss how the number of modification states involved plays an essential role in the stability of epigenetic states. In addition, DNA duplication and the consequent dilution of marked histones act as a large perturbation for a stable state of histone modifications. The requirement that this large perturbation falls into the basin of attraction of the original state sometimes leads to additional constraints on effective models. Two such models, inspired by two different biological systems, are compared in their fulfilling the requirements of multistability and of recovery after DNA duplication. We conclude that in the presence of multiple histone modifications that characterize alternative epigenetic stable states, these requirements are more easily fulfilled.

  19. [Pathogenesis study of inherited dysfibrinogenemia].

    Science.gov (United States)

    Liao, Zhaoping; Xu, Siqi; Tang, Huqiang; Xie, Yiyi; Duan, Xiuzhi; Liu, Chunhua; Cheng, Yue; Chen, Yuhua; Wang, Deqiang; Luo, Miao; Tao, Zhihua

    2014-03-18

    To explore the pathogenesis of a family with inherited dysfibrinogenemia. Coagulation parameters of peripheral venous blood of a family with inherited dysfibrinogenemia from November 2012 were measured. And platelet and fibrinogen functions were examined by thromboelastogram. The antigen concentration of fibrinogen was detected by immune nephelometry. All exons and exon-intron boundaries of FGA, FGB and FGG were amplified and subjected to mutation screening by direct/reverse sequencing. And the influences of mutant fibrinogen structure and function were analyzed and predicated by a molecular structure model. The values of activated partial thromboplastin time (APTT), D-dimer and fibrinogen antigen of the propositus and his mother (I-2), younger brother (II-3), younger sister (II-2) and daughter (III-1) were all in normal reference value ranges.However thrombin time (TT) was significantly prolonged and the activity of fibrinogen was much lower compared to its antigenicity. Thromboelastogram indicated normal function of platelet and impaired function of fibrinogen of I-2, II-2 and III-1.However the fibrinogen functions of proband and II-3 became much more impaired. Mutation screening demonstrated the homozygous mutation of proband and II-3 while I-2, II-2 and III-1 showed heterozygous mutation of FGG c.1001 A>C (p. Asn308Thr). No mutation was detected among other family members and reducing SDS-PAGE immunoblot showed no variants. Asn308, located at the interface of fibrinogen dimmer, participated in the fibrous structure assembling from the structure model. And mutation at this position will affect the stability of fiber structure. FGG c.1001 A>C mutation may account for dominant genetic dysfibrinogenemia in these family members.

  20. Beyond Mendelian randomization: how to interpret evidence of shared genetic predictors.

    Science.gov (United States)

    Burgess, Stephen; Butterworth, Adam S; Thompson, John R

    2016-01-01

    Mendelian randomization is a popular technique for assessing and estimating the causal effects of risk factors. If genetic variants which are instrumental variables for a risk factor are shown to be additionally associated with a disease outcome, then the risk factor is a cause of the disease. However, in many cases, the instrumental variable assumptions are not plausible, or are in doubt. In this paper, we provide a theoretical classification of scenarios in which a causal conclusion is justified or not justified, and discuss the interpretation of causal effect estimates. A list of guidelines based on the 'Bradford Hill criteria' for judging the plausibility of a causal finding from an applied Mendelian randomization study is provided. We also give a framework for performing and interpreting investigations performed in the style of Mendelian randomization, but where the choice of genetic variants is statistically, rather than biologically motivated. Such analyses should not be assigned the same evidential weight as a Mendelian randomization investigation. We discuss the role of such investigations (in the style of Mendelian randomization), and what they add to our understanding of potential causal mechanisms. If the genetic variants are selected solely according to statistical criteria, and the biological roles of genetic variants are not investigated, this may be little more than what can be learned from a well-designed classical observational study. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar.

    Science.gov (United States)

    Rodriguez-Flores, Juan L; Fakhro, Khalid; Hackett, Neil R; Salit, Jacqueline; Fuller, Jennifer; Agosto-Perez, Francisco; Gharbiah, Maey; Malek, Joel A; Zirie, Mahmoud; Jayyousi, Amin; Badii, Ramin; Al-Nabet Al-Marri, Ajayeb; Chouchane, Lotfi; Stadler, Dora J; Mezey, Jason G; Crystal, Ronald G

    2014-01-01

    Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared with 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Premarital genetic screening in Qatar tests for only four out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance. © 2013 WILEY PERIODICALS, INC.

  2. Legal Portion in Russian Inheritance Law

    Science.gov (United States)

    Inshina, Roza; Murzalimova, Lyudmila

    2013-01-01

    In this paper the authors describe the right to inherit as one of the basic human rights guaranteed by the Constitution of the Russian Federation. The state has set rules according to which after a person's death, his or her property is inherited by other persons. The Russian civil legislation establishes the institution of legal portions that is…

  3. Moderate alcohol use and cardiovascular disease from Mendelian randomization.

    Directory of Open Access Journals (Sweden)

    Shiu Lun Au Yeung

    Full Text Available BACKGROUND: Observational studies show moderate alcohol use negatively associated with ischemic heart disease (IHD and cardiovascular disease (CVD. However, healthier attributes among moderate users compared to never users may confound the apparent association. A potentially less biased way to examine the association is Mendelian randomization, using alcohol metabolizing genes which influence alcohol use. METHODS: We used instrumental variable analysis with aldehyde dehydrogenase 2 (ALDH2 genotypes (AA/GA/GG as instrumental variables for alcohol use to examine the association of alcohol use (10 g ethanol/day with CVD risk factors (blood pressure, lipids and glucose and morbidity (self-reported IHD and CVD among men in the Guangzhou Biobank Cohort Study. RESULTS: ALDH2 genotypes were a credible instrument for alcohol use (F-statistic 74.6. Alcohol was positively associated with HDL-cholesterol (0.05 mmol/L per alcohol unit, 95% confidence interval (CI 0.02 to 0.08 and diastolic blood pressure (1.15 mmHg, 95% CI 0.23 to 2.07 but not with systolic blood pressure (1.00 mmHg, 95% CI -0.74 to 2.74, LDL-cholesterol (0.03 mmol/L, 95% CI -0.03 to 0.08, log transformed triglycerides (0.03 mmol/L, 95% CI -0.01 to 0.08 or log transformed fasting glucose (0.01 mmol/L, 95% CI -0.006 to 0.03, self-reported CVD (odds ratio (OR 0.98, 95% CI 0.76 to 1.27 or self-reported IHD (OR 1.10, 95% CI 0.83 to 1.45. CONCLUSION: Low to moderate alcohol use among men had the expected effects on most CVD risk factors but not fasting glucose. Larger studies are needed to confirm the null associations with IHD, CVD and fasting glucose.

  4. The evolutionary implications of epigenetic inheritance.

    Science.gov (United States)

    Jablonka, Eva

    2017-10-06

    The Modern Evolutionary Synthesis (MS) forged in the mid-twentieth century was built on a notion of heredity that excluded soft inheritance, the inheritance of the effects of developmental modifications. However, the discovery of molecular mechanisms that generate random and developmentally induced epigenetic variations is leading to a broadening of the notion of biological heredity that has consequences for ideas about evolution. After presenting some old challenges to the MS that were raised, among others, by Karl Popper, I discuss recent research on epigenetic inheritance, which provides experimental and theoretical support for these challenges. There is now good evidence that epigenetic inheritance is ubiquitous and is involved in adaptive evolution and macroevolution. I argue that the many evolutionary consequences of epigenetic inheritance open up new research areas and require the extension of the evolutionary synthesis beyond the current neo-Darwinian model.

  5. Leading the Team You Inherit.

    Science.gov (United States)

    Watkins, Michael D

    2016-06-01

    Most leaders don't have the luxury of building their teams from scratch. Instead they're put in charge of an existing group, and they need guidance on the best way to take over and improve performance. Watkins, an expert on transitions, suggests a three-step approach: Assess. Act quickly to size up the personnel you've inherited, systematically gathering data from one-on-one chats, team meetings, and other sources. Reflect, too, on the business challenges you face, the kinds of people you want in various roles, and the degree to which they need to collaborate. Reshape. Adjust the makeup of the team by moving people to new positions, shifting their responsibilities, or replacing them. Make sure that everyone is aligned on goals and how to achieve them--you may need to change the team's stated direction. Consider also making changes in the way the team operates (reducing the frequency of meetings, for example, or creating new subteams). Then establish ground rules and processes to sustain desired behaviors, and revisit those periodically. Accelerate team development. Set your people up for some early wins. Initial successes will boost everyone's confidence and reinforce the value of your new operating model, thus paving the way for ongoing growth.

  6. Inheritance pattern of microsatellite loci and their use for kinship analysis in the Japanese scallop Patinopecten yessoensis

    Science.gov (United States)

    Xu, Kefeng; Li, Qi

    2009-06-01

    The inheritance mode of seven microsatellite markers was investigated in Patinopecten yessoensis larvae from four controlled crosses, and the feasibility of using these markers for kinship estimation was also examined. All the seven microsatellite loci were compatible with Mendelian inheritance. Neither sex-linked barriers to transmission nor major barriers to fertilization between gametes from the parents were evident. Two of the seven loci showed the presence of null alleles in two families, suggesting the need to conduct comprehensive species-specific inheritance studies for microsatellite loci used in population genetic studies. However, even if the null allele heterozygotes were considered as homozygotes in the calculation of genetic distance, offspring from four families were all unambiguously discriminated in the neighbor-joining dendrogram. This result indicates that the microsatellite markers used may be capable of discriminating between related and unrelated scallop larvae in the absence of pedigree information, and of investigating the effective number of parents contributing to the hatchery population of the Japanese scallop.

  7. Inheritance mode of microsatellite loci and their use for kinship analysis in the Pacific oyster ( Crassostrea gigas)

    Science.gov (United States)

    Li, Qi; Zheng, Xiaodong; Yu, Ruihai

    2008-08-01

    Five full-sib families of the Pacific oyster ( Crassostrea gigas) larvae were used to study the mode of inheritance at eight microsatellite loci, and the feasibility of these markers for kinship estimate was also examined. All eight microsatellite loci were compatible with Mendelian inheritance. Neither evidence of sex-linked barriers to transmission nor evidence of major barriers to fertilization between gametes from the parents was shown. Three of the eight loci showed the presence of null alleles in four families, demonstrating the need to conduct comprehensive species-specific inheritance studies for microsatellite loci used in population genetic studies. Although the null allele heterozygotes were considered as homozygotes in the calculation of genetic distance, offspring from five full-sib families were unambiguously discriminated in the neighbor-joining dendrogram. This result indicates that the microsatellite markers may be capable of discriminating between related and unrelated oyster larvae in the absence of pedigree information, and is applicable to the investigation of the effective number of parents contributing to the hatchery population of the Pacific oyster.

  8. Current perspectives on mitochondrial inheritance in fungi

    Directory of Open Access Journals (Sweden)

    Xu J

    2015-08-01

    Full Text Available Jianping Xu,1,2 He Li2 1Department of Biology, McMaster University, Hamilton, Canada; 2The Key Laboratory for Non-Wood Forest Cultivation and Conservation of the Federal Ministry of Education, Central South University of Forestry and Technology, Changsha, People’s Republic of China Abstract: The mitochondrion is an essential organelle of eukaryotes, generating the universal energy currency, adenosine triphosphate, through oxidative phosphorylation. However, aside from generation of adenosine triphosphate, mitochondria have also been found to impact a diversity of cellular functions and organ system health in humans and other eukaryotes. Thus, inheriting and maintaining functional mitochondria are essential for cell health. Due to the relative ease of conducting genetic and molecular biological experiments using fungi, they (especially the budding yeast Saccharomyces cerevisiae have been used as model organisms for investigating the patterns of inheritance and intracellular dynamics of mitochondria and mitochondrial DNA. Indeed, the diversity of mitochondrial inheritance patterns in fungi has contributed to our broad understanding of the genetic, cellular, and molecular controls of mitochondrial inheritance and their evolutionary implications. In this review, we briefly summarize the patterns of mitochondrial inheritance in fungi, describe the genes and processes involved in controlling uniparental mitochondrial DNA inheritance in sexual crosses in basidiomycete yeasts, and provide an overview of the molecular and cellular processes governing mitochondrial inheritance during asexual budding in S. cerevisiae. Together, these studies reveal that complex regulatory networks and molecular processes are involved in ensuring the transmission of healthy mitochondria to the progeny. Keywords: uniparental inheritance, biparental inheritance, mating type, actin cable, mitochore, mitochondrial partition 

  9. Conformal symmetry inheritance in null fluid spacetimes

    CERN Document Server

    Tupper, B O J; Hall, G S; Coley, Alan A; Carot, J

    2003-01-01

    We define inheriting conformal Killing vectors for null fluid spacetimes and find the maximum dimension of the associated inheriting Lie algebra. We show that for non-conformally flat null fluid spacetimes, the maximum dimension of the inheriting algebra is seven and for conformally flat null fluid spacetimes the maximum dimension is eight. In addition, it is shown that there are two distinct classes of non-conformally flat generalized plane wave spacetimes which possess the maximum dimension, and one class in the conformally flat case.

  10. Testamental inheritance: Just a legal osmosis?

    Directory of Open Access Journals (Sweden)

    Đorđević-Crnobrnja Jadranka

    2011-01-01

    Full Text Available Bequeath, a dispose of personal property by the last will is an example of intervention of legislation within the complex of customary law. This influence is not unusual but certainly is less frequent than the influence of customary into civil law, especially so in their interaction within inheritance. This paper therefore tries to explain this example of legal osmosis in practice. In addition, the practice in testament inheritance shows also an influence of customary law into legislation. Hence, the paper will also try to discuss a relationship between customary and civil laws and succeeding problems in inheritance at the levels of individual and that of the society.

  11. Instrumental variables and Mendelian randomization with invalid instruments

    Science.gov (United States)

    Kang, Hyunseung

    Instrumental variables (IV) methods have been widely used to determine the causal effect of a treatment, exposure, policy, or an intervention on an outcome of interest. The IV method relies on having a valid instrument, a variable that is (A1) associated with the exposure, (A2) has no direct effect on the outcome, and (A3) is unrelated to the unmeasured confounders associated with the exposure and the outcome. However, in practice, finding a valid instrument, especially those that satisfy (A2) and (A3), can be challenging. For example, in Mendelian randomization studies where genetic markers are used as instruments, complete knowledge about instruments' validity is equivalent to complete knowledge about the involved genes' functions. The dissertation explores the theory, methods, and application of IV methods when invalid instruments are present. First, when we have multiple candidate instruments, we establish a theoretical bound whereby causal effects are only identified as long as less than 50% of instruments are invalid, without knowing which of the instruments are invalid. We also propose a fast penalized method, called sisVIVE, to estimate the causal effect. We find that sisVIVE outperforms traditional IV methods when invalid instruments are present both in simulation studies as well as in real data analysis. Second, we propose a robust confidence interval under the multiple invalid IV setting. This work is an extension of our work on sisVIVE. However, unlike sisVIVE which is robust to violations of (A2) and (A3), our confidence interval procedure provides honest coverage even if all three assumptions, (A1)-(A3), are violated. Third, we study the single IV setting where the one IV we have may actually be invalid. We propose a nonparametric IV estimation method based on full matching, a technique popular in causal inference for observational data, that leverages observed covariates to make the instrument more valid. We propose an estimator along with

  12. Center for Inherited Disease Research (CIDR)

    Science.gov (United States)

    The Center for Inherited Disease Research (CIDR) Program at The Johns Hopkins University provides high-quality next generation sequencing and genotyping services to investigators working to discover genes that contribute to common diseases.

  13. Defeasible inheritance-based description logics

    CSIR Research Space (South Africa)

    Casini, G

    2013-01-01

    Full Text Available Defeasible inheritance networks are a non-monotonic framework that deals with hierarchical knowledge. On the other hand, rational closure is acknowledged as a landmark of the preferential approach to non-monotonic reasoning. We will combine...

  14. Developmental origins of epigenetic transgenerational inheritance.

    Science.gov (United States)

    Hanson, Mark A; Skinner, Michael K

    Environmental factors can induce epigenetic alterations in the germ cells that can potentially be transmitted transgenerationally. This non-genetic form of inheritance is termed epigenetic transgenerational inheritance and has been shown in a variety of species including plants, flies, worms, fish, rodents, pigs, and humans. This phenomenon operates during specific critical windows of exposure, linked to the developmental biology of the germ cells (sperm and eggs). Therefore, concepts of the developmental origins of transgenerational inheritance of phenotypic variation and subsequent disease risk need to include epigenetic processes affecting the developmental biology of the germ cell. These developmental impacts on epigenetic transgenerational inheritance, in contrast to multigenerational exposures, are the focus of this Perspective.

  15. Genetic Testing for Inherited Heart Disease

    Science.gov (United States)

    ... of the American Heart Association Cardiology Patient Page Genetic Testing for Inherited Heart Disease Allison L. Cirino , ... for developing the family’s heart condition. What Is Genetic Testing and What Can it Tell Me? Genetic ...

  16. Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study.

    LENUS (Irish Health Repository)

    Hung, Chi-Fa

    2014-07-01

    Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.

  17. Association of vitamin D status with arterial blood pressure and hypertension risk : A mendelian randomisation study

    NARCIS (Netherlands)

    Vimaleswaran, Karani S.; Cavadino, Alana; Berry, Diane J.; Jorde, Rolf; Dieffenbach, Aida Karina; Lu, Chen; Alves, Alexessander Couto; Lambers Heerspink, Hiddo J.; Tikkanen, Emmi; Eriksson, Joel; Wong, Andrew; Mangino, Massimo; Jablonski, Kathleen A.; Nolte, Ilja M.; Houston, Denise K.; Ahluwalia, Tarunveer Singh; van der Most, Peter J.; Pasko, Dorota; Zgaga, Lina; Thiering, Elisabeth; Vitart, Veronique; Fraser, Ross M.; Huffman, Jennifer E.; de Boer, Rudolf A.; Schoettker, Ben; Saum, Kai-Uwe; McCarthy, Mark I.; Dupuis, Josee; Herzig, Karl-Heinz; Sebert, Sylvain; Pouta, Anneli; Laitinen, Jaana; Kleber, Marcus E.; Navis, Gerjan; Lorentzon, Mattias; Jameson, Karen; Arden, Nigel; Cooper, Jackie A.; Acharya, Jayshree; Hardy, Rebecca; Raitakari, Olli; Ripatti, Samuli; Billings, Liana K.; Lahti, Jari; Osmond, Clive; Penninx, Brenda W.; Rejnmark, Lars; Lohman, Kurt K.; Paternoster, Lavinia; Stolk, Ronald P.; Hernandez, Dena G.; Byberg, Liisa; Hagstrom, Emil; Melhus, Hakan; Ingelsson, Erik; Mellstroem, Dan; Ljunggren, Osten; Tzoulaki, Ioanna; McLachlan, Stela; Theodoratou, Evropi; Tiesler, Carla M. T.; Jula, Antti; Navarro, Pau; Wright, Alan F.; Polasek, Ozren; Hayward, Caroline; Wilson, James F.; Rudan, Igor; Salomaa, Veikko; Heinrich, Joachim; Campbell, Harry; Price, Jacqueline F.; Karlsson, Magnus; Lind, Lars; Michaesson, Karl; Bandinelli, Stefania; Frayling, Timothy M.; Hartman, Catharina A.; Sorensen, Thorkild I. A.; Kritchevsky, Stephen B.; Langdahl, Bente Lomholt; Eriksson, Johan G.; Florez, Jose C.; Spector, Tim D.; Lehtimaki, Terho; Kuh, Diana; Humphries, Steve E.; Cooper, Cyrus; Ohlsson, Claes; Maerz, Winfried; de Borst, Martin H.; Kumari, Meena; Kivimaki, Mika; Wang, Thomas J.; Power, Chris; Brenner, Hermann; Grimnes, Guri; van der Harst, Pim; Snieder, Harold; Hingorani, Aroon D.; Pilz, Stefan; Whittaker, John C.; Jarvelin, Marjo-Riitta; Hypponen, Elina

    BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with

  18. Adult height, coronary heart disease and stroke : A multi-locus Mendelian randomization meta-analysis

    NARCIS (Netherlands)

    Nüesch, Eveline; Dale, Caroline; Palmer, Tom M.; White, Jon; Keating, Brendan J.; van Iperen, Erik P A; Goel, Anuj; Padmanabhan, Sandosh; Asselbergs, F. W.; Verschuren, W. M.; Wijmenga, C.; Van der Schouw, Y. T.; Onland-Moret, N. C.; Lange, Leslie A.; Hovingh, G. K.; Sivapalaratnam, Suthesh; Morris, Richard W.; Whincup, Peter H.; Wannamethe, Goya S.; Gaunt, Tom R.; Ebrahim, Shah; Steel, Laura; Nair, Nikhil; Reiner, Alexander P.; Kooperberg, Charles; Wilson, James F.; Bolton, Jennifer L.; McLachlan, Stela; Price, Jacqueline F.; Strachan, Mark W J; Robertson, Christine M.; Kleber, Marcus E.; Delgado, Graciela; März, Winfried; Melander, Olle; Dominiczak, Anna F.; Farrall, Martin; Watkins, Hugh; Leusink, Maarten; Maitland-van der Zee, Anke H.; de Groot, Mark C H; Dudbridge, Frank; Hingorani, Aroon; Ben-Shlomo, Yoav; Lawlor, Debbie A.; Amuzu, A.; Caufield, M.; Cavadino, A.; Cooper, J.; Davies, T. L.; Day, I. N.; Drenos, F.; Engmann, J.; Finan, C.; Giambartolomei, C.; Hardy, R.; Humphries, S. E.; Hypponen, E.; Kivimaki, M.; Kuh, D.; Kumari, M.; Ong, K.; Plagnol, V.; Power, C.; Richards, M.; Shah, S.; Shah, T.; Sofat, R.; Talmud, P. J.; Wareham, N.; Warren, H.; Whittaker, J. C.; Wong, A.; Zabaneh, D.; Smith, George Davey; Wells, Jonathan C.; Leon, David A.; Holmes, Michael V.; Casas, Juan P.

    2016-01-01

    Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. Methods: We developed an allele score based on 69 single nucleotide

  19. Power and sample size calculations for Mendelian randomization studies using one genetic instrument.

    Science.gov (United States)

    Freeman, Guy; Cowling, Benjamin J; Schooling, C Mary

    2013-08-01

    Mendelian randomization, which is instrumental variable analysis using genetic variants as instruments, is an increasingly popular method of making causal inferences from observational studies. In order to design efficient Mendelian randomization studies, it is essential to calculate the sample sizes required. We present formulas for calculating the power of a Mendelian randomization study using one genetic instrument to detect an effect of a given size, and the minimum sample size required to detect effects for given levels of significance and power, using asymptotic statistical theory. We apply the formulas to some example data and compare the results with those from simulation methods. Power and sample size calculations using these formulas should be more straightforward to carry out than simulation approaches. These formulas make explicit that the sample size needed for Mendelian randomization study is inversely proportional to the square of the correlation between the genetic instrument and the exposure and proportional to the residual variance of the outcome after removing the effect of the exposure, as well as inversely proportional to the square of the effect size.

  20. Identification of Mendelian inconsistencies between SNP and pedigree Information of Sibs

    NARCIS (Netherlands)

    Calus, M.P.L.; Mulder, H.A.; Bastiaansen, J.W.M.

    2011-01-01

    Background Using SNP genotypes to apply genomic selection in breeding programs is becoming common practice. Tools to edit and check the quality of genotype data are required. Checking for Mendelian inconsistencies makes it possible to identify animals for which pedigree information and genotype

  1. Mendelian Randomization as an Approach to Assess Causality Using Observational Data.

    Science.gov (United States)

    Sekula, Peggy; Del Greco M, Fabiola; Pattaro, Cristian; Köttgen, Anna

    2016-11-01

    Mendelian randomization refers to an analytic approach to assess the causality of an observed association between a modifiable exposure or risk factor and a clinically relevant outcome. It presents a valuable tool, especially when randomized controlled trials to examine causality are not feasible and observational studies provide biased associations because of confounding or reverse causality. These issues are addressed by using genetic variants as instrumental variables for the tested exposure: the alleles of this exposure-associated genetic variant are randomly allocated and not subject to reverse causation. This, together with the wide availability of published genetic associations to screen for suitable genetic instrumental variables make Mendelian randomization a time- and cost-efficient approach and contribute to its increasing popularity for assessing and screening for potentially causal associations. An observed association between the genetic instrumental variable and the outcome supports the hypothesis that the exposure in question is causally related to the outcome. This review provides an overview of the Mendelian randomization method, addresses assumptions and implications, and includes illustrative examples. We also discuss special issues in nephrology, such as inverse risk factor associations in advanced disease, and outline opportunities to design Mendelian randomization studies around kidney function and disease. Copyright © 2016 by the American Society of Nephrology.

  2. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects.

    Science.gov (United States)

    Burgess, Stephen; Thompson, Simon G

    2015-02-15

    A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This "multivariable Mendelian randomization" approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

  3. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator.

    Science.gov (United States)

    Bowden, Jack; Davey Smith, George; Haycock, Philip C; Burgess, Stephen

    2016-05-01

    Developments in genome-wide association studies and the increasing availability of summary genetic association data have made application of Mendelian randomization relatively straightforward. However, obtaining reliable results from a Mendelian randomization investigation remains problematic, as the conventional inverse-variance weighted method only gives consistent estimates if all of the genetic variants in the analysis are valid instrumental variables. We present a novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate. This estimator is consistent even when up to 50% of the information comes from invalid instrumental variables. In a simulation analysis, it is shown to have better finite-sample Type 1 error rates than the inverse-variance weighted method, and is complementary to the recently proposed MR-Egger (Mendelian randomization-Egger) regression method. In analyses of the causal effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol on coronary artery disease risk, the inverse-variance weighted method suggests a causal effect of both lipid fractions, whereas the weighted median and MR-Egger regression methods suggest a null effect of high-density lipoprotein cholesterol that corresponds with the experimental evidence. Both median-based and MR-Egger regression methods should be considered as sensitivity analyses for Mendelian randomization investigations with multiple genetic variants. © 2016 The Authors. *Genetic Epidemiology Published by Wiley Periodicals, Inc.

  4. Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study

    Science.gov (United States)

    This study examined whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal. A Mendelian randomization study was employed, using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental var...

  5. Association between alcohol and cardiovascular disease : Mendelian randomisation analysis based on individual participant data

    NARCIS (Netherlands)

    Holmes, Michael V.; Dale, Caroline E.; Zuccolo, Luisa; Silverwood, Richard J.; Guo, Yiran; Ye, Zheng; Prieto-Merino, David; Dehghan, Abbas; Trompet, Stella; Wong, Andrew; Cavadino, Alana; Drogan, Dagmar; Padmanabhan, Sandosh; Li, Shanshan; Yesupriya, Ajay; Leusink, Maarten; Sundstrom, Johan; Hubacek, Jaroslav A.; Pikhart, Hynek; Swerdlow, Daniel I.; Panayiotou, Andrie G.; Borinskaya, Svetlana A.; Finan, Chris; Shah, Sonia; Kuchenbaecker, Karoline B.; Shah, Tina; Engmann, Jorgen; Folkersen, Lasse; Eriksson, Per; Ricceri, Fulvio; Melander, Olle; Sacerdote, Carlotta; Gamble, Dale M.; Rayaprolu, Sruti; Ross, Owen A.; McLachlan, Stela; Vikhireva, Olga; Sluijs, Ivonne; Scott, Robert A.; Adamkova, Vera; Flicker, Leon; Van Bockxmeer, Frank M.; Power, Christine; Marques-Vidal, Pedro; Meade, Tom; Marmot, Michael G.; Ferro, Jose M.; Paulos-Pinheiro, Sofia; Humphries, Steve E.; Talmud, Philippa J.; Mateo Leach, Irene; Verweij, Niek; Linneberg, Allan; Skaaby, Tea; Doevendans, Pieter A.; Cramer, Maarten J.; Van der Harst, Pim; Klungel, Olaf H.; Dowling, Nicole F.; Dominiczak, Anna F.; Kumari, Meena; Nicolaides, Andrew N.; Weikert, Cornelia; Boeing, Heiner; Ebrahim, Shah; Gaunt, Tom R.; Price, Jackie F.; Lannfelt, Lars; Peasey, Anne; Kubinova, Ruzena; Pajak, Andrzej; Malyutina, Sofia; Voevoda, Mikhail I.; Tamosiunas, Abdonas; Maitland-van der Zee, Anke H.; Norman, Paul E.; Hankey, Graeme J.; Bergmann, Manuela M.; Hofman, Albert; Franco, Oscar H.; Cooper, Jackie; Palmen, Jutta; Spiering, Wilko; de Jong, Pim A.; Kuh, Diana; Hardy, Rebecca; Uitterlinden, Andre G.; Ikram, M. Arfan; Ford, Ian; Hyppoenen, Elina; Almeida, Osvaldo P.; Wareham, Nicholas J.; Khaw, Kay-Tee; Hamsten, Anders; Husemoen, Lise Lotte N.; Tjonneland, Anne; Tolstrup, Janne S.; Rimm, Eric; Beulens, Joline W. J.; Verschuren, W. M. Monique; Onland-Moret, N. Charlotte; Hofker, Marten H.; Wannamethee, S. Goya; Whincup, Peter H.; Morris, Richard; Vicente, Astrid M.; Watkins, Hugh; Farrall, Martin; Jukema, J. Wouter; Meschia, James; Cupples, L. Adrienne; Sharp, Stephen J.; Fornage, Myriam; Kooperberg, Charles; LaCroix, Andrea Z.; Dai, James Y.; Lanktree, Matthew B.; Siscovick, David S.; Jorgenson, Eric; Spring, Bonnie; Coresh, Josef; Li, Yun R.; Buxbaum, Sarah G.; Schreiner, Pamela J.; Ellison, R. Curtis; Tsai, Michael Y.; Patel, Sanjay R.; Redline, Susan; Johnson, Andrew D.; Hoogeveen, Ron C.; Rotter, Jerome I.; Boerwinkle, Eric; de Bakker, Paul I. W.; Kivimaki, Mika; Asselbergs, Folkert W.; Sattar, Naveed; Lawlor, Debbie A.; Whittaker, John; Smith, George Davey; Mukamal, Kenneth; Psaty, Bruce M.; Wilson, James G.; Lange, Leslie A.; Hamidovic, Ajna; Hingorani, Aroon D.; Nordestgaard, Borge G.; Bobak, Martin; Leon, David A.; Langenberg, Claudia; Palmer, Tom M.; Reiner, Alex P.; Keating, Brendan J.; Dudbridge, Frank; Casas, Juan P.

    2014-01-01

    Objective To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Design Mendelian randomisation meta-analysis of 56 epidemiological studies. Participants 261 991 individuals of European descent,

  6. Association between alcohol and cardiovascular disease : Mendelian randomisation analysis based on individual participant data

    NARCIS (Netherlands)

    Holmes, Michael V.; Dale, Caroline E.; Zuccolo, Luisa; Silverwood, Richard J.; Guo, Yiran; Ye, Zheng; Prieto-Merino, David; Dehghan, Abbas; Trompet, Stella; Wong, Andrew; Cavadino, Alana; Drogan, Dagmar; Padmanabhan, Sandosh; Li, Shanshan; Yesupriya, Ajay; Leusink, Maarten|info:eu-repo/dai/nl/357581164; Sundstrom, Johan; Hubacek, Jaroslav A.; Pikhart, Hynek; Swerdlow, Daniel I.; Panayiotou, Andrie G.; Borinskaya, Svetlana A.; Finan, Chris; Shah, Sonia; Kuchenbaecker, Karoline B.; Shah, Tina; Engmann, Jorgen; Folkersen, Lasse; Eriksson, Per; Ricceri, Fulvio; Melander, Olle; Sacerdote, Carlotta; Gamble, Dale M.; Rayaprolu, Sruti; Ross, Owen A.; McLachlan, Stela; Vikhireva, Olga; Sluijs, Ivonne; Scott, Robert A.; Adamkova, Vera; Flicker, Leon; Van Bockxmeer, Frank M.; Power, Christine; Marques-Vidal, Pedro; Meade, Tom; Marmot, Michael G.; Ferro, Jose M.; Paulos-Pinheiro, Sofia; Humphries, Steve E.; Talmud, Philippa J.; Leach, Irene Mateo; Verweij, Niek; Linneberg, Allan; Skaaby, Tea; Doevendans, Pieter A.; Cramer, Maarten J.; Van Der Harst, Pim; Klungel, Olaf H.|info:eu-repo/dai/nl/181447649; Dowling, Nicole F.; Dominiczak, Anna F.; Kumari, Meena; Nicolaides, Andrew N.; Weikert, Cornelia; Boeing, Heiner; Ebrahim, Shah; Gaunt, Tom R.; Price, Jackie F.; Lannfelt, Lars; Peasey, Anne; Kubinova, Ruzena; Pajak, Andrzej; Malyutina, Sofia; Voevoda, Mikhail I.; Tamosiunas, Abdonas; Maitland-van Der Zee, Anke H.|info:eu-repo/dai/nl/255164688; Norman, Paul E.; Hankey, Graeme J.; Bergmann, Manuela M.; Hofman, Albert; Franco, Oscar H.; Cooper, Jackie; Palmen, Jutta; Spiering, Wilko; De Jong, Pim A.; Kuh, Diana; Hardy, Rebecca; Uitterlinden, Andre G.; Ikram, M. Arfan; Ford, Ian; Hyppönen, Elina; Almeida, Osvaldo P.; Wareham, Nicholas J.; Khaw, Kay Tee; Hamsten, Anders; Husemoen, Lise Lotte N; Tjønneland, Anne; Tolstrup, Janne S.; Rimm, Eric; Beulens, Joline W J; Verschuren, W. M Monique; Onland-Moret, N. Charlotte; Hofker, Marten H.; Wannamethee, S. Goya; Whincup, Peter H.; Morris, Richard; Vicente, Astrid M.; Watkins, Hugh; Farrall, Martin; Jukema, J. Wouter; Meschia, James; Cupples, L. Adrienne; Sharp, Stephen J.; Fornage, Myriam; Kooperberg, Charles; LaCroix, Andrea Z.; Dai, James Y.; Lanktree, Matthew B.; Siscovick, David S.; Jorgenson, Eric; Spring, Bonnie; Coresh, Josef; Li, Yun R.; Buxbaum, Sarah G.; Schreiner, Pamela J.; Ellison, R. Curtis; Tsai, Michael Y.; Patel, Sanjay R.; Redline, Susan; Johnson, Andrew D.; Hoogeveen, Ron C.; Hakonarson, Hakon; Rotter, Jerome I.; Boerwinkle, Eric; De Bakker, Paul I W; Kivimaki, Mika; Asselbergs, Folkert W.; Sattar, Naveed; Lawlor, Debbie A.; Whittaker, John; Smith, George Davey; Mukamal, Kenneth; Psaty, Bruce M.; Wilson, James G.; Lange, Leslie A.; Hamidovic, Ajna; Nordestgaard, Børge G.; Bobak, Martin; Leon, David A.; Langenberg, Claudia; Palmer, Tom M.; Reiner, Alex P.; Keating, Brendan J.; Dudbridge, Frank; Casas, Juan P.

    2014-01-01

    Objective: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Design: Mendelian randomisation meta-analysis of 56 epidemiological studies. Participants: 261 991 individuals of European

  7. Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

    NARCIS (Netherlands)

    Carreras-Torres, R.; Johansson, M.; Haycock, P.C.; Wade, K.H.; Relton, C.L.; Martin, R.M.; Smith, G.; Albanes, D.; Aldrich, M.C.; Andrew, A.; Arnold, S.M.; Bickeboller, H.; Bojesen, S.E.; Brunnstrom, H.; Manjer, J.; Bruske, I.; Caporaso, N.E.; Chen, C.; Christiani, D.C.; Christian, W.J.; Doherty, J.A.; Duell, E.J.; Field, J.K.; Davies, M.P.; Marcus, M.W.; Goodman, G.E.; Grankvist, K.; Haugen, A.; Hong, Y.C.; Kiemeney, L.A.L.M.; Heijden, E.H.F.M. van der; Kraft, P.; Johansson, M.B.; Lam, S.; Landi, M.T.; Lazarus, P.; Marchand, L. Le; Liu, G.; Melander, O.; Park, S.L.; Rennert, G.; Risch, A.; Haura, E.B.; Scelo, G.; Zaridze, D.; Mukeriya, A.; Savic, M.; Lissowska, J.; Swiatkowska, B.; Janout, V.; Holcatova, I.; Mates, D.; Schabath, M.B.; Shen, H.; Tardon, A.; Teare, M.D.; Woll, P.; Tsao, M.S.; Wu, X.; Yuan, J.M.; Hung, R.J.; Amos, C.I.; McKay, J.; Brennan, P.

    2017-01-01

    BACKGROUND: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.

  8. Adiposity as a cause of cardiovascular disease: A Mendelian randomization study

    NARCIS (Netherlands)

    S. Hägg (Sara); M. Fall (Magnus); A. Ploner (Alexander); R. Mägi (Reedik); K. Fischer (Krista); G. Draisma (Gerrit); M. Kals (Mart); P.S. de Vries (Paul); A. Dehghan (Abbas); S.M. Willems (Sara); A.-P. Sarin; K. Kristiansson (Kati); M.-L. Nuotio (Marja-Liisa); A.S. Havulinna (Aki); R.F.A.G. de Bruijn (Renée); M.A. Ikram (Arfan); M. Kuningas (Maris); B.H.Ch. Stricker (Bruno); O.H. Franco (Oscar); B. Benyamin (Beben); C. Gieger (Christian); A.S. Hall (Alistair); V. Huikari (Ville); A. Jula (Antti); M.-R. Jarvelin (Marjo-Riitta); M. Kaakinen (Marika); J. Kaprio (Jaakko); M. Kobl (Michael); M. Mangino (Massimo); C.P. Nelson (Christopher P.); A. Palotie (Aarno); N.J. Samani (Nilesh); T.D. Spector (Timothy); D.P. Strachan (David); M.D. Tobin (Martin); J.B. Whitfield (John B.); A.G. Uitterlinden (André); V. Salomaa (Veikko); A.C. Syvanen; K. Kuulasmaa (Kari); P.K. Magnusson (Patrik); T. Esko (Tõnu); A. Hofman (Albert); E.J.C. de Geus (Eco); L. Lind (Lars); V. Giedraitis (Vilmantas); M. Perola (Markus); A. Evans (Alun); J. Ferrieres (Jean); J. Virtamo (Jarmo); F. Kee (F.); D.-A. Tregouet (David-Alexandre); D. Arveiler (Dominique); P. Amouyel (Philippe); F. Gianfagna (Francesco); P. Brambilla (Paolo); S. Ripatti (Samuli); C.M. van Duijn (Cornelia); A. Metspalu (Andres); I. Prokopenko (Inga); M.I. McCarthy (Mark); N.L. Pedersen (Nancy L.); E. Ingelsson (Erik)

    2015-01-01

    textabstractBackground: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. Methods: The associations of BMI with

  9. Heavier smoking increases coffee consumption: Findings from a Mendelian randomization analysis

    NARCIS (Netherlands)

    Bjö rngaard, J.H.; Nordestgaard, A.T.; Taylor, A.E.; Treur, J.L.; Gabrielsen, M.E.; Munafò , M.R.; Nordestgaard, B.G.; Asvold, B.A.; Romundstad, P.R.; Smith, G.D.

    2017-01-01

    There is evidence for a positive relationship between cigarette and coffee consumption in smokers. Cigarette smoke increases metabolism of caffeine, so this may represent a causal effect of smoking on caffeine intake. We performed Mendelian randomization analyses in the UK Biobank (N = 114 029), the

  10. Inherited thrombophilia: a double-edged sword.

    Science.gov (United States)

    Middeldorp, Saskia

    2016-12-02

    Inherited thrombophilia is a blood coagulation disorder that increases the risk for venous thromboembolism (VTE). During the last decades, the practice of testing has evolved from testing selected populations, leading to high perceived risks, to broad testing for various conditions that included VTE, arterial thrombosis, and pregnancy complications. Because results of such tests usually do not guide treatment decisions, not testing patients with VTE for inherited thrombophilia is on the "Choosing Wisely" list endorsed by multiple specialty societies, including ASH. Inherited thrombophilia can be regarded a double-edged sword, as despite the rationale not to test, it is still being performed frequently. Another way of seeing inherited thrombophilia as a double-edged sword lies in its 2-sided association with reproduction, both in men and in women. Current areas of research are whether women with inherited thrombophilia and pregnancy complications benefit from anticoagulant therapy with regard to improving the chance of a successful pregnancy. Potential effects of inherited thrombophilia, most notably factor V Leiden, on improved embryo implantation in women and sperm counts in men are intriguing, but are currently poorly understood. © 2016 by The American Society of Hematology. All rights reserved.

  11. Identification of Mendelian inconsistencies between SNP and pedigree information of sibs

    Directory of Open Access Journals (Sweden)

    Calus Mario PL

    2011-10-01

    Full Text Available Abstract Background Using SNP genotypes to apply genomic selection in breeding programs is becoming common practice. Tools to edit and check the quality of genotype data are required. Checking for Mendelian inconsistencies makes it possible to identify animals for which pedigree information and genotype information are not in agreement. Methods Straightforward tests to detect Mendelian inconsistencies exist that count the number of opposing homozygous marker (e.g. SNP genotypes between parent and offspring (PAR-OFF. Here, we develop two tests to identify Mendelian inconsistencies between sibs. The first test counts SNP with opposing homozygous genotypes between sib pairs (SIBCOUNT. The second test compares pedigree and SNP-based relationships (SIBREL. All tests iteratively remove animals based on decreasing numbers of inconsistent parents and offspring or sibs. The PAR-OFF test, followed by either SIB test, was applied to a dataset comprising 2,078 genotyped cows and 211 genotyped sires. Theoretical expectations for distributions of test statistics of all three tests were calculated and compared to empirically derived values. Type I and II error rates were calculated after applying the tests to the edited data, while Mendelian inconsistencies were introduced by permuting pedigree against genotype data for various proportions of animals. Results Both SIB tests identified animal pairs for which pedigree and genomic relationships could be considered as inconsistent by visual inspection of a scatter plot of pairwise pedigree and SNP-based relationships. After removal of 235 animals with the PAR-OFF test, SIBCOUNT (SIBREL identified 18 (22 additional inconsistent animals. Seventeen animals were identified by both methods. The numbers of incorrectly deleted animals (Type I error, were equally low for both methods, while the numbers of incorrectly non-deleted animals (Type II error, were considerably higher for SIBREL compared to SIBCOUNT. Conclusions

  12. Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis

    Science.gov (United States)

    White, Jon; Sofat, Reecha; Hemani, Gibran; Shah, Tina; Engmann, Jorgen; Dale, Caroline; Shah, Sonia; Kruger, Felix A; Giambartolomei, Claudia; Swerdlow, Daniel I; Palmer, Tom; McLachlan, Stela; Langenberg, Claudia; Zabaneh, Delilah; Lovering, Ruth; Cavadino, Alana; Jefferis, Barbara; Finan, Chris; Wong, Andrew; Amuzu, Antoinette; Ong, Ken; Gaunt, Tom R; Warren, Helen; Davies, Teri-Louise; Drenos, Fotios; Cooper, Jackie; Ebrahim, Shah; Lawlor, Debbie A; Talmud, Philippa J; Humphries, Steve E; Power, Christine; Hypponen, Elina; Richards, Marcus; Hardy, Rebecca; Kuh, Diana; Wareham, Nicholas; Ben-Shlomo, Yoav; Day, Ian N; Whincup, Peter; Morris, Richard; Strachan, Mark W J; Price, Jacqueline; Kumari, Meena; Kivimaki, Mika; Plagnol, Vincent; Whittaker, John C; Smith, George Davey; Dudbridge, Frank; Casas, Juan P; Holmes, Michael V; Hingorani, Aroon D

    2016-01-01

    Summary Background Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. Methods We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. Findings In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04–1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08–1·29), 1·10 (1·00–1·22), and 1·05 (0·92–1·20), respectively, per 1 SD increment in plasma urate. Interpretation Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for

  13. Clinical characteristics and mode of inheritance of familial focal seizures in Standard Poodles.

    Science.gov (United States)

    Licht, Barbara G; Lin, Shili; Luo, Yuqun; Hyson, Linda L; Licht, Mark H; Harper, Kathleen M; Sullivan, Stacey A; Fernandez, Soledad A; Johnston, Eric V

    2007-11-15

    To determine clinical characteristics and mode of inheritance of seizures in a family of Standard Poodles. Case series. 90 Standard Poodles descended from the same maternal bloodline (30 with probable idiopathic epilepsy [PIE] and 60 without any history of seizures). Researchers contacted owners to determine whether dogs had ever had any seizures and, if so, the nature of any such seizures and any potential underlying causes. Dogs were considered to have PIE if they were between 6 months and 7.5 years old at the time of seizure onset and had no evidence of any underlying cause. To determine the mode of inheritance, segregation analyses were designed to allow the family to be analyzed as a whole, as opposed to as nuclear families. Competing models of inheritance were compared statistically for their ability to explain the data. Of the dogs with PIE, 28 (93%) had focal onset seizures with or without secondary generalization. Median age of onset was 3.7 years; 6 dogs were > 5 years old at the onset of seizures. Segregation analyses strongly suggested that PIE was inherited as a simple recessive autosomal trait with complete or almost complete penetrance. Results suggested that in this family of Standard Poodles, PIE was inherited as a simple recessive autosomal trait with complete or almost complete penetrance. Seizures often had focal, as opposed to generalized, onsets, and it was not uncommon for seizures to begin after 5 years of age.

  14. Inheritance of telomere length in a bird.

    Directory of Open Access Journals (Sweden)

    Thorsten Horn

    Full Text Available Telomere dynamics are intensively studied in human ageing research and epidemiology, with many correlations reported between telomere length and age-related diseases, cancer and death. While telomere length is influenced by environmental factors there is also good evidence for a strong heritable component. In human, the mode of telomere length inheritance appears to be paternal and telomere length differs between sexes, with females having longer telomeres than males. Genetic factors, e.g. sex chromosomal inactivation, and non-genetic factors, e.g. antioxidant properties of oestrogen, have been suggested as possible explanations for these sex-specific telomere inheritance and telomere length differences. To test the influence of sex chromosomes on telomere length, we investigated inheritance and sex-specificity of telomere length in a bird species, the kakapo (Strigops habroptilus, in which females are the heterogametic sex (ZW and males are the homogametic (ZZ sex. We found that, contrary to findings in humans, telomere length was maternally inherited and also longer in males. These results argue against an effect of sex hormones on telomere length and suggest that factors associated with heterogamy may play a role in telomere inheritance and sex-specific differences in telomere length.

  15. Molecular autopsy in victims of inherited arrhythmias.

    Science.gov (United States)

    Semsarian, Christopher; Ingles, Jodie

    2016-10-01

    Sudden cardiac death (SCD) is a rare but devastating complication of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, inherited cardiac disorders comprise a substantial proportion of SCD cases aged less than 40 years. Inherited cardiac disorders include primary inherited arrhythmogenic disorders such as familial long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and inherited cardiomyopathies, most commonly hypertrophic cardiomyopathy (HCM). In up to 40% of young SCD victims (defined as 1-40 years old, excluding sudden unexplained death in infancy from 0 to 1 years, referred to as SIDS), no cause of death is identified at postmortem [so-called "autopsy negative" or "sudden arrhythmic death syndrome" (SADS)]. Management of families following a SCD includes the identification of the cause of death, based either on premorbid clinical details or the pathological findings at the postmortem. When no cause of death is identified, genetic testing of DNA extracted from postmortem tissue (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Targeted clinical testing in a specialized multidisciplinary clinic in surviving family members combined with the results from genetic testing, provide the optimal setting for the identification of relatives who may be at risk of having the same inherited heart disease and are therefore also predisposed to an increased risk of SCD.

  16. Molecular autopsy in victims of inherited arrhythmias

    Directory of Open Access Journals (Sweden)

    Christopher Semsarian, MBBS, PhD, MPH

    2016-10-01

    Full Text Available Sudden cardiac death (SCD is a rare but devastating complication of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, inherited cardiac disorders comprise a substantial proportion of SCD cases aged less than 40 years. Inherited cardiac disorders include primary inherited arrhythmogenic disorders such as familial long QT syndrome (LQTS, Brugada syndrome (BrS, catecholaminergic polymorphic ventricular tachycardia (CPVT, and inherited cardiomyopathies, most commonly hypertrophic cardiomyopathy (HCM. In up to 40% of young SCD victims (defined as 1–40 years old, excluding sudden unexplained death in infancy from 0 to 1 years, referred to as SIDS, no cause of death is identified at postmortem [so-called “autopsy negative” or “sudden arrhythmic death syndrome” (SADS]. Management of families following a SCD includes the identification of the cause of death, based either on premorbid clinical details or the pathological findings at the postmortem. When no cause of death is identified, genetic testing of DNA extracted from postmortem tissue (the molecular autopsy may identify a cause of death in up to 30% of SADS cases. Targeted clinical testing in a specialized multidisciplinary clinic in surviving family members combined with the results from genetic testing, provide the optimal setting for the identification of relatives who may be at risk of having the same inherited heart disease and are therefore also predisposed to an increased risk of SCD.

  17. Asymmetric inheritance of cytoophidia in Schizosaccharomyces pombe

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    2014-10-01

    Full Text Available A general view is that Schizosaccharomyces pombe undergoes symmetric cell division with two daughter cells inheriting equal shares of the content from the mother cell. Here we show that CTP synthase, a metabolic enzyme responsible for the de novo synthesis of the nucleotide CTP, can form filamentous cytoophidia in the cytoplasm and nucleus of S. pombe cells. Surprisingly, we observe that both cytoplasmic and nuclear cytoophidia are asymmetrically inherited during cell division. Our time-lapse studies suggest that cytoophidia are dynamic. Once the mother cell divides, the cytoplasmic and nuclear cytoophidia independently partition into one of the two daughter cells. Although the two daughter cells differ from one another morphologically, they possess similar chances of inheriting the cytoplasmic cytoophidium from the mother cell, suggesting that the partition of cytoophidium is a stochastic process. Our findings on asymmetric inheritance of cytoophidia in S. pombe offer an exciting opportunity to study the inheritance of metabolic enzymes in a well-studied model system.

  18. Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis

    DEFF Research Database (Denmark)

    Taylor, Amy E; Fluharty, Meg E; Bjørngaard, Johan H

    2014-01-01

    OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational.......02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.......06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety....

  19. Dairy consumption and body mass index among adults: Mendelian randomization analysis of 184802 individuals from 25 studies

    Science.gov (United States)

    Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined. We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upst...

  20. Inherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathy.

    Science.gov (United States)

    Roberts, Jason D; Veinot, John P; Rutberg, Julie; Gollob, Michael H

    2010-01-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) represents an inherited cardiomyopathy that manifests clinically with malignant ventricular arrhythmias, sudden cardiac death, and less commonly heart failure. The condition is characterized by replacement of the myocardium, primarily of the right ventricle, with fibrofatty tissue. Extensive fibrofatty replacement of the myocardium has been previously thought to be pathognomonic of ARVC; however, this report details two other forms of inherited cardiomyopathy, namely hypertrophic cardiomyopathy (HCM) and the PRKAG2 cardiac syndrome, that were found to have significant fibrofatty myocardial replacement at pathologic examination. This report represents the first documentation of inherited cardiomyopathies mimicking ARVC and highlights the concept that other cardiac conditions can be associated with fibrofatty replacement of the myocardium. Copyright 2010 Elsevier Inc. All rights reserved.

  1. Transgenerational epigenetic inheritance: an open discussion.

    Science.gov (United States)

    Nagy, Corina; Turecki, Gustavo

    2015-08-01

    Much controversy surrounds the idea of transgenerational epigenetics. Recent papers argue that epigenetic marks acquired through experience are passed to offspring, but as in much of the field of epigenetics, there is lack of precision in the definitions and perhaps too much eagerness to translate animal research to humans. Here, we review operational definitions of transgenerational inheritance and the processes of epigenetic programing during early development. Subsequently, based on this background, we critically examine some recent findings of studies investigating transgenerational inheritance. Finally, we discuss possible mechanisms that may explain transgenerational inheritance, including transmission of an epigenetic blueprint, which may predispose offspring to specific epigenetic patterning. Taken together, we conclude that presently, the evidence suggesting that acquired epigenetic marks are passed to the subsequent generation remains limited.

  2. Environmental stress and epigenetic transgenerational inheritance.

    Science.gov (United States)

    Skinner, Michael K

    2014-09-05

    Previous studies have shown a wide variety of environmental toxicants and abnormal nutrition can promote the epigenetic transgenerational inheritance of disease. More recently a number of studies have indicated environmental stress can also promote epigenetic alterations that are transmitted to subsequent generations to induce pathologies. A recent study by Yao and colleagues demonstrated gestational exposure to restraint stress and forced swimming promoted preterm birth risk and adverse newborn outcomes generationally. This ancestral stress promoted the epigenetic transgenerational inheritance of abnormalities in the great-grand offspring of the exposed gestating female. Several studies now support the role of environmental stress in promoting the epigenetic transgenerational inheritance of disease. Observations suggest ancestral environmental stress may be a component of disease etiology in the current population.

  3. Mendelian Randomization: How It Can—and Cannot—Help Confirm Causal Relations between Nutrition and Cancer

    OpenAIRE

    Schatzkin, Arthur; Abnet, Christian C.; Cross, Amanda J.; Gunter, Marc; Pfeiffer, Ruth; Gail, Mitchell; Lim, Unhee; Davey-Smith, George

    2009-01-01

    Observational epidemiologic studies of nutrition and cancer have faced formidable methodologic obstacles, including dietary measurement error and confounding. We consider whether Mendelian randomization can help surmount these obstacles. The Mendelian randomization strategy, building on both the accuracy of genotyping and the random assortment of alleles at meiosis, involves searching for an association between a nutritional exposure-mimicking gene variant (a type of “instrumental variable”) ...

  4. Complex aetiology of an apparently Mendelian form of Mental Retardation

    Directory of Open Access Journals (Sweden)

    Wetterberg Lennart

    2008-02-01

    Full Text Available Abstract Background Mental Retardation is a common heterogeneous neurodevelopment condition, which causes are still largely elusive. It has been suggested that half of the phenotypic variation of intelligence is explained by genetic variation. And genetic or inherited factors indeed account for most of the cases of mental retardation with an identifiable cause. However, only a few autosomal genes have been mapped and identified to date. In this report, the genetic causes for an apparently recessive form of mental retardation, in a large nordern swedish pedigree, are investigated. Methods After extensive evaluation of the patients, which ruled out recognizable patterns of malformation and excluded known causes of MR, a comprehensive genome-wide linkage analysis, with 500 microsatellite markers, was performed in 24 members of this family. Additionally, a genome-wide copy number analysis, using an affimetrix 250 K SNP chip, was performed in this pedigree. Results No significant LOD score was found with either parametric and non-parametric linkage analysis. The highest scores are located at chromosomes 13, 15 and 17. Genome-wide copy number analysis identified no clear cause for the disorder; but rather, several variants were present in the family members, irrespective of their affected status. Conclusion These results suggest that mental retardation in this family, unlikely what was expected, has a heterogeneous aetiology; and that several lower effect genes variants might be involved. To demonstrate such effects, our family may be too small. This study also indicates that the ascertainment of the cause of MR may be challenging, and that a complex aetiology may be present even within a pedigree, constituting an additional obstacle for genetic counselling. Variants in genes involved in molecular mechanisms of cellular plasticity, in genes involved in the development of underlying neural architectures, and in genes involved in neurodevelopment and in

  5. Inheritance of DNA methylation in Coprinus cinereus.

    Science.gov (United States)

    Zolan, M E; Pukkila, P J

    1986-01-01

    We examined the inheritance of 5-methylcytosine residues at a centromere-linked locus in the basidiomycete Coprinus cinereus. Although methylated and unmethylated tracts were inherited both mitotically and meiotically the lengths of these tracts were variable. This variation was not confined to any one phase of the life cycle of the organism, and it usually involved the simultaneous de novo methylation of at least four HpaII-MspI sites. We also found that the higher levels of methylation at this locus were transmitted through meiosis, regardless of the level of methylation of the homologous chromosome. Images PMID:3785146

  6. Chromatin insulators: regulatory mechanisms and epigenetic inheritance

    Science.gov (United States)

    Bushey, Ashley M.; Dorman, Elizabeth R.; Corces, Victor G.

    2008-01-01

    Enhancer-blocking insulators are DNA elements that disrupt the communication between a regulatory sequence, such as an enhancer or a silencer, and a promoter. Insulators participate in both transcriptional regulation and global nuclear organization, two features of chromatin that are thought to be maintained from one generation to the next through epigenetic mechanisms. Furthermore, there are many regulatory mechanisms in place that enhance or hinder insulator activity. These modes of regulation could be used to establish cell-type specific insulator activity that is epigenetically inherited along a cell and/or organismal lineage. This review will discuss the evidence for epigenetic inheritance and regulation of insulator function. PMID:18851828

  7. Genetics of Inherited Arrhythmias in Children

    Directory of Open Access Journals (Sweden)

    Maully J. Shah

    2008-05-01

    Full Text Available Over the past two decades, breakthroughs in basic science have revealed the genetic etiology for several inherited arrhythmias. Onset of arrhythmias often commences in childhood and adolescence. The aim of the article is to provide a succinct overview of the genetic background of diseases that may cause life threatening arrhythmias in children and provide a description of reported genotype-phenotype relationships. Inherited channelopathies, namely, those causing long QT syndrome, short QT syndrome, catecholamine sensitive ventricular polymorphic ventricular tachycardia and Brugada syndrome and two cardiomyopathies (hypertrophic and arrhythmogenic right ventricular dysplasia associated with ventricular arrhythmias are discussed.

  8. Toward accurate high-throughput SNP genotyping in the presence of inherited copy number variation

    Directory of Open Access Journals (Sweden)

    Aldred Micheala A

    2007-07-01

    Full Text Available Abstract Background The recent discovery of widespread copy number variation in humans has forced a shift away from the assumption of two copies per locus per cell throughout the autosomal genome. In particular, a SNP site can no longer always be accurately assigned one of three genotypes in an individual. In the presence of copy number variability, the individual may theoretically harbor any number of copies of each of the two SNP alleles. Results To address this issue, we have developed a method to infer a "generalized genotype" from raw SNP microarray data. Here we apply our approach to data from 48 individuals and uncover thousands of aberrant SNPs, most in regions that were previously unreported as copy number variants. We show that our allele-specific copy numbers follow Mendelian inheritance patterns that would be obscured in the absence of SNP allele information. The interplay between duplication and point mutation in our data shed light on the relative frequencies of these events in human history, showing that at least some of the duplication events were recurrent. Conclusion This new multi-allelic view of SNPs has a complicated role in disease association studies, and further work will be necessary in order to accurately assess its importance. Software to perform generalized genotyping from SNP array data is freely available online 1.

  9. Mendelian Genes and Risk of Intracerebral Hemorrhage and Small-Vessel Ischemic Stroke in Sporadic Cases.

    Science.gov (United States)

    Chong, Michael; O'Donnell, Martin; Thijs, Vincent; Dans, Antonio; López-Jaramillo, Patricio; Gómez-Arbeláez, Diego; Mondo, Charles; Czlonkowska, Anna; Skowronska, Marta; Oveisgharan, Shahram; Yusuf, Salim; Paré, Guillaume

    2017-08-01

    Mendelian strokes are rare genetic disorders characterized by early-onset small-vessel stroke. Although extensively studied among families with syndromic features, whether these genes affect risk among sporadic cases is unknown. We sequenced 8 genes responsible for Mendelian stroke in a case-control study of sporadic stroke cases (≤70 years). Participants included 1251 primary stroke cases of small-vessel pathology (637 intracerebral hemorrhage and 614 small-vessel ischemic stroke cases) and 1716 controls from the INTERSTROKE study (Study of the Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World). Overall, the prevalence of canonical disease-causing mutations was 0.56% in cases and 0.23% in controls (odds ratio=1.89; 95% confidence interval, 0.54-7.57; P=0.33). CADASIL (Cerebral Autosomal Dominant Arteriopathies with Subcortical Infarcts and Leukoencephalopathies) mutations were more frequent among cases (0.48%) than controls (0.23%) but were not significantly associated with stroke risk (odds ratio=2.03; 95% confidence interval, 0.58-8.02; P=0.27). Next, we included all rare nonsynonymous mutations to investigate whether other types of mutations may contribute to stroke risk. Overall, 13.5% of cases and 14.2% of controls were carriers of at least one rare nonsynonymous mutation among the 8 Mendelian stroke genes. Mutation carriers were not at elevated risk of stroke (odds ratio=0.93; 95% confidence interval, 0.75-1.16; P=0.55). In the absence of syndromic features and family history of stroke, screening for Mendelian mutations among small-vessel stroke patients is unlikely to have high diagnostic utility. © 2017 American Heart Association, Inc.

  10. Mendel Lives: The Survival of Mendelian Genetics in the Lysenkoist Classroom, 1937-1964

    Science.gov (United States)

    Peacock, Margaret

    2015-01-01

    The demise of Soviet genetics in the 1930s, 40s, and 50s has stood for many as a prime example of the damage that social and political dogmatism can do when allowed to meddle in the workings of science. In particular, the story of Trofim Lysenko's rise to preeminence and the fall of Mendelian genetics in the Soviet Union has become a lasting…

  11. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.

    Science.gov (United States)

    Bowden, Jack; Davey Smith, George; Burgess, Stephen

    2015-04-01

    The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger's test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples. An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation. © The Author 2015; Published by Oxford University Press on behalf of the International Epidemiological Association.

  12. Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease.

    Science.gov (United States)

    Manousaki, Despoina; Mokry, Lauren E; Ross, Stephanie; Goltzman, David; Richards, J Brent

    2016-08-01

    Observational studies support a possible association between decreased vitamin D levels and risk of coronary artery disease (CAD); however, it remains unclear whether this relationship is causal. We aimed to evaluate whether genetically lowered vitamin D levels influence the risk of CAD using a Mendelian randomization approach. In this 2-stage Mendelian randomization study, we first identified single-nucleotide polymorphisms associated with 25-hydroxyvitamin D (25OHD) levels in the SUNLIGHT consortium (n=33 996), then tested them for possible violation of Mendelian randomization assumptions. A count of risk alleles was tested for association with 25OHD levels in a separate cohort (n=2347). Alleles were weighted by their relative effect on 25OHD and tested for their combined effect on CAD in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study (22 233 cases/64 762 controls). Four single-nucleotide polymorphisms were identified to be associated with 25OHD levels, all in or near genes implicated in 25OHD synthesis, transport or metabolism. A count of these risk alleles was strongly associated with 25OHD (n=2347, F-test statistic=49.7, P=2×10(-12)). None of the single-nucleotide polymorphisms associated with 25OHD levels were associated with CAD (all P values >0.6). The Mendelian randomization odds ratio (OR) for CAD was 0.99 (95% confidence interval, 0.84-1.17; P=0.93; I(2)=0) per SD decrease in log-transformed 25OHD levels. These results persisted after sensitivity analyses for population stratification and pleiotropy. Genetically lowered 25OHD levels were not associated with increased risk of CAD in a large, well-powered study, suggesting that previous associations between circulating 25OHD levels and CAD are possibly confounded or due to reverse causation. © 2016 American Heart Association, Inc.

  13. Obesity, metabolic factors and risk of different histological types of lung cancer : a Mendelian randomization study

    OpenAIRE

    Carreras-Torres, R.; Johansson, M.; Haycock, P.C.; Wade, K.H.; Relton, C. L.; Martin, R. M.; Davey Smith, G.; Albanes, D.; Aldrich, M.C.; Andrew, A; Arnold, S. M.; Bickeböller, H; Bojesen, S. E.; Brunnström, H.; Manjer, J.

    2017-01-01

    BackgroundAssessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.Methods and findingsWe identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,4...

  14. Using Mendelian randomisation to infer causality in depression and anxiety research.

    Science.gov (United States)

    Gage, Suzanne H; Smith, George Davey; Zammit, Stanley; Hickman, Matthew; Munafò, Marcus R

    2013-12-01

    Depression and anxiety co-occur with substance use and abuse at a high rate. Ascertaining whether substance use plays a causal role in depression and anxiety is difficult or impossible with conventional observational epidemiology. Mendelian randomisation uses genetic variants as a proxy for environmental exposures, such as substance use, which can address problems of reverse causation and residual confounding, providing stronger evidence about causality. Genetic variants can be used instead of directly measuring exposure levels, in order to gain an unbiased estimate of the effect of various exposures on depression and anxiety. The suitability of the genetic variant as a proxy can be ascertained by confirming that there is no relationship between variant and outcome in those who do not use the substance. At present, there are suitable instruments for tobacco use, so we use that as a case study. Proof-of-principle Mendelian randomisation studies using these variants have found evidence for a causal effect of smoking on body mass index. Two studies have investigated tobacco and depression using this method, but neither found strong evidence that smoking causes depression or anxiety; evidence is more consistent with a self-medication hypothesis. Mendelian randomisation represents a technique that can aid understanding of exposures that may or may not be causally related to depression and anxiety. As more suitable instruments emerge (including the use of allelic risk scores rather than individual single nucleotide polymorphisms), the effect of other substances can be investigated. Linkage disequilibrium, pleiotropy, and population stratification, which can distort Mendelian randomisation studies, are also discussed. © 2013 Wiley Periodicals, Inc.

  15. A community-based resource for automatic exome variant-calling and annotation in Mendelian disorders

    OpenAIRE

    Mutarelli, Margherita; Marwah, Veer Singh; Rispoli, Rossella; Carrella, Diego; Dharmalingam, Gopuraja; Oliva, Gennaro; di Bernardo, Diego

    2014-01-01

    Background Mendelian disorders are mostly caused by single mutations in the DNA sequence of a gene, leading to a phenotype with pathologic consequences. Whole Exome Sequencing of patients can be a cost-effective alternative to standard genetic screenings to find causative mutations of genetic diseases, especially when the number of cases is limited. Analyzing exome sequencing data requires specific expertise, high computational resources and a reference variant database to identify pathogenic...

  16. Estimating Marginal Healthcare Costs Using Genetic Variants as Instrumental Variables: Mendelian Randomization in Economic Evaluation.

    Science.gov (United States)

    Dixon, Padraig; Davey Smith, George; von Hinke, Stephanie; Davies, Neil M; Hollingworth, William

    2016-11-01

    Accurate measurement of the marginal healthcare costs associated with different diseases and health conditions is important, especially for increasingly prevalent conditions such as obesity. However, existing observational study designs cannot identify the causal impact of disease on healthcare costs. This paper explores the possibilities for causal inference offered by Mendelian randomization, a form of instrumental variable analysis that uses genetic variation as a proxy for modifiable risk exposures, to estimate the effect of health conditions on cost. Well-conducted genome-wide association studies provide robust evidence of the associations of genetic variants with health conditions or disease risk factors. The subsequent causal effects of these health conditions on cost can be estimated using genetic variants as instruments for the health conditions. This is because the approximately random allocation of genotypes at conception means that many genetic variants are orthogonal to observable and unobservable confounders. Datasets with linked genotypic and resource use information obtained from electronic medical records or from routinely collected administrative data are now becoming available and will facilitate this form of analysis. We describe some of the methodological issues that arise in this type of analysis, which we illustrate by considering how Mendelian randomization could be used to estimate the causal impact of obesity, a complex trait, on healthcare costs. We describe some of the data sources that could be used for this type of analysis. We conclude by considering the challenges and opportunities offered by Mendelian randomization for economic evaluation.

  17. HDL Cholesterol, LDL Cholesterol, and Triglycerides as Risk Factors for CKD: A Mendelian Randomization Study.

    Science.gov (United States)

    Lanktree, Matthew B; Thériault, Sébastien; Walsh, Michael; Paré, Guillaume

    2017-07-26

    High-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride concentrations are heritable risk factors for vascular disease, but their role in the progression of chronic kidney disease (CKD) is unclear. 2-sample Mendelian randomization analysis of data derived from the largest published lipid and CKD studies. Effect of independent genetic variants significantly associated with lipid concentrations was obtained from the Global Lipids Genetics Consortium (n=188,577), and the effect of these same variants on estimated glomerular filtration rate (eGFR), CKD (defined as eGFRGenetics Consortium (n=133,814). Using conventional, multivariable, and Egger Mendelian randomization approaches, we assessed the causal association between genetically determined lipid concentrations and kidney traits. eGFR, dichotomous eGFRGenetically higher triglyceride concentrations appeared associated with higher eGFRs, but this finding was driven by a single pleiotropic variant in the glucokinase regulator gene (GCKR). After exclusion, genetically higher triglyceride concentration was not associated with any kidney trait. Individual patient-level phenotype and genotype information were unavailable. 2-sample Mendelian randomization analysis of data from the largest lipid and CKD cohorts supports genetically higher HDL cholesterol concentration as causally associated with better kidney function. There was no association between genetically altered LDL cholesterol or triglyceride concentration and kidney function. Further analysis of CKD outcomes in HDL cholesterol intervention trials is warranted. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  18. Accounting for genetic heterogeneity in homozygosity mapping: application to Mendelian susceptibility to mycobacterial disease.

    Science.gov (United States)

    Grant, Audrey V; Boisson-Dupuis, Stéphanie; Herquelot, Eléonore; de Beaucoudrey, Ludovic; Filipe-Santos, Orchidée; Nolan, Daniel K; Feinberg, Jacqueline; Boland, Anne; Al-Muhsen, Saleh; Sanal, Ozden; Camcioglu, Yildiz; Palanduz, Ayse; Kilic, Sara Sebnem; Bustamante, Jacinta; Casanova, Jean-Laurent; Abel, Laurent

    2011-08-01

    Genome-wide homozygosity mapping is a powerful method for locating rare recessive Mendelian mutations. However, statistical power decreases dramatically in the presence of genetic heterogeneity. The authors applied an empirical approach to test for linkage accounting for genetic heterogeneity by calculating the sum of positive per-family multipoint LOD scores (S) across all positions, and obtaining corresponding empirical p values (EmpP) through permutations. The statistical power of the approach was found to be consistently higher than the classical heterogeneity LOD by simulations. Among 21 first-cousin matings with a single affected child, for five families linked to a locus of interest and 16 families to other loci, S/EmpP achieved a power of 40% versus 28% for heterogeneity LOD at an α level of 0.001. The mean size of peak linkage regions was markedly higher for true loci than false positive regions. The S/EmpP approach was applied to a sample of 17 consanguineous families with Mendelian susceptibility to mycobacterial disease, leading to the identification of two mutations in IL12RB1 and TYK2 from the largest of six linkage regions at p<10(-3). The S/EmpP approach is a flexible and powerful approach that can be applied to linkage analysis of families with suspected Mendelian disorders.

  19. Genitourinary complications as initial presentation of inherited ...

    African Journals Online (AJOL)

    Epidermolysis bullosa (EB) is a rare disorder that presents with urological complications. We present a 6-year-old boy admitted with urological symptoms that revealed an inherited EB misdiagnosed. We also review the literature on this disorder and management of the common urological complications.

  20. Lightweight EDF Scheduling with Deadline Inheritance

    NARCIS (Netherlands)

    Jansen, P.G.; Mullender, Sape J.; Scholten, Johan; Havinga, Paul J.M.

    EDFI is a lightweight real-time scheduling protocol that combines EDF with deadline inheritance over shared resources. We will show that EDFI is flexible during a tasks admission control, efficient with scheduling and dispatching, and straightforward in feasibility analysis. The application

  1. Inherited thrombophilia: a double-edged sword

    NARCIS (Netherlands)

    Middeldorp, Saskia

    2016-01-01

    Inherited thrombophilia is a blood coagulation disorder that increases the risk for venous thromboembolism (VTE). During the last decades, the practice of testing has evolved from testing selected populations, leading to high perceived risks, to broad testing for various conditions that included

  2. Prenatal diagnosis of inherited metabolic diseases.

    OpenAIRE

    Diukman, R; Goldberg, J D

    1993-01-01

    Advances in the prenatal diagnosis of inherited metabolic disease have provided new reproductive options to at-risk couples. These advances have occurred in both sampling techniques and methods of analysis. In this review we present an overview of the currently available prenatal diagnostic approaches for the diagnosis of metabolic disease in a fetus.

  3. Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies

    NARCIS (Netherlands)

    Gerard, X.; Garanto Iglesias, A.; Rozet, J.M.; Collin, R.W.J.

    2016-01-01

    Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several

  4. Soft inheritance: challenging the modern synthesis

    Directory of Open Access Journals (Sweden)

    Eva Jablonka

    2008-01-01

    Full Text Available This paper presents some of the recent challenges to the Modern Synthesis of evolutionary theory, which has dominated evolutionary thinking for the last sixty years. The focus of the paper is the challenge of soft inheritance - the idea that variations that arise during development can be inherited. There is ample evidence showing that phenotypic variations that are independent of variations in DNA sequence, and targeted DNA changes that are guided by epigenetic control systems, are important sources of hereditary variation, and hence can contribute to evolutionary changes. Furthermore, under certain conditions, the mechanisms underlying epigenetic inheritance can also lead to saltational changes that reorganize the epigenome. These discoveries are clearly incompatible with the tenets of the Modern Synthesis, which denied any significant role for Lamarckian and saltational processes. In view of the data that support soft inheritance, as well as other challenges to the Modern Synthesis, it is concluded that that synthesis no longer offers a satisfactory theoretical framework for evolutionary biology.

  5. Difficulties in Learning Inheritance and Polymorphism

    Science.gov (United States)

    Liberman, Neomi; Beeri, Catriel; Kolikant, Yifat Ben-David

    2011-01-01

    This article reports on difficulties related to the concepts of inheritance and polymorphism, expressed by a group of 22 in-service CS teachers with an experience with the procedural paradigm, as they coped with a course on OOP. Our findings are based on the analysis of tests, questionnaires that the teachers completed in the course, as well as on…

  6. Legal Inheritance in the Republic of Kosovo

    Directory of Open Access Journals (Sweden)

    Dr.Sc. Hamdi Podvorica

    2011-06-01

    Full Text Available Legal inheritance is one of the most important institutions of inheritance law which regulates the process of legal transition of property of the decedent to one or several heirs. The establish-ment of the legal framework has brought about new reforms to the Inheritance Law. This has enabled the enrichment and functio-ning of the law. A particularly important step was taken towards regulation of legal procedures regarding to how courts, other or-gans and other persons should act regarding inheritance issues. Concretization of the legal authorizations of bodies authorized to enforce the procedure of processing hereditary property has estab-lished the legal basis for realization of the iso jure principle, accor-ding to which, at the moment of death of the person, the heirs gain the right of inheritance and the hereditary property is never left without a titleholder. This is a great advantage that we have noted in undertaking this analysis of the norms in this work, because leaving hereditary property for a longer period of time without a titleholder would render the property vulnerable to des-truction, theft and extermination. The goal of this paper is to avoid focusing only on finding the positive sides of the normative regulation of the legal inheritance process, but also in finding practical deficiencies that are weighing down at the moment on this important process in Kosovo, and in proposing measures for overcoming them. The dark side of the legal inheritance process is linked to the inefficiency of courts and the still fragile legal system in Kosovo. By implementing empirical methods, we have come to the con-clusion that the low number of judges in proportion with the huge number of cases has become a key liability for practical implemen-tation of the principle of initiating the legal procedure ex officio. The failure in enforcing this principle and initiating the procedu-res for processing of hereditary property by courts, even though they

  7. Evaluation of breeding strategies for polledness in dairy cattle using a newly developed simulation framework for quantitative and Mendelian traits.

    Science.gov (United States)

    Scheper, Carsten; Wensch-Dorendorf, Monika; Yin, Tong; Dressel, Holger; Swalve, Herrmann; König, Sven

    2016-06-29

    Intensified selection of polled individuals has recently gained importance in predominantly horned dairy cattle breeds as an alternative to routine dehorning. The status quo of the current polled breeding pool of genetically-closely related artificial insemination sires with lower breeding values for performance traits raises questions regarding the effects of intensified selection based on this founder pool. We developed a stochastic simulation framework that combines the stochastic simulation software QMSim and a self-designed R program named QUALsim that acts as an external extension. Two traits were simulated in a dairy cattle population for 25 generations: one quantitative (QMSim) and one qualitative trait with Mendelian inheritance (i.e. polledness, QUALsim). The assignment scheme for qualitative trait genotypes initiated realistic initial breeding situations regarding allele frequencies, true breeding values for the quantitative trait and genetic relatedness. Intensified selection for polled cattle was achieved using an approach that weights estimated breeding values in the animal best linear unbiased prediction model for the quantitative trait depending on genotypes or phenotypes for the polled trait with a user-defined weighting factor. Selection response for the polled trait was highest in the selection scheme based on genotypes. Selection based on phenotypes led to significantly lower allele frequencies for polled. The male selection path played a significantly greater role for a fast dissemination of polled alleles compared to female selection strategies. Fixation of the polled allele implies selection based on polled genotypes among males. In comparison to a base breeding scenario that does not take polledness into account, intensive selection for polled substantially reduced genetic gain for this quantitative trait after 25 generations. Reducing selection intensity for polled males while maintaining strong selection intensity among females

  8. Mendelian randomization: potential use of genetics to enable causal inferences regarding HIV-associated biomarkers and outcomes.

    Science.gov (United States)

    He, Weijing; Castiblanco, John; Walter, Elizabeth A; Okulicz, Jason F; Ahuja, Sunil K

    2010-11-01

    It is unknown whether biomarkers simply correlate with or are causal for HIV-associated outcomes. Mendelian randomization is a genetic epidemiologic approach used to disentangle causation from association. Here, we discuss the potential use of Mendelian randomization for differentiating whether biomarkers are correlating with or causal for HIV-associated outcomes. Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. In observational epidemiology, this refers to the use of genetic variants to estimate a causal effect between a modifiable risk factor and an outcome of interest. A formal Mendelian randomization study using a genetic marker as a proxy for the biomarker has not been conducted in the HIV field. However, in the postgenomic era, this approach is being used increasingly. Examples are evidence for the causal role of BMI in blood pressure and noncausal role of C-reactive protein in coronary heart disease. We discuss the conceptual framework, uses, and limitations of Mendelian randomization in the context of HIV infection as well as specific biomarkers (IL-6, C-reactive protein) and genetic determinants (e.g., in CCR5, chemokine, and DARC genes) that associate with HIV-related outcomes. Making the distinction between correlation and causality has particular relevance when a biomarker (e.g., IL-6) is potentially modifiable, in which case a biomarker-guided targeted treatment strategy may be feasible. Although the tenets of Mendelian randomization rest on strong assumptions, and conducting a Mendelian randomization study in HIV infection presents many challenges, it may offer the potential to identify causal biomarkers for HIV-associated outcomes.

  9. Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology.

    Science.gov (United States)

    Spataro, Nino; Rodríguez, Juan Antonio; Navarro, Arcadi; Bosch, Elena

    2017-02-01

    Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to those acting on genes whose variation contributes to complex disorders? The answers to these questions could shed light on the architecture of human genetic disorders and may have relevant implications when designing mapping strategies in future genetic studies. Here we show that, relative to non-disease genes, human disease (HD) genes have specific evolutionary profiles and protein network properties. Additionally, our results indicate that the mutation-selection balance renders an insufficient account of the evolutionary history of some HD genes and that adaptive selection could also contribute to shape their genetic architecture. Notably, several biological features of HD genes depend on the type of pathology (complex or Mendelian) with which they are related. For example, genes harbouring both causal variants for Mendelian disorders and risk factors for complex disease traits (Complex-Mendelian genes), tend to present higher functional relevance in the protein network and higher expression levels than genes associated only with complex disorders. Moreover, risk variants in Complex-Mendelian genes tend to present higher odds ratios than those on genes associated with the same complex disorders but with no link to Mendelian diseases. Taken together, our results suggest that genetic variation at genes linked to Mendelian disorders plays an important role in driving susceptibility to complex disease. © The Author 2017. Published by Oxford University Press.

  10. Elusive inheritance: Transgenerational effects and epigenetic inheritance in human environmental disease.

    Science.gov (United States)

    Martos, Suzanne N; Tang, Wan-Yee; Wang, Zhibin

    2015-07-01

    Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate. Many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. Unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well. Recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian lifecycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms. This paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Mendel,MD: A user-friendly open-source web tool for analyzing WES and WGS in the diagnosis of patients with Mendelian disorders.

    Science.gov (United States)

    G C C L Cardenas, Raony; D Linhares, Natália; L Ferreira, Raquel; Pena, Sérgio D J

    2017-06-01

    Whole exome and whole genome sequencing have both become widely adopted methods for investigating and diagnosing human Mendelian disorders. As pangenomic agnostic tests, they are capable of more accurate and agile diagnosis compared to traditional sequencing methods. This article describes new software called Mendel,MD, which combines multiple types of filter options and makes use of regularly updated databases to facilitate exome and genome annotation, the filtering process and the selection of candidate genes and variants for experimental validation and possible diagnosis. This tool offers a user-friendly interface, and leads clinicians through simple steps by limiting the number of candidates to achieve a final diagnosis of a medical genetics case. A useful innovation is the "1-click" method, which enables listing all the relevant variants in genes present at OMIM for perusal by clinicians. Mendel,MD was experimentally validated using clinical cases from the literature and was tested by students at the Universidade Federal de Minas Gerais, at GENE-Núcleo de Genética Médica in Brazil and at the Children's University Hospital in Dublin, Ireland. We show in this article how it can simplify and increase the speed of identifying the culprit mutation in each of the clinical cases that were received for further investigation. Mendel,MD proved to be a reliable web-based tool, being open-source and time efficient for identifying the culprit mutation in different clinical cases of patients with Mendelian Disorders. It is also freely accessible for academic users on the following URL: https://mendelmd.org.

  12. Mendel,MD: A user-friendly open-source web tool for analyzing WES and WGS in the diagnosis of patients with Mendelian disorders.

    Directory of Open Access Journals (Sweden)

    Raony G C C L Cardenas

    2017-06-01

    Full Text Available Whole exome and whole genome sequencing have both become widely adopted methods for investigating and diagnosing human Mendelian disorders. As pangenomic agnostic tests, they are capable of more accurate and agile diagnosis compared to traditional sequencing methods. This article describes new software called Mendel,MD, which combines multiple types of filter options and makes use of regularly updated databases to facilitate exome and genome annotation, the filtering process and the selection of candidate genes and variants for experimental validation and possible diagnosis. This tool offers a user-friendly interface, and leads clinicians through simple steps by limiting the number of candidates to achieve a final diagnosis of a medical genetics case. A useful innovation is the "1-click" method, which enables listing all the relevant variants in genes present at OMIM for perusal by clinicians. Mendel,MD was experimentally validated using clinical cases from the literature and was tested by students at the Universidade Federal de Minas Gerais, at GENE-Núcleo de Genética Médica in Brazil and at the Children's University Hospital in Dublin, Ireland. We show in this article how it can simplify and increase the speed of identifying the culprit mutation in each of the clinical cases that were received for further investigation. Mendel,MD proved to be a reliable web-based tool, being open-source and time efficient for identifying the culprit mutation in different clinical cases of patients with Mendelian Disorders. It is also freely accessible for academic users on the following URL: https://mendelmd.org.

  13. An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study

    Science.gov (United States)

    Davies, John R; Field, Sinead; Randerson-Moor, Juliette; Harland, Mark; Kumar, Rajiv; Anic, Gabriella M; Nagore, Eduardo; Hansson, Johan; Höiom, Veronica; Jönsson, Göran; Gruis, Nelleke A; Park, Jong Y; Guan, Jian; Sivaramakrishna Rachakonda, P; Wendt, Judith; Pjanova, Dace; Puig, Susana; Schadendorf, Dirk; Okamoto, Ichiro; Olsson, Håkan; Affleck, Paul; García-Casado, Zaida; Puig-Butille, Joan Anton; Stratigos, Alexander J; Kodela, Elizabeth; Donina, Simona; Sucker, Antje; Hosen, Ismail; Egan, Kathleen M; Barrett, Jennifer H; van Doorn, Remco; Bishop, D Timothy; Newton-Bishop, Julia

    2014-01-01

    An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization. PMID:24219834

  14. Beyond Punnett Squares: Student Word Association and Explanations of Phenotypic Variation through an Integrative Quantitative Genetics Unit Investigating Anthocyanin Inheritance and Expression in Brassica rapa Fast Plants

    Science.gov (United States)

    Smith, Amber R.; Williams, Paul H.; McGee, Seth A.; Dósa, Katalin; Pfammatter, Jesse

    2014-01-01

    Genetics instruction in introductory biology is often confined to Mendelian genetics and avoids the complexities of variation in quantitative traits. Given the driving question “What determines variation in phenotype (Pv)? (Pv=Genotypic variation Gv + environmental variation Ev),” we developed a 4-wk unit for an inquiry-based laboratory course focused on the inheritance and expression of a quantitative trait in varying environments. We utilized Brassica rapa Fast Plants as a model organism to study variation in the phenotype anthocyanin pigment intensity. As an initial curriculum assessment, we used free word association to examine students’ cognitive structures before and after the unit and explanations in students’ final research posters with particular focus on variation (Pv = Gv + Ev). Comparison of pre- and postunit word frequency revealed a shift in words and a pattern of co-occurring concepts indicative of change in cognitive structure, with particular focus on “variation” as a proposed threshold concept and primary goal for students’ explanations. Given review of 53 posters, we found ∼50% of students capable of intermediate to high-level explanations combining both Gv and Ev influence on expression of anthocyanin intensity (Pv). While far from “plug and play,” this conceptually rich, inquiry-based unit holds promise for effective integration of quantitative and Mendelian genetics. PMID:25185225

  15. Systematic review of pregnancy in women with inherited cardiomyopathies

    NARCIS (Netherlands)

    Krul, Sebastien P. J.; van der Smagt, Jasper J.; van den Berg, Maarten P.; Sollie, Krystyna M.; Pieper, Petronella G.; van Spaendonck-Zwarts, Karin Y.

    Pregnancy exposes women with inherited cardiomyopathies to increased risk for heart failure and arrhythmias. In this paper, we review the clinical course and management of pregnant women with the following inherited cardiomyopathies: hypertrophic cardiomyopathy, dilated cardiomyopathy,

  16. Systematic review of pregnancy in women with inherited cardiomyopathies

    NARCIS (Netherlands)

    Krul, Sébastien P. J.; van der Smagt, Jasper J.; van den Berg, Maarten P.; Sollie, Krystyna M.; Pieper, Petronella G.; van Spaendonck-Zwarts, Karin Y.

    2011-01-01

    Pregnancy exposes women with inherited cardiomyopathies to increased risk for heart failure and arrhythmias. In this paper, we review the clinical course and management of pregnant women with the following inherited cardiomyopathies: hypertrophic cardiomyopathy, dilated cardiomyopathy,

  17. Genetic adaptability of inheritance of resistance to biotic and abiotic ...

    African Journals Online (AJOL)

    ajl yemi

    2011-12-30

    Dec 30, 2011 ... (Mendelian viewpoint). In quantitative genetics, epistasis encompasses a wide range of interactions and can be extended to more than two loci. These two definitions coexist because they are typically applied to different types of study populations and different types of traits. (Aylor and Zeng, 2008).

  18. Why the Rediscoverer Ended up on the Sidelines: Hugo De Vries's Theory of Inheritance and the Mendelian Laws

    Science.gov (United States)

    Stamhuis, Ida H.

    2015-01-01

    Eleven years before the "rediscovery" in 1900 of Mendel's work, Hugo De Vries published his theory of heredity. He expected his theory to become a big success, but it was not well-received. To find supporting evidence for this theory De Vries started an extensive research program. Because of the parallels of his ideas with the…

  19. Maternal inheritance of severe hypertriglyceridemia impairs glucose metabolism in offspring

    OpenAIRE

    Ma, Ya-Hong; Yu, Caiguo; Kayoumu, Abudurexiti; Guo, Xin; Ji, Zhili; LIU, GEORGE

    2015-01-01

    Abstract Maternally inherited familial hypercholesterolemia (FH) impairs glucose metabolism and increases cardiovascular risks in the offspring to a greater degree than paternal inherited FH. However, it remains unknown whether hypertriglyceridemia affects glucose metabolism via inheritance. In this study, we sought to compare the impact of maternally and paternally inherited hypertriglyceridemia on glucose and lipid metabolism in mice. ApoCIII transgenic mice with severe hypertriglyceridemia...

  20. Inherited thrombophilia: key points for genetic counseling.

    Science.gov (United States)

    Varga, Elizabeth

    2007-06-01

    With the evolution of medical genetics to focus on highly prevalent, multifactorial conditions, it is inevitable that genetic counselors will be called upon to participate in the evaluation and counseling of individuals with inherited thrombophilia. The purpose of this review is to educate the genetic counselor on key issues related to risk assessment and genetic counseling for hereditary thrombophilia. The information contained in this document is derived from an extensive review of the literature, as well as the author's personal expertise. Upon completion of this review, the genetic counselor will be able to: a) describe inherited and acquired risk factors for thrombosis, b) collect and interpret personal and family histories to assess risk related to hereditary thrombophilia, c) discuss the potential advantages and disadvantages of thrombophilia testing, including psychosocial aspects and implications for medical management, and d) identify educational and support resources for patients and families.

  1. Novel approaches for diagnosing inherited platelet disorders.

    Science.gov (United States)

    Bastida Bermejo, José María; Hernández-Rivas, Jesús María; González-Porras, José Ramón

    2017-01-20

    Inherited platelet disorders diagnosis is based on the clinical history and bleeding assessment tools. The laboratory functional assays as well as the molecular test to identify the pathogenic genetic variant are essential to confirm the accurate diagnosis of these disorders. Nowadays, the main challenges to developing a new diagnostic system are involved in reducing the samples' volume, and faster and more helpful analysis. Moreover, there are no widely available and standardised global tests. High throughput genetic testing such as next-generation sequencing has revolutionised DNA sequencing technologies as it allows the simultaneous and faster investigation of multiple genes at a manageable cost. This technology has improved the molecular characterisation of inherited platelet disorders and has been implemented in the research studies and the clinical routine practice. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  2. Inherited factor V deficient neonate with galactosaemia.

    Science.gov (United States)

    Mansouritorghabeh, Hassan; Sharifi-Hoseini, Mohamad Reza; Shahroudian, Masoud

    2012-03-01

    Reporting a case of inherited factor V deficiency and galactosemia. A neonate was admitted with hematoma, jaundice, splenomegaly, diarrhea, anemia, abdominal ascites and bilateral cataracts that diagnosis of galactosaemia and factor V deficiency was established. Coinheritance of both coagulation disorder and metabolic disorder is very rare episode that was identified in a neonate. Our case indicates that in mild bleeding episodes of neonates that imitate of coagulation disorders should be considered promptly by pediatricians. Copyright © 2012. Published by Elsevier Inc.

  3. Problem of technological inheritance in machine engineering

    Science.gov (United States)

    Blumenstein, Valery; Rakhimyanov, Kharis; Heifetz, Mikhail; Kleptzov, Alexander

    2016-01-01

    This article demonstrates the importance of the research study with regard to the technological inheritance of the properties, which characterize the surface layer, at different stages of a part's life cycle. It looks back at the major achievements and gives the findings relating to the technological inheritance of the parameters of the surface layer strength and quality as well as to how they affect the performance properties of machine parts. It demonstrates that high rates of machine engineering development, occurrence of new materials and more complicated machine operation environment require a shorter period for design-to-manufacture facility by reducing experiments and increasing design work. That, in its turn, generates the necessity in more complex but also more accurate models of metal behavior under stressing. It is especially critical for strengthening treatment. Among them are the models developed within the mechanics of technological inheritance. It is assumed that at the stages of a part's life cycle deformation accumulates on a continuous basis and the plasticity reserve of the metal, which the surface layer is made of, depletes. The research study of technological inheritance and the discovery of physical patterns of the evolution and degradation of the structures in a thin surface layer, which occur during machining and operational stressing of parts made from existing and unique including nanopatterned metals, is a crucial scientific challenge. This leads to the acquisition of new knowledge in the plasticity of state-of-the-art metals in the conditions of complex non monotonous stressing and to the development of efficient integrated and combined methods of technological impact.

  4. Menorrhagia in adolescents with inherited bleeding disorders.

    Science.gov (United States)

    Chi, Claudia; Pollard, Debra; Tuddenham, Edward G D; Kadir, Rezan A

    2010-08-01

    We reviewed the management and treatment outcomes of menorrhagia in adolescents with inherited bleeding disorders and assessed the impact of menorrhagia on their quality of life. Retrospective review of case notes and a questionnaire study. Comprehensive-care hemophilia treatment center. Adolescents with inherited bleeding disorders who had registered at the center and were attending the multidisciplinary hemophilia and gynecology clinic for management of menorrhagia. Review of medical records and assessment of menstrual blood loss using the pictorial blood assessment chart and quality of life measurements during menstruation using a questionnaire. Scores on pictorial blood assessment charts and quality of life measurements before and after treatment. Of 153 girls aged 12 to 19 years who had registered at the center and had an inherited bleeding disorder, 42 (27%) attended the multidisciplinary clinic for management of menorrhagia. The majority (38/42; 90%) had experienced menorrhagia since menarche. Of the group, 5 (12%) required hospital admission for acute menorrhagia and severe anemia. Treatment options for menorrhagia included tranexamic acid, desmopressin, combined oral contraceptive pills, clotting factor concentrate, and the levonorgestrel intrauterine system. These treatment modalities, alone or in combination, were associated with a reduction in menstrual blood loss (median pre- and posttreatment pictorial blood assessment chart scores were 215 and 88, respectively) and improvement in quality of life scores (median pre- and posttreatment were 26 and 44, respectively). Menorrhagia is a common symptom in adolescents with inherited bleeding disorders. It can present acutely, and it adversely affects quality of life. Treatment options include hemostatic and/or hormonal therapies and can improve the quality of life of affected girls. Copyright 2010 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

  5. Defeasible inheritance-based description logics

    OpenAIRE

    Casini, Giovanni; Straccia, Umberto

    2011-01-01

    Defeasible inheritance networks are a non-monotonic framework dealing with hierarchical knowledge. On the other hand, rational closure, a main representative of the preferential approach, is acknowledged as a landmark. We will combine these two approaches and define a new non-monotonic closure operation for propositional knowledge bases that combines the advantages of both. Then we redefine such a procedure for Description Logics, a family of logics well-suited to model structured information...

  6. A Regulatory RNA Inducing Transgenerationally Inherited Phenotypes

    DEFF Research Database (Denmark)

    Jensen, Lea Møller

    . The variation in Arabidopsis enables different regulatory networks and mechanisms to shape the phenotypic characteristics. The thesis describes the identification of regulatory RNA encoded by an enzyme encoding gene. The RNA regulates by inducing transgenerationally inherited phenotypes. The function of the RNA...... is dependent on the genetic background illustrating that polymorphisms are found in either interactors or target genes of the RNA. Furthermore, the RNA provides a mechanistic link between accumulation of glucosinolate and onset of flowering....

  7. Inherited predisposition to chronic lymphocytic leukemia

    OpenAIRE

    Brown, Jennifer R.

    2008-01-01

    Inherited susceptibility to chronic lymphocytic leukemia (CLL) has been recognized for decades. Approximately 10% of individuals with CLL report a family history of CLL or a related lymphoproliferative disorder, and genetic predisposition is the best understood risk factor for CLL. Studies of familial CLL have suggested that the disease features are largely similar to sporadic CLL, although recent data suggest that familial CLL may more commonly show somatic hypermutation of the immunoglobuli...

  8. Epigenetic inheritance, genetic assimilation and speciation.

    Science.gov (United States)

    Pál, C; Miklós, I

    1999-09-07

    Epigenetic inheritance systems enable the environmentally induced phenotypes to be transmitted between generations. Jablonka and Lamb (1991, 1995) proposed that these systems have a substantial role during speciation. They argued that divergence of isolated populations may be first triggered by the accumulation of (heritable) phenotypic differences that are later followed and strengthened by genetic changes. The plausibility of this idea is examined in this paper. At first, we discuss the "exploratory" behaviour of an epigenetic inheritance system on a one peak adaptive landscape. If a quantitative trait is far from the optimum, then it is advantageous to induce heritable phenotypic variation. Conversely, if the genotypes get closer to the peak, it is more favorable to canalize the phenotypic expression of the character. This process would lead to genetic assimilation. Next we show that the divergence of heritable epigenetic marks acts to reduce or to eliminate the genetic barrier between two adaptive peaks. Therefore, an epigenetic inheritance system can increase the probability of transition from one adaptive state to another. Peak shift might be initiated by (i) slight changes in the inducing environment or by (ii) genetic drift of the genes controlling epigenetic variability. Remarkably, drift-induced transition is facilitated even if phenotypic variation is not heritable. A corollary of our thesis is that evolution can proceed through suboptimal phenotypic states, without passing through a deep adaptive valley of the genotype. We also consider the consequences of this finding on the dynamics and mode of reproductive isolation. Copyright 1999 Academic Press.

  9. Paternal inheritance in mealybugs (Hemiptera: Coccoidea: Pseudococcidae)

    Science.gov (United States)

    Kol-Maimon, Hofit; Mendel, Zvi; Franco, José Carlos; Ghanim, Murad

    2014-10-01

    Mealybugs have a haplodiploid reproduction system, with paternal genome elimination (PGE); the males are diploid soon after fertilization, but during embryogenesis, the male paternal set of chromosomes becomes heterochromatic (HC) and therefore inactive. Previous studies have suggested that paternal genes can be passed on from mealybug males to their sons, but not necessarily by any son, to the next generation. We employed crosses between two mealybug species— Planococcus ficus (Signoret) and Planococcus citri (Risso)—and between two populations of P. ficus, which differ in their mode of pheromone attraction, in order to demonstrate paternal inheritance from males to F2 through F1 male hybrids. Two traits were monitored through three generations: mode of male pheromone attraction (pherotype) and sequences of the internal transcribed spacer 2 (ITS2) gene segment (genotype). Our results demonstrate that paternal inheritance in mealybugs can occur from males to their F2 offspring, through F1 males (paternal line). F2 backcrossed hybrid males expressed paternal pherotypes and ITS2 genotypes although their mother originated through a maternal population. Further results revealed other, hitherto unknown, aspects of inheritance in mealybugs, such as that hybridization between the two species caused absence of paternal traits in F2 hybrid females produced by F1 hybrid females. Furthermore, hybridization between the two species raised the question of whether unattracted males have any role in the interactions between P. ficus and P. citri.

  10. Inheritance law in an aging society.

    Science.gov (United States)

    Hill, G J

    1995-01-01

    An exploratory analysis of states' inheritance law changes between 1961 and 1990 was conducted in order to discern major trends and their implications for older families. Results suggested that states were modifying their laws in ways similar to suggestions of the law community's Uniform Probate Code, with about one third of the states adopting the Code itself. Consequently, inheritance law has become less traditional and paternalistic and more like "facilitative law," that is, flexible, accommodating, and supportive of family autonomy and decisionmaking authority. These changes and new laws that simplify procedures, protect the dependent and vulnerable, treat marital property more like community property, recognize variant family forms, and enable extrafamilial bequests, may serve to minimize family disruption, conserve resources, and allow families to tailor property divisions and procedures to particular needs and wishes. An impact study is proposed for disclosing the actual effects on inheritance law reforms. Also, while trends observed in this study were fairly evident, states' adoption of new laws was uneven and selective, inviting continuing trend analyses and further research into the reasons for interstate variation.

  11. Inherited ichthyosis: Non-syndromic forms.

    Science.gov (United States)

    Takeichi, Takuya; Akiyama, Masashi

    2016-03-01

    Inherited ichthyoses are a group of genetic disorders characterized by generalized dry skin, scaling and hyperkeratosis, and often associated with erythroderma. These manifestations are due to mutations in genes mostly involved in skin barrier formation. Inherited ichthyoses consist of non-syndromic ichthyoses and ichthyosis syndromes. Non-syndromic ichthyoses are characterized by the phenotypic expression of the disorder being seen only in the skin. Non-syndromic ichthyoses include ichthyosis vulgaris, recessive X-linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis and other forms. This review focuses on updates for each type of non-syndromic ichthyosis, highlighting molecular mechanisms and phenotype/genotype correlations. Included in autosomal recessive congenital ichthyosis are three of the major phenotypes (harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma) and three of the minor subtypes (self-healing collodion baby, acral self-healing collodion baby and bathing suit ichthyosis). Keratinopathic ichthyosis is proposed as an umbrella term for ichthyoses caused by mutations in keratin genes. Next-generation sequencing technologies have become powerful tools for the diagnosis of inherited ichthyoses and the discovery of their genetic causes. This article reviews the current understanding of molecular pathomechanisms for non-syndromic ichthyoses and explores future perspectives. © 2016 Japanese Dermatological Association.

  12. Phenotype as Agent for Epigenetic Inheritance

    Directory of Open Access Journals (Sweden)

    John S. Torday

    2016-07-01

    Full Text Available The conventional understanding of phenotype is as a derivative of descent with modification through Darwinian random mutation and natural selection. Recent research has revealed Lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. In consequence, the role of phenotype can productively be reconsidered. The possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. It is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of Darwinian selection towards reproductive success. The reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. Furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state.

  13. Mendelian randomization: how genetics is pushing the boundaries of epidemiology to identify new causes of heart disease.

    Science.gov (United States)

    Thanassoulis, George

    2013-01-01

    The past 10 years have seen a remarkable revolution in the genetics of cardiovascular (CV) disease. Although much work remains to bring these discoveries to the bedside, genetics has opened up remarkable possibilities in understanding the causes of CV disease through a relatively novel study design known as "Mendelian randomization." Akin to a randomized trial, Mendelian randomization is a genetic study design that takes advantage of the "randomization" of genetic information at birth to evaluate a potential causal relationship between a genetically determined biomarker and an outcome. By providing evidence for causal relationships, Mendelian randomization can improve our understanding of fundamental mechanisms in human disease, potentially accelerate the identification of bona fide drug targets, and ultimately improve the care of patients with CV disease. This review describes the concept and design of Mendelian randomization genetic studies, discusses their strengths and weaknesses, and presents recent examples of Mendelian randomization studies in the CV literature that have helped clarify the causal role of selected biomarkers in CV medicine. Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  14. No clear support for a role for vitamin D in Parkinson's disease: A Mendelian randomization study.

    Science.gov (United States)

    Larsson, Susanna C; Singleton, Andrew B; Nalls, Mike A; Richards, J Brent

    2017-08-01

    Observational studies have found that relative to healthy controls, patients with Parkinson's disease have lower circulating concentrations of 25-hydroxyvitamin D, a clinical biomarker of vitamin D status. However, the causality of this association is uncertain. We undertook a Mendelian randomization study to investigate whether genetically decreased 25-hydroxyvitamin D concentrations are associated with PD to minimize confounding and prevent bias because of reverse causation. As instrumental variables for the Mendelian randomization analysis, we used 4 single-nucleotide polymorphisms that affect 25-hydroxyvitamin D concentrations (rs2282679 in GC, rs12785878 near DHCR7, rs10741657 near CYP2R1, and rs6013897 near CYP24A1). Summary effect size estimates of the 4 single-nucleotide polymorphisms on PD were obtained from the International Parkinson's Disease Genomics Consortium (including 5333 PD cases and 12,019 controls). The estimates of the 4 single-nucleotide polymorphisms were combined using an inverse-variance weighted meta-analysis. Of the 4 single-nucleotide polymorphisms associated with 25-hydroxyvitamin D concentrations, one (rs6013897 in CYP24A1) was associated with PD (odds ratio per 25-hydroxyvitamin D-decreasing allele, 1.09; 95% confidence interval, 1.02-1.16; P = 0.008), whereas no association was observed with the other 3 single-nucleotide polymorphisms (P > 0.23). The odds ratio of PD per genetically predicted 10% lower 25-hydroxyvitamin D concentration, based on the 4 single-nucleotide polymorphisms, was 0.98 (95% confidence interval, 0.93-1.04; P = 0.56). This Mendelian randomization study provides no clear support that lowered 25-hydroxyvitamin D concentration is causally associated with risk of PD. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  15. Blood lipid genetic scores, the HMGCR gene and cancer risk: a Mendelian randomization study.

    Science.gov (United States)

    Orho-Melander, Marju; Hindy, George; Borgquist, Signe; Schulz, Christina-Alexandra; Manjer, Jonas; Melander, Olle; Stocks, Tanja

    2017-11-20

    It is unclear whether there are causal associations between blood lipids, statin use and cancer risks. Under certain assumptions, Mendelian randomization analysis of a genetic marker for an exposure eliminates reverse causation and confounding. We applied Mendelian randomization analysis to genetic scores, comprising 26-41 single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) for triglycerides and low- and high-density lipoprotein cholesterol (LDLC, HDLC), using a prospective cohort of 26 904 individuals in which there were 6607 incident cancers. We also investigated cancer risk for a SNP (rs12916) in the gene encoding hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the targeted enzyme in statin treatment. We used logistic regression and SNP pleiotropy-adjusted analyses to estimate the odds ratio per standard deviation (OR). The OR for the triglyceride IV as a predictor of any cancer was 0.91 [95% confidence interval (CI): 0.80-1.03] unadjusted, and 0.87 (95% CI: 0.78-0.95) from the pleiotropy-adjusted analysis. For the HMGCR rs12916 per LDLC-lowering T-allele, the OR was 1.09 (95% CI: 1.01-1.18) for prostate cancer and 0.89 (95% CI: 0.82-0.96) for breast cancer. The LDLC IV was not associated with prostate cancer or breast cancer. There were no associations between IVs and cancers of the lung, colon or bladder. Under the assumptions of Mendelian randomization, there is a causal and negative association between serum triglycerides and risk of any cancer. Further, the HMGCR genetic variant might be associated with risks of prostate and breast cancers but the biological mechanisms behind these findings are unclear, as the LDLC IV was not associated with these cancers.

  16. Mendelian randomization analysis to examine for a causal effect of urate on bone mineral density.

    Science.gov (United States)

    Dalbeth, Nicola; Topless, Ruth; Flynn, Tanya; Cadzow, Murray; Bolland, Mark J; Merriman, Tony R

    2015-06-01

    In observational studies, serum urate concentrations are positively associated with bone mineral density (BMD) and reduced risk of fragility fractures, raising the possibility that urate is a direct mediator of bone density. We used Mendelian randomization analysis to examine whether urate has a causal effect on BMD. We analyzed data from the Generation 3 cohort in the Framingham Heart Study (FHS) (N = 2501 total; 1265 male, 1236 female). A weighted genetic urate score was calculated using the SLC2A9, ABCG2, SLC17A1, SLC22A11, and SLC22A12 single-nucleotide polymorphisms (SNPs) that explains 3.4% of the variance in serum urate. Mendelian randomization analysis was performed using the two-stage least squares method with >80% power at α = 0.05 to detect an effect size equivalent to that observed in the ordinary least squares analysis between serum urate and total femur BMD. A strong association between serum urate and BMD was observed in the crude ordinary least squares analysis (total femur crude beta = 0.47, p = 1.7E-51). In the two-stage least squares analysis using the weighted genetic urate score as the instrumental variable, no significant relationship was observed between serum urate and BMD (total femur crude beta =-0.36, p = 0.06). Similar findings were observed in both the male and female subgroups, and there was no evidence for causality when individual SNPs were analyzed. Serum urate is strongly associated with BMD. However, controlling for confounders by Mendelian randomization analysis does not provide evidence that increased urate has a causal effect on increasing BMD. © 2014 American Society for Bone and Mineral Research.

  17. Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study.

    Science.gov (United States)

    Zhan, Yiqiang; Karlsson, Ida K; Karlsson, Robert; Tillander, Annika; Reynolds, Chandra A; Pedersen, Nancy L; Hägg, Sara

    2017-07-21

    Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention. To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design. Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality-was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with -0.07 (95% confidence interval, -0.01 to -0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; P=0.04). Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis. © 2017 American Heart Association, Inc.

  18. Mendelian randomization study of body mass index and colorectal cancer risk

    Science.gov (United States)

    Thrift, Aaron P.; Gong, Jian; Peters, Ulrike; Chang-Claude, Jenny; Rudolph, Anja; Slattery, Martha L.; Chan, Andrew T.; Locke, Adam E.; Kahali, Bratati; Justice, Anne E.; Pers, Tune H.; Gallinger, Steven; Hayes, Richard B; Baron, John A.; Caan, Bette J.; Ogino, Shuji; Berndt, Sonja I.; Chanock, Stephen J.; Casey, Graham; Haile, Robert W.; Du, Mengmeng; Harrison, Tabitha A.; Thornquist, Mark; Duggan, David J.; Le Marchand, Loïc; Lindor, Noralane M.; Seminara, Daniela; Song, Mingyang; Wu, Kana; Thibodeau, Stephen N.; Cotterchio, Michelle; Win, Aung Ko; Jenkins, Mark A.; Hopper, John L.; Ulrich, Cornelia M.; Potter, John D.; Newcomb, Polly A.; Hoffmeister, Michael; Brenner, Hermann; White, Emily; Hsu, Li; Campbell, Peter T.

    2015-01-01

    Background High body mass index (BMI) is consistently linked to increased risk of colorectal cancer (CRC) for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and CRC. Methods We used data from 10,226 CRC cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results Individuals carrying greater numbers of BMI-increasing alleles had higher CRC risk (per weighted allele OR, 1.31; 95% confidence interval [CI], 1.10–1.57). Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for CRC (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of CRC among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with CRC (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92). Conclusions High BMI was associated with increased CRC risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of CRC. PMID:25976416

  19. A community-based resource for automatic exome variant-calling and annotation in Mendelian disorders.

    Science.gov (United States)

    Mutarelli, Margherita; Marwah, Veer; Rispoli, Rossella; Carrella, Diego; Dharmalingam, Gopuraja; Oliva, Gennaro; di Bernardo, Diego

    2014-01-01

    Mendelian disorders are mostly caused by single mutations in the DNA sequence of a gene, leading to a phenotype with pathologic consequences. Whole Exome Sequencing of patients can be a cost-effective alternative to standard genetic screenings to find causative mutations of genetic diseases, especially when the number of cases is limited. Analyzing exome sequencing data requires specific expertise, high computational resources and a reference variant database to identify pathogenic variants. We developed a database of variations collected from patients with Mendelian disorders, which is automatically populated thanks to an associated exome-sequencing pipeline. The pipeline is able to automatically identify, annotate and store insertions, deletions and mutations in the database. The resource is freely available online http://exome.tigem.it. The exome sequencing pipeline automates the analysis workflow (quality control and read trimming, mapping on reference genome, post-alignment processing, variation calling and annotation) using state-of-the-art software tools. The exome-sequencing pipeline has been designed to run on a computing cluster in order to analyse several samples simultaneously. The detected variants are annotated by the pipeline not only with the standard variant annotations (e.g. allele frequency in the general population, the predicted effect on gene product activity, etc.) but, more importantly, with allele frequencies across samples progressively collected in the database itself, stratified by Mendelian disorder. We aim at providing a resource for the genetic disease community to automatically analyse whole exome-sequencing samples with a standard and uniform analysis pipeline, thus collecting variant allele frequencies by disorder. This resource may become a valuable tool to help dissecting the genotype underlying the disease phenotype through an improved selection of putative patient-specific causative or phenotype-associated variations.

  20. Inherited metabolic liver diseases in infants and children: an overview

    Directory of Open Access Journals (Sweden)

    Ivo Barić

    2013-10-01

    Full Text Available Inborn errors of metabolism, which affect the liver are a large, continuously increasing group of diseases. Their clinical onset can occur at any age, from intrauterine period presenting as liver failure already at birth to late adulthood. Inherited metabolic disorders must be considered in differential diagnosis of every unexplained liver disease. Specific diagnostic work-up for either their confirmation or exclusion should start immediately since any postponing can result in delayed diagnosis and death or irreversible disability. This can be particularly painful while many inherited metabolic liver diseases are relatively easily treatable if diagnosed on time, for instance galactosemia or hereditary fructose intolerance by simple dietary means. Any unexplained liver disease, even one looking initially benign, should be considered as a potential liver failure and therefore should deserve proper attention. Diagnosis in neonates is additionally complicated because of the factors which can mask liver disease, such as physiological neonatal jaundice, normally relatively enlarged liver and increased transaminases at that age. In everyday practice, in order to reveal the etiology, it is useful to classify and distinguish some clinical patterns which, together with a few routine, widely available laboratory tests (aminotransferases, prothrombine time, albumin, gammaGT, total and conjugated bilirubin, ammonia, alkaline phosphatase and glucose make the search for the cause much easier. These patterns are isolated hyperbilirubinemia, syndrome of cholestasis in early infancy, hepatocellular jaundice, Reye syndrome, portal cirrhosis and isolated hepatomegaly. Despite the fact that some diseases can present with more than one pattern (for instance, alpha-1-antitrypsin deficiency as infantile cholestasis, but also as hepatocellular jaundice, and that in some disesases one pattern can evolve into another (for instance, Wilson disease from hepatocellular

  1. Molecular-based mechanisms of Mendelian forms of salt-dependent hypertension: questioning the prevailing theory.

    Science.gov (United States)

    Kurtz, Theodore W; Dominiczak, Anna F; DiCarlo, Stephen E; Pravenec, Michal; Morris, R Curtis

    2015-05-01

    This critical review directly challenges the prevailing theory that a transient increase in cardiac output caused by genetically mediated increases in activity of the ENaC in the aldosterone sensitive distal nephron, or of the NCC in the distal convoluted tubule, accounts entirely for the hemodynamic initiation of all Mendelian forms of salt-dependent hypertension (Figure 1). The prevailing theory of how genetic mutations enable salt to hemodynamically initiate Mendelian forms of salt-dependent hypertension in humans (Figure 1) depends on the results of salt-loading studies of cardiac output and systemic vascular resistance in nongenetic models of hypertension that lack appropriate normal controls. The theory is inconsistent with the results of studies that include measurements of the initial hemodynamic changes induced by salt loading in normal, salt-resistant controls. The present analysis, which takes into account the results of salt-loading studies that include the requisite normal controls, indicates that mutation-induced increases in the renal tubular activity of ENaC or NCC that lead to transient increases in cardiac output will generally not be sufficient to enable increases in salt intake to initiate the increased BP that characterizes Mendelian forms of salt-dependent hypertension (Table). The present analysis also raises questions about whether mutation-dependent increases in renal tubular activity of ENaC or NCC are even necessary to account for increased risk for salt-dependent hypertension in most patients with such mutations. We propose that for the genetic alterations underlying Mendelian forms of salt-dependent hypertension to enable increases in salt intake to initiate the increased BP, they must often cause vasodysfunction, ie, an inability to normally vasodilate and decrease systemic vascular resistance in response to increases in salt intake within dietary ranges typically observed in most modern societies. A subnormal ability to vasodilate in

  2. Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study.

    Science.gov (United States)

    Censin, J C; Nowak, Christoph; Cooper, Nicholas; Bergsten, Peter; Todd, John A; Fall, Tove

    2017-08-01

    The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations. We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study. This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the

  3. Diagnosis and management of inherited cardiomyopathies.

    Science.gov (United States)

    Millar, Lynne; Sharma, Sanjay

    2014-10-01

    Inherited heart conditions are the most common cause of sudden cardiac death in those under the age of 35 and the leading cause of non-traumatic death in young athletes. Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease affecting 1 in 500 of the population. Some patients may exhibit severe left ventricular hypertrophy, others may show nothing more than an abnormal ECG. Left ventricular hypertrophy most commonly manifests in the second decade of life. Sudden death is rare and usually affects patients in the first three decades whereas older patients present with heart failure, atrial fibrillation and stroke. Arrhythmogenic right ventricular cardiomyopathy is a rare, autosomal dominant heart muscle disorder which affects between 1 in 1,000 and 1 in 5,000 of the population. Dilated cardiomyopathy (DCM) is characterised by a dilated left ventricle with impaired function that cannot be explained by ischaemic heart disease, hypertension or valvular heart disease. At least 25% of cases of DCM are familial. DCM may be associated with multisystem conditions such as muscular dystrophy. Chemotherapy and certain other drugs, alcohol abuse and myocarditis may also lead to a dilated and poorly contracting left ventricle. In many cases the first manifestation of an inherited cardiomyopathy can be a sudden cardiac arrest. Other presentations include chest pain or breathlessness during exertion, palpitations and syncope. In many of the cardiomyopathies, the diagnosis can be made with a standard ECG and echocardiogram. However if the diagnosis is not certain or the cardiologist wishes to look at the heart structure in greater detail, a cardiac MRI may be performed.

  4. Transgenerational Epigenetic Inheritance: myths and mechanisms

    Science.gov (United States)

    Heard, Edith; Martienssen, Robert A.

    2014-01-01

    Since the human genome was sequenced, the term “epigenetics” is increasingly being associated with the hope that we are more than just the sum of our genes. Might what we eat, the air we breathe, or even the emotions we feel, influence not only our genes but those of descendents? The environment can certainly influence gene expression, and can lead to disease, but trans-generational consequences are another matter. While the inheritance of epigenetic characters can certainly occur - particularly in plants – how much is due to the environment and the extent to which it happens in humans, remains unclear. PMID:24679529

  5. Intermediate form of osteopetrosis with recessive inheritance

    Energy Technology Data Exchange (ETDEWEB)

    Kaibara, N.; Katsuki, I.; Hotokebuchi, T.; Takagishi, K.

    1982-11-01

    The clinical and radiographic features of the intermediate form of osteopetrosis in two sibs are presented in which the disorder appears to have been inherited as a recessive trait. Although this form of osteopetrosis has been poorly delineated, its recognition is practically important in order to give an accurate prognosis. This paper also presents an unusual complication of bilateral avascular necrosis of the femoral head in the younger sib. Radiographic changes of the femoral heads suggest those of Legg-Calve-Perthes disease, though the possibility of avascular necrosis following unrecognized femoral neck fracture is not completely excluded.

  6. Genetic modifiers of Mendelian disease: Huntington's disease and the trinucleotide repeat disorders.

    Science.gov (United States)

    Holmans, Peter A; Massey, Thomas H; Jones, Lesley

    2017-10-01

    In the decades since the genes and mutations associated with the commoner Mendelian disorders were first discovered, technological advances in genetic analysis have made finding genomic variation a much less onerous task. Recently, the global efforts to collect subjects with Mendelian disorders, to better define the disorders and to empower appropriate clinical trials, along with improved genetic technologies, have allowed the identification of genetic variation that does not cause disease, but substantially modifies disease presentation. The advantage of this is it identifies biological pathways and molecules, that, if modified in people, might alter disease presentation. In Huntington's disease (HD), caused by an expanded CAG repeat tract in HTT, genetic variation has been uncovered that is associated with change in the onset or progression of disease. Some of this variation lies in genes that are part of the DNA damage response, previously suggested to be important in modulating expansion of the repeat tract in germline and somatic cells. The genetic evidence implicates a DNA damage response-related pathway in modulating the pathogenicity of the repeat tracts in HD, and possibly, in other trinucleotide repeat disorders. These findings offer new targets for drug development in these currently intractable disorders. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders.

    Science.gov (United States)

    Yavarna, Tarunashree; Al-Dewik, Nader; Al-Mureikhi, Mariam; Ali, Rehab; Al-Mesaifri, Fatma; Mahmoud, Laila; Shahbeck, Noora; Lakhani, Shenela; AlMulla, Mariam; Nawaz, Zafar; Vitazka, Patrik; Alkuraya, Fowzan S; Ben-Omran, Tawfeg

    2015-09-01

    Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60%. Consanguinity and positive family history predicted a higher diagnostic yield. In 5% (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4% (6/149) and actionable incidental findings in 2% (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.

  8. Mendelian Randomization Study of Body Mass Index and Colorectal Cancer Risk

    DEFF Research Database (Denmark)

    Thrift, Aaron P.; Gong, Jian; Peters, Ulrike

    2015-01-01

    Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate...... the causal association between BMI and colorectal cancer. Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated...... cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity...

  9. Neuromuscular imaging in inherited muscle diseases

    Energy Technology Data Exchange (ETDEWEB)

    Wattjes, Mike P. [VU University Medical Center, Department of Radiology, De Boelelaan 1117, HV, Amsterdam (Netherlands); Kley, Rudolf A. [Klinken Bergmannsheil, Ruhr-University, Department of Neurology, Neuromuscular Centre Ruhrgebiet, Bochum (Germany); Fischer, Dirk [University Hospital of Basel, Department of Neurology, Basel (Switzerland); University Children' s Hospital Basel, Department of Neuropaediatrics, Basel (Switzerland)

    2010-10-15

    Driven by increasing numbers of newly identified genetic defects and new insights into the field of inherited muscle diseases, neuromuscular imaging in general and magnetic resonance imaging (MRI) in particular are increasingly being used to characterise the severity and pattern of muscle involvement. Although muscle biopsy is still the gold standard for the establishment of the definitive diagnosis, muscular imaging is an important diagnostic tool for the detection and quantification of dystrophic changes during the clinical workup of patients with hereditary muscle diseases. MRI is frequently used to describe muscle involvement patterns, which aids in narrowing of the differential diagnosis and distinguishing between dystrophic and non-dystrophic diseases. Recent work has demonstrated the usefulness of muscle imaging for the detection of specific congenital myopathies, mainly for the identification of the underlying genetic defect in core and centronuclear myopathies. Muscle imaging demonstrates characteristic patterns, which can be helpful for the differentiation of individual limb girdle muscular dystrophies. The aim of this review is to give a comprehensive overview of current methods and applications as well as future perspectives in the field of neuromuscular imaging in inherited muscle diseases. We also provide diagnostic algorithms that might guide us through the differential diagnosis in hereditary myopathies. (orig.)

  10. Ultrasound of Inherited vs. Acquired Demyelinating Polyneuropathies

    Science.gov (United States)

    Zaidman, Craig M.; Harms, Matthew B.; Pestronk, Alan

    2013-01-01

    Introduction We compared features of nerve enlargement in inherited and acquired demyelinating neuropathies using ultrasound. Methods We measured median and ulnar nerve cross-sectional areas in proximal and distal regions in 128 children and adults with inherited (Charcot-Marie Tooth-1 (CMT-1) (n=35)) and acquired (Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (n=55), Guillaine-Barre Syndrome (GBS) (n=21) and Multifocal Motor Neuropathy (MMN) (n=17)) demyelinating neuropathies. We classified nerve enlargement by degree and number of regions affected. We defined patterns of nerve enlargement as: none- no enlargement; mild-nerves enlarged but never more than twice normal; regional- nerves normal at at least one region and enlarged more than twice normal at atleast one region; diffuse- nerves enlarged at all four regions with atleast one region more than twice normal size. Results Nerve enlargement was commonly diffuse (89%) and generally more than twice normal size in CMT-1, but not (pdemyelinating polyneuropathy suggests an acquired etiology. Early treatment in CIDP may impede nerve enlargement. PMID:24101129

  11. Inheritable and sporadic non-autoimmune hyperthyroidism.

    Science.gov (United States)

    Ferraz, Carolina; Paschke, Ralf

    2017-03-01

    Hyperthyroidism is a clinical state that results from high thyroid hormone levels which has multiple etiologies, manifestations, and potential therapies. Excluding the autoimmune Graves disease, autonomic adenomas account for the most import cause of non-autoimmune hyperthyroidism. Activating germline mutations of the TSH receptor are rare etiologies for hyperthyroidism. They can be inherited in an autosomal dominant manner (familial or hereditary, FNAH), or may occur sporadically as a de novo condition, also called: persistent sporadic congenital non-autoimmune hyperthyroidism (PSNAH). These three conditions: autonomic adenoma, FNAH and PSNAH constitute the inheritable and sporadic non-autoimmune hyperthyroidism. Particularities in epidemiology, etiology, molecular and clinical aspects of these three entities will be discussed in this review in order to guide to an accurate diagnosis allowing among others genetic counseling and presymptomatic diagnosis for the affected families. The optimal treatment based on the right diagnosis will avoid consequences of a persistent or relapsing hyperthyroidism. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  12. Digenic Inheritance in Cystinuria Mouse Model.

    Directory of Open Access Journals (Sweden)

    Meritxell Espino

    Full Text Available Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b0,+AT, cause cystinuria type B. By crossing Slc3a1-/- with Slc7a9-/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months and late stage (8-months of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9+/-Slc3a1+/- present lower expression of system b0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9+/-Slc3a1+/+ and Slc7a9+/+Slc3a1+/- and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients.

  13. Digenic Inheritance in Cystinuria Mouse Model

    Science.gov (United States)

    Espino, Meritxell; Font-Llitjós, Mariona; Vilches, Clara; Salido, Eduardo; Prat, Esther; López de Heredia, Miguel; Palacín, Manuel; Nunes, Virginia

    2015-01-01

    Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b0,+AT, cause cystinuria type B. By crossing Slc3a1-/- with Slc7a9-/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months) and late stage (8-months) of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9+/-Slc3a1+/-) present lower expression of system b0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9+/-Slc3a1+/+ and Slc7a9+/+Slc3a1+/-) and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients. PMID:26359869

  14. Mendelian Genetics as a Platform for Teaching about Nature of Science and Scientific Inquiry: The Value of Textbooks

    Science.gov (United States)

    Campanile, Megan F.; Lederman, Norman G.; Kampourakis, Kostas

    2015-01-01

    The purpose of this study was to analyze seven widely used high school biology textbooks in order to assess the nature of science knowledge (NOS) and scientific inquiry (SI) aspects they, explicitly or implicitly, conveyed in the Mendelian genetics sections. Textbook excerpts that directly and/or fully matched our statements about NOS and SI were…

  15. Using Genetic Variation to Explore the Causal Effect of Maternal Pregnancy Adiposity on Future Offspring Adiposity: A Mendelian Randomisation Study

    NARCIS (Netherlands)

    R.C. Richmond (Rebecca C.); N.J. Timpson (Nicholas); J.F. Felix (Janine); T.M. Palmer (Tom); R. Gaillard (Romy); G. Mcmahon (George); G.D. Smith; V.W.V. Jaddoe (Vincent); Lawlor, D.A. (Debbie A.)

    2017-01-01

    textabstractBackground: It has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body

  16. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

    NARCIS (Netherlands)

    Haycock, P.C.; Burgess, S.; Nounu, A.; Zheng, J.; Okoli, G.N.; Bowden, J.; Wade, K.H.; Timpson, N.J.; Evans, D.M.; Willeit, P.; Aviv, A.; Gaunt, T.R.; Hemani, G.; Mangino, M.; Ellis, H.P.; Kurian, K.M.; Pooley, K.A.; Eeles, R.A.; Lee, J.E.; Fang, S.; Chen, W.V.; Law, M.H.; Bowdler, L.M.; Iles, M.M.; Yang, Q.; Worrall, B.B.; Markus, H.S.; Hung, R.J.; Amos, C.I.; Spurdle, A.B.; Thompson, D.J.; O'Mara, T.A.; Wolpin, B.; Amundadottir, L.; Stolzenberg-Solomon, R.; Trichopoulou, A.; Onland-Moret, N.C.; Lund, E.; Duell, E.J.; Canzian, F.; Severi, G.; Overvad, K.; Gunter, M.J.; Tumino, R.; Svenson, U.; Rij, A. van; Baas, A.F.; Bown, M.J.; Samani, N.J.; t'Hof, F.N.G. van; Tromp, G.; Jones, G.T.; Kuivaniemi, H.; Elmore, J.R.; Johansson, M.; McKay, J.; Scelo, G.; Carreras-Torres, R.; Gaborieau, V.; Brennan, P.; Bracci, P.M.; Neale, R.E.; Olson, S.H.; Gallinger, S.; Li, D.; Petersen, G.M.; Risch, H.A.; Klein, A.P.; Han, J.; Abnet, C.C.; Freedman, N.D.; Taylor, P.R.; Maris, J.M.; Aben, K.K.H.; Kiemeney, L.A.; Vermeulen, S.H.; Wiencke, J.K.; Walsh, K.M.; Wrensch, M.; Rice, T.; Turnbull, C.; Litchfield, K.; Paternoster, L.; Standl, M.; Abecasis, G.R.; SanGiovanni, J.P.; Li, Y.; Mijatovic, V.; Sapkota, Y.; Low, S.K.; Zondervan, K.T.; Montgomery, G.W.; Nyholt, D.R.; Heel, D.A. van; Hunt, K.; Arking, D.E.; Ashar, F.N.; Sotoodehnia, N.; Woo, D.; et al.,

    2017-01-01

    Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study,

  17. The importance of cultural inheritance in psychiatric genetics.

    Science.gov (United States)

    Peedicayil, J

    2002-02-01

    Cultural inheritance, a genetic-based inheritance system transmitted by the brain, has previously been proposed to underlie normal behaviour and mental disorders. In cultural inheritance epigenetic mechanisms are involved in gene expression. This paper proposes that since there are marked epigenetic mechanisms involved in the expression of genes underlying primary (idiopathic) mental disorders, epimutations, rather than genetic mutations, underlie these disorders. Copyright 2002 Harcourt Publishers Ltd.

  18. Proceedings of the Inheritance Workshop at ECOOP 2002

    DEFF Research Database (Denmark)

    2002-01-01

    The Inheritance Workshop at ECOOP 2002, which took place on Tuesday, 11 June, was the first ECOOP workshop focusing on inheritance after the successful workshops in 1991 and 1992. The workshop was intended as a forum for designers and implementers of object-oriented languages, and for software...... developers with an interest in inheritance. It was organized by Andrew P. Black, Erik Ernst, Peter Grogono, and Markku Sakkinen....

  19. Prevalence and mode of inheritance of major genetic eye diseases in China.

    Science.gov (United States)

    Hu, D N

    1987-01-01

    The prevalence and mode of inheritance of major genetic eye diseases have been investigated in China since the establishment of the Section of Ophthalmic Genetics of the Chinese Society of Genetics. Mass screening of genetic eye diseases has been undertaken in many districts in China, covering more than 700,000 people, and more than 5000 pedigrees of genetic eye diseases have been collected and analysed all over China. Based on these data, the prevalence and mode of inheritance of dyschromatopsia, degenerative myopia, retinitis pigmentosa, congenital ptosis, congenital microphthalmos, congenital cataract, congenital glaucoma, Leber's optic atrophy, corneal dystrophy, congenital nystagmus, coloboma of the eye, congenital aniridia, retinoblastoma, macular dystrophy, simple myopia, primary glaucoma, and strabismus have been investigated, and the results are presented. PMID:3500313

  20. Emulating Multiple Inheritance in Fortran 2003/2008

    Directory of Open Access Journals (Sweden)

    Karla Morris

    2015-01-01

    in Fortran 2003. The design unleashes the power of the associated class relationships for modeling complicated data structures yet avoids the ambiguities that plague some multiple inheritance scenarios.

  1. Evidence for major gene inheritance of Alzheimer disease in families of patients with and without Apolipoprotein E {epsilon}4

    Energy Technology Data Exchange (ETDEWEB)

    Rao, V.S.; Auerbach, S.A.; Farrer, L.A. [Boston Univ. School of Medicine, MA (United States)] [and others

    1996-09-01

    Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one {epsilon}4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking E4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband`s APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility. 76 refs., 4 tabs.

  2. Using default inheritance to describe LTAG

    CERN Document Server

    Evans, R; Weir, D; Evans, Roger; Gazdar, Gerald; Weir, David

    1995-01-01

    We present the results of an investigation into how the set of elementary trees of a Lexicalized Tree Adjoining Grammar can be represented in the lexical knowledge representation language DATR (Evans & Gazdar 1989a,b). The LTAG under consideration is based on the one described in Abeille et al. (1990). Our approach is similar to that of Vijay-Shanker & Schabes (1992) in that we formulate an inheritance hierarchy that efficiently encodes the elementary trees. However, rather than creating a new representation formalism for this task, we employ techniques of established utility in other lexically-oriented frameworks. In particular, we show how DATR's default mechanism can be used to eliminate the need for a non-immediate dominance relation in the descriptions of the surface LTAG entries. This allows us to embed the tree structures in the feature theory in a manner reminiscent of HPSG subcategorisation frames, and hence express lexical rules as relations over feature structures.

  3. Molecular mechanisms for protein-encoded inheritance

    Energy Technology Data Exchange (ETDEWEB)

    Wiltzius, Jed J.W.; Landau, Meytal; Nelson, Rebecca; Sawaya, Michael R.; Apostol, Marcin I.; Goldschmidt, Lukasz; Soriaga, Angela B.; Cascio, Duilio; Rajashankar, Kanagalaghatta; Eisenberg, David; (Cornell); (HHMI)

    2009-12-01

    In prion inheritance and transmission, strains are phenotypic variants encoded by protein 'conformations'. However, it is unclear how a protein conformation can be stable enough to endure transmission between cells or organisms. Here we describe new polymorphic crystal structures of segments of prion and other amyloid proteins, which offer two structural mechanisms for the encoding of prion strains. In packing polymorphism, prion strains are encoded by alternative packing arrangements (polymorphs) of {beta}-sheets formed by the same segment of a protein; in segmental polymorphism, prion strains are encoded by distinct {beta}-sheets built from different segments of a protein. Both forms of polymorphism can produce enduring conformations capable of encoding strains. These molecular mechanisms for transfer of protein-encoded information into prion strains share features with the familiar mechanism for transfer of nucleic acid-encoded information into microbial strains, including sequence specificity and recognition by noncovalent bonds.

  4. Inherited renal tubular defects with hypokalemia

    Directory of Open Access Journals (Sweden)

    Muthukrishnan J

    2009-01-01

    Full Text Available Bartter′s and Gitelman′s syndrome are two ends of a spectrum of inherited renal tubular disorders that present with hypokalemic metabolic alkalosis of varying severity. Clinical features and associated calcium and magnesium ion abnormalities are used to diagnose these cases after excluding other commoner causes. We report on two cases, the first being a young boy, born of pregnancy complicated by polyhydramnios, who had classical dysmorphic features, polyuria, hypokalemia and hypercalciuria and was diagnosed as having Bartter′s syndrome. The second patient is a lady who had recurrent tetany as the only manifestation of Gitelman′s syndrome, which is an unusual presentation. Potassium replacement with supplementation of other deficient ions led to satisfactory clinical and biochemical response.

  5. Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases.

    Science.gov (United States)

    Southwell, Amber L; Skotte, Niels H; Bennett, C Frank; Hayden, Michael R

    2012-11-01

    The rising median age of our population and the age-dependent risk of neurodegeneration translate to exponentially increasing numbers of afflicted individuals in the coming years. Although symptomatic treatments are available for some neurodegenerative diseases, most are only moderately efficacious and are often associated with significant side effects. The development of small molecule, disease-modifying drugs has been hindered by complex pathogenesis and a failure to clearly define the rate-limiting steps in disease progression. An alternative approach is to directly target the mutant gene product or a defined causative protein. Antisense oligonucleotides (ASOs) - with their diverse functionality, high target specificity, and relative ease of central nervous system (CNS) delivery - are uniquely positioned as potential therapies for neurological diseases. Here we review the development of ASOs for the treatment of inherited neurodegenerative diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Equilibrium, scale and inheritance in geomorphology

    Science.gov (United States)

    Ahnert, Frank

    1994-12-01

    Of the many "equilibrium" terms that have been proposed, only two are needed: dynamic equilibrium in the original sense of G.K. Gilbert (1877) and steady state. The former refers to the relationship between the process components of a system, the latter to the system as a whole. The tendency towards establishing a dynamic equilibrium is inherent in all natural systems that contain negative feedbacks between processes capable of compensating each other. In geomorphology, equilibrium tendencies of the mass budget are more relevant than those of the energy budget. The validity of the equilibrium concept is discussed at several scales from a slope point to entire slopes, drainage basins and mountain ranges. The effects of eksystemic changes vary depending upon the length of the intervals between such changes in comparison to the length of the required relaxation times. This relationship also applies to the influence of inherited forms, patterns and materials that have become components of present-day systems.

  7. Inherited epidermolysis bullosa: Case report of finger localization

    Directory of Open Access Journals (Sweden)

    Anne- Aurore Sankale

    2012-01-01

    Full Text Available Inherited epidermolysis bullosa is a rare condition that often present at birth with skin blisters and erosions. They are associated with defective cohesion of the dermis and epidermis. There are 3 principal types: Simple, junctional and dystrophic. The severity of the condition is quite variable. The most severe forms are incompatible with life. The most common types in our country are the severe ones such as the Hallopeau -Siemens subtype. Hands and mucosal areas can develop synechia. We report here a case of dystrophic epidermolysis bullosa in a 27-year-old woman whose finger lesion was managed surgically. This treatment consisted of complete removal of constrictions and adhesions, accompanied by use of a Hueston flap and skin graft to repair the tissue deficit. The patient′s clinical course required several repeat operations. This surgery allowed the possible total loss of hand function to be delayed but the inevitable progression of the illness made the treatment somewhat disappointing. Psychosocial implications are very significant in our setting.

  8. Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study.

    Science.gov (United States)

    Gan, Wei; Clarke, Robert J; Mahajan, Anubha; Kulohoma, Benard; Kitajima, Hidetoshi; Robertson, Neil R; Rayner, N William; Walters, Robin G; Holmes, Michael V; Chen, Zhengming; McCarthy, Mark I

    2017-01-01

    Background: Observational studies have demonstrated that increased bone mineral density is associated with a higher risk of type 2 diabetes (T2D), but the relationship with risk of coronary heart disease (CHD) is less clear. Moreover, substantial uncertainty remains about the causal relevance of increased bone mineral density for T2D and CHD, which can be assessed by Mendelian randomisation studies.  Methods: We identified 235 independent single nucleotide polymorphisms (SNPs) associated at pMendelian randomization approaches was used to investigate the causal relevance of eBMD for risk of T2D and CHD. In addition, we explored the relationship of eBMD, instrumented by the 235 SNPs, on 12 cardiovascular and metabolic risk factors. Finally, we conducted Mendelian randomization analysis in the reverse direction to investigate reverse causality. Results: Each one standard deviation increase in genetically instrumented eBMD (equivalent to 0.14 g/cm 2) was associated with an 8% higher risk of T2D (odds ratio [OR] 1.08; 95% confidence interval [CI]: 1.02 to 1.14; p=0.012) and 5% higher risk of CHD (OR 1.05; 95%CI: 1.00 to 1.10; p=0.034). Consistent results were obtained in sensitivity analyses using several different Mendelian randomization approaches. Equivalent increases in eBMD were also associated with lower plasma levels of HDL-cholesterol and increased insulin resistance. Mendelian randomization in the reverse direction using 94 T2D SNPs or 52 CHD SNPs showed no evidence of reverse causality with eBMD. Conclusions: These findings suggest a causal relationship between elevated bone mineral density with risks of both T2D and CHD.

  9. Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases.

    Directory of Open Access Journals (Sweden)

    Anna Bauer-Mehren

    Full Text Available BACKGROUND: Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. PRINCIPAL FINDINGS: We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. CONCLUSIONS: For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and

  10. Mendelian randomisation analysis provides no evidence for a relationship between adult height and testicular cancer risk.

    Science.gov (United States)

    Levy, M; Hall, D; Sud, A; Law, P; Litchfield, K; Dudakia, D; Haugen, T B; Karlsson, R; Reid, A; Huddart, R A; Grotmol, T; Wiklund, F; Houlston, R S; Turnbull, C

    2017-09-01

    Observational studies have suggested anthropometric traits, particularly increased height are associated with an elevated risk of testicular cancer (testicular germ cell tumour). However, there is an inconsistency between study findings, suggesting the possibility of the influence of confounding factors. To examine the association between anthropometric traits and testicular germ cell tumour using an unbiased approach, we performed a Mendelian randomisation study. We used genotype data from genome wide association studies of testicular germ cell tumour totalling 5518 cases and 19,055 controls. Externally weighted polygenic risk scores were created and used to evaluate associations with testicular germ cell tumour risk per one standard deviation (s.d) increase in genetically-defined adult height, adult BMI, adult waist hip ratio adjusted for BMI (WHRadjBMI), adult hip circumference adjusted for BMI (HIPadjBMI), adult waist circumference adjusted for BMI (WCadjBMI), birth weight (BW) and childhood obesity. Mendelian randomisation analysis did not demonstrate an association between any anthropometric trait and testicular germ cell tumour risk. In particular, despite good power, there was no global evidence for association between height and testicular germ cell tumour. However, three SNPs for adult height individually showed association with testicular germ cell tumour (rs4624820: OR = 1.47, 95% CI: 1.41-1.55, p = 2.7 × 10-57 ; rs12228415: OR = 1.17, 95% CI: 1.11-1.22, p = 3.1 × 10-10 ; rs7568069: OR = 1.13, 95% CI: 1.07-1.18, p = 1.1 × 10-6 ). This Mendelian randomisation analysis, based on the largest testicular germ cell tumour genome wide association dataset to date, does not support a causal etiological association between anthropometric traits and testicular germ cell tumour aetiology. Our findings are more compatible with confounding by shared environmental factors, possibly related to prenatal growth with exposure to these risk factors

  11. Gene-Disease Network Analysis Reveals Functional Modules in Mendelian, Complex and Environmental Diseases

    Science.gov (United States)

    Bauer-Mehren, Anna; Bundschus, Markus; Rautschka, Michael; Mayer, Miguel A.; Sanz, Ferran; Furlong, Laura I.

    2011-01-01

    Background Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. Principal Findings We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. Conclusions For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors

  12. Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study.

    Science.gov (United States)

    Hartwig, Fernando Pires; Borges, Maria Carolina; Horta, Bernardo Lessa; Bowden, Jack; Davey Smith, George

    2017-12-01

    Positive associations between inflammatory biomarkers and risk of psychiatric disorders, including schizophrenia, have been reported in observational studies. However, conventional observational studies are prone to bias, such as reverse causation and residual confounding, thus limiting our understanding of the effect (if any) of inflammatory biomarkers on schizophrenia risk. To evaluate whether inflammatory biomarkers have an effect on the risk of developing schizophrenia. Two-sample mendelian randomization study using genetic variants associated with inflammatory biomarkers as instrumental variables to improve inference. Summary association results from large consortia of candidate gene or genome-wide association studies, including several epidemiologic studies with different designs, were used. Gene-inflammatory biomarker associations were estimated in pooled samples ranging from 1645 to more than 80 000 individuals, while gene-schizophrenia associations were estimated in more than 30 000 cases and more than 45 000 ancestry-matched controls. In most studies included in the consortia, participants were of European ancestry, and the prevalence of men was approximately 50%. All studies were conducted in adults, with a wide age range (18 to 80 years). Genetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R). Risk of developing schizophrenia. Individuals with schizophrenia or schizoaffective disorders were included as cases. Given that many studies contributed to the analyses, different diagnostic procedures were used. The pooled odds ratio estimate using 18 CRP genetic instruments was 0.90 (random effects 95% CI, 0.84-0.97; P = .005) per 2-fold increment in CRP levels; consistent results were obtained using different mendelian randomization methods and a more conservative set of instruments. The odds ratio for sIL-6R was 1.06 (95% CI, 1.01-1.12; P = .02

  13. Elusive inheritance: Transgenerational effects and epigenetic inheritance in human environmental disease

    OpenAIRE

    Martos, Suzanne N.; Tang, Wan-yee; Wang, Zhibin

    2015-01-01

    Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be i...

  14. Does high tobacco consumption cause psychological distress? A mendelian randomization study

    DEFF Research Database (Denmark)

    Skov-Ettrup, Lise S.; Nordestgaard, Børge G.; Petersen, Christina B.

    2017-01-01

    Background: Increasing evidence suggests that smoking influences mental health negatively. This study investigated whether high tobacco consumption is causally related to psychological distress in a Mendelian randomization design, using a variant in the nicotine acetylcholine receptor gene CHRNA3...... variable for tobacco consumption. Three dimensions of psychological distress were studied: Stress, fatigue, and hopelessness. Analyses with the CHRNA3 genotype were stratified by smoking status. Results: Self-reported amount of smoking was associated with all three dimensions of psychological distress......, homozygotes and heterozygotes for the CHRNA3 genotype had higher tobacco consumption than noncarriers. Nevertheless, the CHRNA3 genotype was not associated with psychological distress neither in current nor in former or never-smokers. For instance among current smokers, the OR for stress was 1.02 (95% CI 0...

  15. C reactive protein and chronic obstructive pulmonary disease: a Mendelian randomisation approach

    DEFF Research Database (Denmark)

    Vestbo, Jørgen; Lange, Peter; Nordestgaard, Børge G

    2011-01-01

    Background It is unclear whether elevated plasma C reactive protein (CRP) is causally related to chronic obstructive pulmonary disease (COPD). The authors tested the hypothesis that genetically elevated plasma CRP causes COPD using a Mendelian randomisation design. Methods The authors measured high...... versus a doubling of genetically elevated CRP resulted in ORs for COPD of 1.27 (95% CI 1.25 to 1.30) versus 1.01 (0.81 to 1.26) and for COPD hospitalisation of 1.47 (1.43 to 1.51) versus 0.82(0.59 to 1.13). Conclusion Although elevated CRP is related to both a diagnosis of COPD and subsequent hospital...... admission, genetically elevated plasma CRP is not associated with an increased risk of clinical COPD. This suggests that the association between CRP levels and COPD is not causal....

  16. Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait.

    Science.gov (United States)

    Franić, Sanja; Groen-Blokhuis, Maria M; Dolan, Conor V; Kattenberg, Mathijs V; Pool, René; Xiao, Xiangjun; Scheet, Paul A; Ehli, Erik A; Davies, Gareth E; van der Sluis, Sophie; Abdellaoui, Abdel; Hansell, Narelle K; Martin, Nicholas G; Hudziak, James J; van Beijsterveldt, Catherina E M; Swagerman, Suzanne C; Hulshoff Pol, Hilleke E; de Geus, Eco J C; Bartels, Meike; Ropers, H Hilger; Hottenga, Jouke-Jan; Boomsma, Dorret I

    2015-10-01

    Multiple inquiries into the genetic etiology of human traits indicated an overlap between genes underlying monogenic disorders (eg, skeletal growth defects) and those affecting continuous variability of related quantitative traits (eg, height). Extending the idea of a shared genetic basis between a Mendelian disorder and a classic polygenic trait, we performed an association study to examine the effect of 43 genes implicated in autosomal recessive cognitive disorders on intelligence in an unselected Dutch population (N=1316). Using both single-nucleotide polymorphism (SNP)- and gene-based association testing, we detected an association between intelligence and the genes of interest, with genes ELP2, TMEM135, PRMT10, and RGS7 showing the strongest associations. This is a demonstration of the relevance of genes implicated in monogenic disorders of intelligence to normal-range intelligence, and a corroboration of the utility of employing knowledge on monogenic disorders in identifying the genetic variability underlying complex traits.

  17. Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization.

    Science.gov (United States)

    Zhang, Ben; Shu, Xiao-Ou; Delahanty, Ryan J; Zeng, Chenjie; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Wen, Wanqing; Long, Jirong; Li, Chun; Dunning, Alison M; Chang-Claude, Jenny; Shah, Mitul; Perkins, Barbara J; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; Floris, Giuseppe; Schmidt, Marjanka K; Rookus, Matti A; van den Hurk, Katja; de Kort, Wim L A M; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Li, Jingmei; Humphreys, Keith; Brand, Judith; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Menegaux, Florence; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Benitez, Javier; Zamora, M Pilar; Perez, Jose I A; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Chenevix-Trench, Georgia; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Marchand, Loic Le; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J; Martens, John W M; Tilanus-Linthorst, Madeleine M A; Collée, J Margriet; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Giles, Graham G; Milne, Roger L; McLean, Catriona; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony J; Ashworth, Alan; Orr, Nick; Jones, Michael; Figueroa, Jonine; Garcia-Closas, Montserrat; Brinton, Louise; Lissowska, Jolanta; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Radice, Paolo; Bogdanova, Natalia; Antonenkova, Natalia; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Seynaeve, Caroline; Van Asperen, Christi J; Jakubowska, Anna; Lubiński, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Hamann, Ute; Torres, Diana; Schmutzler, Rita K; Neuhausen, Susan L; Anton-Culver, Hoda; Kristensen, Vessela N; Grenaker Alnæs, Grethe I; Pierce, Brandon L; Kraft, Peter; Peters, Ulrike; Lindstrom, Sara; Seminara, Daniela; Burgess, Stephen; Ahsan, Habibul; Whittemore, Alice S; John, Esther M; Gammon, Marilie D; Malone, Kathleen E; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Pharoah, Paul D P; Simard, Jacques; Hall, Per; Hunter, David J; Easton, Douglas F; Zheng, Wei

    2015-11-01

    Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients. The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Involvement of the modifier gene of a human Mendelian disorder in a negative selection process.

    Directory of Open Access Journals (Sweden)

    Isabelle Jéru

    Full Text Available BACKGROUND: Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA in patients with familial Mediterranean fever (FMF, a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA. METHODOLOGY/PRINCIPAL FINDINGS: HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%, and Karabakh, where RA is rare (2.5%. Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4% as compared to Armenian patients (24% (p = 5.10(-5. Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE. CONCLUSIONS/SIGNIFICANCE: The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder.

  19. Mendelian randomization estimates of alanine aminotransferase with cardiovascular disease: Guangzhou Biobank Cohort study.

    Science.gov (United States)

    Xu, Lin; Jiang, Chao Qiang; Lam, Tai Hing; Zhang, Wei Sen; Zhu, Feng; Jin, Ya Li; Thomas, G Neil; Cheng, Kar Keung; Schooling, C Mary

    2017-01-15

    Observational studies of the association of alanine aminotransferase (ALT) levels with ischaemic heart disease (IHD) and cardiovascular disease (CVD) risk factors are inconsistent, probably because of confounding and reverse causality. Mendelian randomization (MR) provides less confounded results. We used MR analysis to assess the associations of ALT (U/L) with IHD, diabetes and other CVD risk factors. We used instrumental variable analysis based on two single nucleotide polymorphism (SNPs) HSD17B13/MAPK10 (rs6834314) and PNPLA3/SAMM50 (rs738409) to assess the associations of ALT (U/L) with IHD, diabetes and other CVD risk factors in the Guangzhou Biobank Cohort Study (GBCS). Observationally in 19,925 participants ALT levels were strongly positively associated with self-reported IHD, systolic and diastolic blood pressure, low-density lipoprotein- and total cholesterol, triglycerides, fasting glucose, body mass index, waist circumference, heart rate (HR) and diabetes, but were not associated with uncorrected QT interval, HR-corrected QT interval or high-density lipoprotein-cholesterol. In the MR study, using a credible genetic instrument (F-statistic = 23) for ALT, ALT levels were negatively associated with IHD (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.87 to 0.97) and triglycerides (β - 0.08, 95% CI - 0.13 to - 0.03), but were not associated with other CVD risk factors. Our results using Mendelian randomization suggest that ALT reduces the risk of IHD, probably through reducing triglyceride levels. The underlying mechanisms deserve further investigation. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways.

    Science.gov (United States)

    Burgess, Stephen; Daniel, Rhian M; Butterworth, Adam S; Thompson, Simon G

    2015-04-01

    Mendelian randomization uses genetic variants, assumed to be instrumental variables for a particular exposure, to estimate the causal effect of that exposure on an outcome. If the instrumental variable criteria are satisfied, the resulting estimator is consistent even in the presence of unmeasured confounding and reverse causation. We extend the Mendelian randomization paradigm to investigate more complex networks of relationships between variables, in particular where some of the effect of an exposure on the outcome may operate through an intermediate variable (a mediator). If instrumental variables for the exposure and mediator are available, direct and indirect effects of the exposure on the outcome can be estimated, for example using either a regression-based method or structural equation models. The direction of effect between the exposure and a possible mediator can also be assessed. Methods are illustrated in an applied example considering causal relationships between body mass index, C-reactive protein and uric acid. These estimators are consistent in the presence of unmeasured confounding if, in addition to the instrumental variable assumptions, the effects of both the exposure on the mediator and the mediator on the outcome are homogeneous across individuals and linear without interactions. Nevertheless, a simulation study demonstrates that even considerable heterogeneity in these effects does not lead to bias in the estimates. These methods can be used to estimate direct and indirect causal effects in a mediation setting, and have potential for the investigation of more complex networks between multiple interrelated exposures and disease outcomes. © The Author 2014. Published by Oxford University Press on behalf of the International Epidemiological Association.

  1. The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

    Science.gov (United States)

    Ploner, Alexander; Fischer, Krista; Horikoshi, Momoko; Sarin, Antti-Pekka; Thorleifsson, Gudmar; Ladenvall, Claes; Kals, Mart; Kuningas, Maris; Draisma, Harmen H. M.; Ried, Janina S.; van Zuydam, Natalie R.; Huikari, Ville; Mangino, Massimo; Sonestedt, Emily; Benyamin, Beben; Nelson, Christopher P.; Rivera, Natalia V.; Kristiansson, Kati; Shen, Huei-yi; Havulinna, Aki S.; Dehghan, Abbas; Donnelly, Louise A.; Kaakinen, Marika; Nuotio, Marja-Liisa; Robertson, Neil; de Bruijn, Renée F. A. G.; Ikram, M. Arfan; Amin, Najaf; Balmforth, Anthony J.; Braund, Peter S.; Doney, Alexander S. F.; Döring, Angela; Elliott, Paul; Esko, Tõnu; Franco, Oscar H.; Gretarsdottir, Solveig; Hartikainen, Anna-Liisa; Heikkilä, Kauko; Herzig, Karl-Heinz; Holm, Hilma; Hottenga, Jouke Jan; Hyppönen, Elina; Illig, Thomas; Isaacs, Aaron; Isomaa, Bo; Karssen, Lennart C.; Kettunen, Johannes; Koenig, Wolfgang; Kuulasmaa, Kari; Laatikainen, Tiina; Laitinen, Jaana; Lindgren, Cecilia; Lyssenko, Valeriya; Läärä, Esa; Rayner, Nigel W.; Männistö, Satu; Pouta, Anneli; Rathmann, Wolfgang; Rivadeneira, Fernando; Ruokonen, Aimo; Savolainen, Markku J.; Sijbrands, Eric J. G.; Small, Kerrin S.; Smit, Jan H.; Steinthorsdottir, Valgerdur; Syvänen, Ann-Christine; Taanila, Anja; Tobin, Martin D.; Uitterlinden, Andre G.; Willems, Sara M.; Willemsen, Gonneke; Witteman, Jacqueline; Perola, Markus; Evans, Alun; Ferrières, Jean; Virtamo, Jarmo; Kee, Frank; Tregouet, David-Alexandre; Arveiler, Dominique; Amouyel, Philippe; Ferrario, Marco M.; Brambilla, Paolo; Hall, Alistair S.; Heath, Andrew C.; Madden, Pamela A. F.; Martin, Nicholas G.; Montgomery, Grant W.; Whitfield, John B.; Jula, Antti; Knekt, Paul; Oostra, Ben; van Duijn, Cornelia M.; Penninx, Brenda W. J. H.; Davey Smith, George; Kaprio, Jaakko; Samani, Nilesh J.; Gieger, Christian; Peters, Annette; Wichmann, H.-Erich; Boomsma, Dorret I.; de Geus, Eco J. C.; Tuomi, TiinaMaija; Power, Chris; Hammond, Christopher J.; Spector, Tim D.; Lind, Lars; Orho-Melander, Marju; Palmer, Colin Neil Alexander; Morris, Andrew D.; Groop, Leif; Järvelin, Marjo-Riitta; Salomaa, Veikko; Vartiainen, Erkki; Hofman, Albert; Ripatti, Samuli; Metspalu, Andres; Thorsteinsdottir, Unnur; Stefansson, Kari; Pedersen, Nancy L.; McCarthy, Mark I.; Ingelsson, Erik; Prokopenko, Inga

    2013-01-01

    Background The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all padiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all padiposity and heart failure as well as between adiposity and increased liver enzymes. Please see later in the article for the Editors' Summary PMID:23824655

  2. Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change.

    Science.gov (United States)

    Würtz, Peter; Wang, Qin; Kangas, Antti J; Richmond, Rebecca C; Skarp, Joni; Tiainen, Mika; Tynkkynen, Tuulia; Soininen, Pasi; Havulinna, Aki S; Kaakinen, Marika; Viikari, Jorma S; Savolainen, Markku J; Kähönen, Mika; Lehtimäki, Terho; Männistö, Satu; Blankenberg, Stefan; Zeller, Tanja; Laitinen, Jaana; Pouta, Anneli; Mäntyselkä, Pekka; Vanhala, Mauno; Elliott, Paul; Pietiläinen, Kirsi H; Ripatti, Samuli; Salomaa, Veikko; Raitakari, Olli T; Järvelin, Marjo-Riitta; Smith, George Davey; Ala-Korpela, Mika

    2014-12-01

    Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood. We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (pBMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (pBMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92). Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly

  3. Prenatal alcohol exposure and offspring cognition and school performance. A ‘Mendelian randomization’ natural experiment

    Science.gov (United States)

    Zuccolo, Luisa; Lewis, Sarah J; Davey Smith, George; Sayal, Kapil; Draper, Elizabeth S; Fraser, Robert; Barrow, Margaret; Alati, Rosa; Ring, Sue; Macleod, John; Golding, Jean; Heron, Jon; Gray, Ron

    2013-01-01

    Background There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance. Methods We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring’s IQ score had been assessed in clinic (N = 4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N = 6268), contributed to the analyses. Results Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers’ genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification. Conclusions Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes. PMID:24065783

  4. Prenatal alcohol exposure and offspring cognition and school performance. A 'Mendelian randomization' natural experiment.

    Science.gov (United States)

    Zuccolo, Luisa; Lewis, Sarah J; Smith, George Davey; Sayal, Kapil; Draper, Elizabeth S; Fraser, Robert; Barrow, Margaret; Alati, Rosa; Ring, Sue; Macleod, John; Golding, Jean; Heron, Jon; Gray, Ron

    2013-10-01

    There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance. We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring's IQ score had been assessed in clinic (N=4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N=6268), contributed to the analyses. Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers' genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification. Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.

  5. Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

    Science.gov (United States)

    Zhang, Ben; Shu, Xiao-Ou; Delahanty, Ryan J.; Zeng, Chenjie; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Wen, Wanqing; Long, Jirong; Li, Chun; Dunning, Alison M.; Chang-Claude, Jenny; Shah, Mitul; Perkins, Barbara J.; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; Floris, Giuseppe; Schmidt, Marjanka K.; Rookus, Matti A.; van den Hurk, Katja; de Kort, Wim L. A. M.; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Li, Jingmei; Humphreys, Keith; Brand, Judith; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Menegaux, Florence; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Benitez, Javier; Zamora, M. Pilar; Perez, Jose I. A.; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Chenevix-Trench, Georgia; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Marchand, Loic Le; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J.; Martens, John W. M.; Tilanus-Linthorst, Madeleine M. A.; Collée, J. Margriet; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Slager, Susan; Toland, Amanda E.; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony J.; Ashworth, Alan; Orr, Nick; Jones, Michael; Figueroa, Jonine; Garcia-Closas, Montserrat; Brinton, Louise; Lissowska, Jolanta; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Radice, Paolo; Bogdanova, Natalia; Antonenkova, Natalia; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Devilee, Peter; Seynaeve, Caroline; Van Asperen, Christi J.; Jakubowska, Anna; Lubiński, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Hamann, Ute; Torres, Diana; Schmutzler, Rita K.; Neuhausen, Susan L.; Anton-Culver, Hoda; Kristensen, Vessela N.; Grenaker Alnæs, Grethe I.; Pierce, Brandon L.; Kraft, Peter; Peters, Ulrike; Lindstrom, Sara; Seminara, Daniela; Burgess, Stephen; Ahsan, Habibul; Whittemore, Alice S.; John, Esther M.; Gammon, Marilie D.; Malone, Kathleen E.; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Pharoah, Paul D. P.; Simard, Jacques; Hall, Per; Hunter, David J.; Easton, Douglas F.

    2015-01-01

    Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control subjects. Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor–positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer. PMID:26296642

  6. Statutory Law, Patriarchy and Inheritance: Home ownership among ...

    African Journals Online (AJOL)

    Studies in western countries reveal that inheritance is one of the ways in which ... Africa, statutory law does not guarantee a widow's inheritance rights except user rights of the .... the administration of most estates, which include the matrimonial home, no .... Evelyn spent part of her income from her business on building.

  7. Inheritance of pod colour in cowpea ( Vigna unguiculata (l.) Walp ...

    African Journals Online (AJOL)

    Inheritance of pod colour in cowpea (Vigna unguiculata (l.) Walp). Y Mustapha, B.B Singh. Abstract. Hybridization experiments were conducted in the screen house to study the pattern of inheritance of pod and pod tip pigmentation in cowpea. Segregating F2 populations were raised along with F1 and parental lines while F3 ...

  8. Women's Inheritance Rights and Intergenerational Transmission of Resources in India

    Science.gov (United States)

    Deininger, Klaus; Goyal, Aparajita; Nagarajan, Hari

    2013-01-01

    We use inheritance patterns over three generations of individuals to assess the impact of changes in the Hindu Succession Act that grant daughters equal coparcenary birth rights in joint family property that were denied to daughters in the past. We show that the amendment significantly increased daughters' likelihood to inherit land, but that…

  9. Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer : Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses

    NARCIS (Netherlands)

    Khankari, Nikhil K.; Shu, Xiao Ou; Wen, Wanqing; Kraft, Peter; Lindström, Sara; Peters, Ulrike; Schildkraut, Joellen; Schumacher, Fredrick; Bofetta, Paolo; Risch, Angela; Bickeböller, Heike; Amos, Christopher I.; Easton, Douglas; Eeles, Rosalind A.; Gruber, Stephen B.; Haiman, Christopher A.; Hunter, David J.; Chanock, Stephen J.; Pierce, Brandon L.; Zheng, Wei; Blalock, Kendra; Campbell, Peter T.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Figueiredo, Jane; James Gauderman, W.; Gong, Jian; Green, Roger C.; Harju, John F.; Harrison, Tabitha A.; Jacobs, Eric J.; Jenkins, Mark A.; Jiao, Shuo; Li, Li; Lin, Yi; Manion, Frank J.; Moreno, Victor; Mukherjee, Bhramar; Raskin, Leon; Schumacher, Fredrick R.; Seminara, Daniela; Severi, Gianluca; Stenzel, Stephanie L.; Thomas, Duncan C.; Hopper, John L.; Southey, Melissa C.; Makalic, Enes; Schmidt, Daniel F.; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos Santos Silva, Isabel; Ahsan, Habib; Whittemore, Alice; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel; van der Luijt, Rob B.; Uitterlinden, Andre G.; Hofman, Albert; Meindl, Alfons; Schmutzler, Rita K.; Müller-Myhsok, Bertram; Lichtner, Peter; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Hein, Rebecca; Dahmen, Norbert; Beckman, Lars; Crisponi, Laura; Hall, Per; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Easton, Douglas F.; Turnbull, Clare; Rahman, Nazneen; Eeles, Rosalind; Kote-Jarai, Zsofia; Muir, Kenneth; Giles, Graham; Neal, David; Donovan, Jenny L.; Hamdy, Freddie C.; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher; Schumacher, Fred; Travis, Ruth; Riboli, Elio; Hunter, David; Gapstur, Susan; Berndt, Sonja; Chanock, Stephen; Han, Younghun; Su, Li; Wei, Yongyue; Hung, Rayjean J.; Brhane, Yonathan; McLaughlin, John; Brennan, Paul; McKay, James D.; Rosenberger, Albert; Houlston, Richard S.; Caporaso, Neil; Teresa Landi, Maria; Heinrich, Joachim; Wu, Xifeng; Ye, Yuanqing; Christiani, David C.

    2016-01-01

    Background: Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using

  10. Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization

    Science.gov (United States)

    Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet- disease relationships through Mendelian randomization. We meta- analytically (n

  11. Empowering international canine inherited disorder management.

    Science.gov (United States)

    Wilson, Bethany J; Wade, Claire M

    2012-02-01

    The mapping of the canine genome and the study of canine breed genomic architecture has revolutionized the discovery of genetic tests for inherited disorders in dogs. As the genetics underlying complex disorders are revealed, canine breeders and their registering organisations will be required to understand genetics in a much more sophisticated way. To facilitate the management of genetic disorders in the era of new complex information, we consider how best to apply the results of new research and analytical techniques to benefit the wider canine breeding community with the aims of improving canine health and maintaining benevolent genetic diversity. If this is not done, there is a serious risk that expensive and valuable genetic research will remain unused or be misused to the detriment of breeds. In this review, we make a case for the formation of an international organisation that will exist as a central repository for breed-based genetic analysis and information sharing. This organisation ("Inter-Dog") could be modelled on a similar organisation that is monitoring genetic improvement of dairy cattle. The formation of such an organisation will require the collaboration of international kennel management organisations, researchers, and agencies offering genetic testing services.

  12. Inheritance of in vitro response in wheat

    Directory of Open Access Journals (Sweden)

    Mitić Nevena

    2004-01-01

    Full Text Available The inheritance of in vitro culture response was studied by using immature embryos from five wheat cultivars and their reciprocal hybrids. In vitro culture response was evaluated according to callus formation, percentage of regenerative calli and the number of plants per embryo. By crossing the cultivar Vesna (VS with highest tissue culture response and the two cultivars with lowest response Leda (LD and Zajecarska 65 (ZA, it was demonstrated that the regeneration potential was heritable. VS as female parent, enhanced regeneration response in hybrids VSxLD and VSxZA, while as a male parent, VS did not affect the regeneration ability of hybrids LD and ZA. However, hybrids having LD and ZA as a male parents exhibited a decreased regeneration potential, as compared to self-pollinated VS. The results suggest the presence of a class of extra-nuclear factors in the VS cultivar. They significantly account for relatively higher regeneration capacity in the hybrids having this cultivar as a female parent than in those where the VS was male parent.

  13. [Inherited metabolic disorders in pediatric emergency services].

    Science.gov (United States)

    Molina Gutiérrez, M A; López López, R; Morais López, A; Bueno Barriocanal, M; Martínez Ojinaga Nodal, E; Alcolea Sánchez, A M; García García, S

    2015-06-01

    Advances in the early diagnosis and treatment have led to improved survival, and a better quality of life for patients with inherited metabolic disorders (IMD). They can go to the Pediatric Emergency Services (PES) for reasons unrelated to their disease. The purpose of this study was to review the characteristics of visitors to the PES of these patients in a tertiary hospital. A retrospective observational study was conducted on all visits from patients with IMD to the PES of Hospital Infantil La Paz over the years 2011 and 2012. IMD type, complaint, duration of symptoms, need for hospitalization, and presence of metabolic decompensation was recorded. A total of 107 visits were analyzed, with the most frequent reason being for consultation of respiratory processes (30.8%). When the consultation was for vomiting, patients with protein-related disorders were those who delayed less in going to PES. One third of visitors were admitted, half of them due to metabolic decompensation of the underlying pathology. Patients with IMD came to PES for many different reasons, which in some cases were the cause or consequence of an acute metabolic decompensation that led to hospitalization. Being diseases with low prevalence, it would be useful to have diagnostic and therapeutic protocols in order to provide optimal care. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  14. Nuclear receptors in transgenerational epigenetic inheritance.

    Science.gov (United States)

    Ozgyin, Lilla; Erdős, Edina; Bojcsuk, Dóra; Balint, Balint L

    2015-07-01

    Nuclear Receptors are ligand-activated transcription factors that translate information about the lipid environment into specific genetic programs, a property that renders them good candidates to be mediators of rapid adaptation changes of a species. Lipid-based morphogens, endocrine hormones, fatty acids and xenobiotics might act through this class of transcription factors making them regulators able to fine-tune physiological processes. Here we review the basic concepts and current knowledge on the process whereby small molecules act through nuclear receptors and contribute to transgenerational changes. Several molecules shown to cause transgenerational changes like phthalates, BPA, nicotine, tributylin bind and activate nuclear receptors like ERs, androgen receptors, glucocorticoid receptors or PPARγ. A specific subset of observations involving nuclear receptors has focused on the effects of environmental stress or maternal behaviour on the development of transgenerational traits. While these effects do not involve environmental ligands, they change the expression levels of Estrogen and glucocorticoid receptors of the second generation and consequently initiate an altered genetic program in the second generation. In this review we summarize the available literature about the role of nuclear receptors in transgenerational inheritance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Genetics of inherited primary arrhythmia disorders

    Directory of Open Access Journals (Sweden)

    Spears DA

    2015-09-01

    Full Text Available Danna A Spears, Michael H Gollob Division of Cardiology – Electrophysiology, University Health Network, Toronto General Hospital, Toronto, ON, Canada Abstract: A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening. Keywords: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, short QT syndrome, genetics

  16. The inheritance of pathogenic mitochondrial DNA mutations.

    Science.gov (United States)

    Cree, L M; Samuels, D C; Chinnery, P F

    2009-12-01

    Mitochondrial DNA mutations cause disease in >1 in 5000 of the population, and approximately 1 in 200 of the population are asymptomatic carriers of a pathogenic mtDNA mutation. Many patients with these pathogenic mtDNA mutations present with a progressive, disabling neurological syndrome that leads to major disability and premature death. There is currently no effective treatment for mitochondrial disorders, placing great emphasis on preventing the transmission of these diseases. An empiric approach can be used to guide genetic counseling for common mtDNA mutations, but many families transmit rare or unique molecular defects. There is therefore a pressing need to develop techniques to prevent transmission based on a solid understanding of the biological mechanisms. Several recent studies have cast new light on the genetics and cell biology of mtDNA inheritance, but these studies have also raised new controversies. Here we compare and contrast these findings and discuss their relevance for the transmission of human mtDNA diseases.

  17. Inheritance of seed coat color in sesame

    Directory of Open Access Journals (Sweden)

    Hernán Laurentin

    2014-04-01

    Full Text Available The objective of this work was to determine the inheritance mode of seed coat color in sesame. Two crosses and their reciprocals were performed: UCLA37 x UCV3 and UCLA90 x UCV3, of which UCLA37 and UCLA90 are white seed, and UCV3 is brown seed. Results of reciprocal crosses within each cross were identical: F1 seeds had the same phenotype as the maternal parent, and F2 resulted in the phenotype brown color. These results are consistent only with the model in which the maternal effect is the responsible for this trait. This model was validated by recording the seed coat color of 100 F2 plants (F3 seeds from each cross with its reciprocal, in which the 3:1 expected ratio for plants producing brown and white seeds was tested with the chi-square test. Sesame seed color is determined by the maternal genotype. Proposed names for the alleles participating in sesame seed coat color are: Sc1, for brown color; and Sc2, for white color; Sc1 is dominant over Sc2.

  18. How-to-Do-It. Using Human Pedigrees to Teach Mendelian Genetics.

    Science.gov (United States)

    Mertens, Thomas R.

    1990-01-01

    Presented are suggestions for using human pedigrees in the classroom and a generic pedigree that can be modified and used by instructors to provide variants for analysis. Eight single-gene mechanisms of inheritance are defined for use in this activity. (CW)

  19. Cancer resistance as an acquired and inheritable trait

    DEFF Research Database (Denmark)

    Koch, Janne; Hau, Jann; Jensen, Henrik Elvang

    2014-01-01

    AIM: To induce cancer resistance in wild-type mice and detect if the resistance could be inherited to the progeny of the induced resistant mice. Furthermore to investigate the spectrum and immunology of this inherited cancer resistance. MATERIALS AND METHODS: Resistance to with live S180 cancer c...... of the resistance is unknown but may involve epigenetic mechanisms. Other examples of inheritability of acquired phenotypic changes exist but, to our knowledge, this is the first demonstration of acquired, inherited cancer resistance.......AIM: To induce cancer resistance in wild-type mice and detect if the resistance could be inherited to the progeny of the induced resistant mice. Furthermore to investigate the spectrum and immunology of this inherited cancer resistance. MATERIALS AND METHODS: Resistance to with live S180 cancer...... cells in BALB/c mice was induced by immunization with inactivated S180 cancer cells. The immunization was performed by either frozen/thawed or irradiated cancer cells or cell-free ascitic fluid (CFAF). RESULTS: In all instances the induced resistance was demonstrated to be inheritable. The phenotype...

  20. Uniparental Inheritance Promotes Adaptive Evolution in Cytoplasmic Genomes.

    Science.gov (United States)

    Christie, Joshua R; Beekman, Madeleine

    2017-03-01

    Eukaryotes carry numerous asexual cytoplasmic genomes (mitochondria and plastids). Lacking recombination, asexual genomes should theoretically suffer from impaired adaptive evolution. Yet, empirical evidence indicates that cytoplasmic genomes experience higher levels of adaptive evolution than predicted by theory. In this study, we use a computational model to show that the unique biology of cytoplasmic genomes-specifically their organization into host cells and their uniparental (maternal) inheritance-enable them to undergo effective adaptive evolution. Uniparental inheritance of cytoplasmic genomes decreases competition between different beneficial substitutions (clonal interference), promoting the accumulation of beneficial substitutions. Uniparental inheritance also facilitates selection against deleterious cytoplasmic substitutions, slowing Muller's ratchet. In addition, uniparental inheritance generally reduces genetic hitchhiking of deleterious substitutions during selective sweeps. Overall, uniparental inheritance promotes adaptive evolution by increasing the level of beneficial substitutions relative to deleterious substitutions. When we assume that cytoplasmic genome inheritance is biparental, decreasing the number of genomes transmitted during gametogenesis (bottleneck) aids adaptive evolution. Nevertheless, adaptive evolution is always more efficient when inheritance is uniparental. Our findings explain empirical observations that cytoplasmic genomes-despite their asexual mode of reproduction-can readily undergo adaptive evolution. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  1. Genetic Determinism in the Genetics Curriculum - An Exploratory Study of the Effects of Mendelian and Weldonian Emphases

    Science.gov (United States)

    Jamieson, Annie; Radick, Gregory

    2017-07-01

    Twenty-first-century biology rejects genetic determinism, yet an exaggerated view of the power of genes in the making of bodies and minds remains a problem. What accounts for such tenacity? This article reports an exploratory study suggesting that the common reliance on Mendelian examples and concepts at the start of teaching in basic genetics is an eliminable source of support for determinism. Undergraduate students who attended a standard `Mendelian approach' university course in introductory genetics on average showed no change in their determinist views about genes. By contrast, students who attended an alternative course which, inspired by the work of a critic of early Mendelism, W. F. R. Weldon (1860-1906), replaced an emphasis on Mendel's peas with an emphasis on developmental contexts and their role in bringing about phenotypic variability, were less determinist about genes by the end of teaching. Improvements in both the new Weldonian curriculum and the study design are in view for the future.

  2. Inheritance after Apocalypse: the Dystopian Environment

    Directory of Open Access Journals (Sweden)

    Serban Dan Blidariu

    2013-05-01

    Full Text Available Utopias are perfect places but the term itself says that they are nowhere to be found, making them practically impossible. Dystopias, even if they are written as a warning of how things can get worse, seem much more probable. All utopian societies are systems of plenty where everyone has enough and no one lacks the basic necessities. Yet resources do not come out of nowhere. A political system may be needed in a utopia but it is not the sole condition. A barren environment would make perfection impossible. A devastated land, then, can lead to a dystopia. Our way of life is connected to the environment around us. A drastic change there would alter human behavior significantly. If utopia is the dream situation, the dystopia is obviously the nightmare. The late 20th century had a feeling of “the end”, a lot of finalities were imagined, including “the end of history”. However, once those notions were left behind, even dystopias started to imagine events happening in a post-apocalyptic situation. One such dystopia is The Road, a novel about the struggles of a father and a son trying to survive after an unnamed cataclysm. The father’s desire to take his child toward the sea, where he thinks it might be safe, also implies a journey through the devastated land. In their travel they will witness the devastation of nature and the changes that brings to human behavior, a change that was unwanted and, for the son, an inheritance the father was unwilling to pass on.

  3. Mendelian randomization provides no evidence for a causal role of serum urate in increasing serum triglyceride levels.

    Science.gov (United States)

    Rasheed, Humaira; Hughes, Kim; Flynn, Tanya J; Merriman, Tony R

    2014-12-01

    Triglycerides and their lipoprotein transport molecules are risk factors for heart disease. Observational studies have associated elevated levels of serum urate (SU) with triglycerides and risk of heart disease. However, owing to unmeasured confounding, observational studies do not provide insight into the causal relationship between SU and triglyceride. The aim of this study was to test for a causal role of SU in increasing triglyceride using Mendelian randomization that accounts for unmeasured confounding. Subjects were of European ancestry from the atherosclerosis risk in communities (n=5237) and Framingham heart (n=2971) studies. Mendelian randomization by the 2-stage least squares regression method was done with SU as the exposure, a uric acid transporter genetic risk score as instrumental variable, and triglyceride as the outcome. In ordinary linear regression, SU was significantly associated with triglyceride levels (β=2.69 mmol/L change in triglyceride per mmol/L increase in SU). However, Mendelian randomization-based estimation showed no evidence for a direct causal association of SU with triglyceride concentration-there was a nonsignificant 1.01 mmol/L decrease in triglyceride per mmol/L increase in SU attributable to the genetic risk score (P=0.21). The reverse analysis using a triglyceride genetic risk score provided evidence of a causal role for triglyceride in raising urate in men (P(Corrected)=0.018). These data provide no evidence for a causal role for SU in raising triglyceride levels, consistent with a previous Mendelian randomization report of no association between SU and ischemic heart disease. © 2014 American Heart Association, Inc.

  4. Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomization Meta-Analysis in the CARTA Consortium.

    Science.gov (United States)

    Linneberg, Allan; Jacobsen, Rikke K; Skaaby, Tea; Taylor, Amy E; Fluharty, Meg E; Jeppesen, Jørgen L; Bjorngaard, Johan H; Åsvold, Bjørn O; Gabrielsen, Maiken E; Campbell, Archie; Marioni, Riccardo E; Kumari, Meena; Marques-Vidal, Pedro; Kaakinen, Marika; Cavadino, Alana; Postmus, Iris; Ahluwalia, Tarunveer S; Wannamethee, S Goya; Lahti, Jari; Räikkönen, Katri; Palotie, Aarno; Wong, Andrew; Dalgård, Christine; Ford, Ian; Ben-Shlomo, Yoav; Christiansen, Lene; Kyvik, Kirsten O; Kuh, Diana; Eriksson, Johan G; Whincup, Peter H; Mbarek, Hamdi; de Geus, Eco J C; Vink, Jacqueline M; Boomsma, Dorret I; Smith, George Davey; Lawlor, Debbie A; Kisialiou, Aliaksei; McConnachie, Alex; Padmanabhan, Sandosh; Jukema, J Wouter; Power, Chris; Hyppönen, Elina; Preisig, Martin; Waeber, Gerard; Vollenweider, Peter; Korhonen, Tellervo; Laatikainen, Tiina; Salomaa, Veikko; Kaprio, Jaakko; Kivimaki, Mika; Smith, Blair H; Hayward, Caroline; Sørensen, Thorkild I A; Thuesen, Betina H; Sattar, Naveed; Morris, Richard W; Romundstad, Pål R; Munafò, Marcus R; Jarvelin, Marjo-Riitta; Husemoen, Lise Lotte N

    2015-12-01

    Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate. © 2015 American Heart Association, Inc.

  5. Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study.

    Directory of Open Access Journals (Sweden)

    Raquel Granell

    2014-07-01

    Full Text Available Observational studies have reported associations between body mass index (BMI and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC. A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV estimates of causal risk ratios (RRs. 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001 and with childhood asthma (RR 2.56, 95% CI 1.38-4.76 per unit score, p = 0.003. The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16-2.07 per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19-3.03 than for atopic asthma (1.37, 95% CI 0.89-2.11 though there was little evidence of heterogeneity (p = 0.31. The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11-1.79 per 0.5 kg and 2.25 (95% CI 1.23-4.11 per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary.

  6. Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study.

    Science.gov (United States)

    Granell, Raquel; Henderson, A John; Evans, David M; Smith, George Davey; Ness, Andrew R; Lewis, Sarah; Palmer, Tom M; Sterne, Jonathan A C

    2014-07-01

    Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach. We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38-4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16-2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19-3.03) than for atopic asthma (1.37, 95% CI 0.89-2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11-1.79) per 0.5 kg and 2.25 (95% CI 1.23-4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects. Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary.

  7. The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.

    Directory of Open Access Journals (Sweden)

    Tove Fall

    Full Text Available The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV for body mass index (BMI in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i rs9939609 and BMI (n  =  198,502, (ii rs9939609 and 24 traits, and (iii BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39 and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05. For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05. The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p  =  0

  8. Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change.

    Directory of Open Access Journals (Sweden)

    Peter Würtz

    2014-12-01

    Full Text Available Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2. Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures. Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%. A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2= 0.89, suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures, including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects

  9. Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study

    Science.gov (United States)

    Granell, Raquel; Henderson, A. John; Evans, David M.; Smith, George Davey; Ness, Andrew R.; Lewis, Sarah; Palmer, Tom M.; Sterne, Jonathan A. C.

    2014-01-01

    Background Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach. Methods and Findings We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-valuesBMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects. Conclusions Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary PMID:24983943

  10. Height, body mass index, and socioeconomic status: mendelian randomisation study in UK Biobank.

    Science.gov (United States)

    Tyrrell, Jessica; Jones, Samuel E; Beaumont, Robin; Astley, Christina M; Lovell, Rebecca; Yaghootkar, Hanieh; Tuke, Marcus; Ruth, Katherine S; Freathy, Rachel M; Hirschhorn, Joel N; Wood, Andrew R; Murray, Anna; Weedon, Michael N; Frayling, Timothy M

    2016-03-08

    To determine whether height and body mass index (BMI) have a causal role in five measures of socioeconomic status. Mendelian randomisation study to test for causal effects of differences in stature and BMI on five measures of socioeconomic status. Mendelian randomisation exploits the fact that genotypes are randomly assigned at conception and thus not confounded by non-genetic factors. UK Biobank. 119,669 men and women of British ancestry, aged between 37 and 73 years. Age completed full time education, degree level education, job class, annual household income, and Townsend deprivation index. In the UK Biobank study, shorter stature and higher BMI were observationally associated with several measures of lower socioeconomic status. The associations between shorter stature and lower socioeconomic status tended to be stronger in men, and the associations between higher BMI and lower socioeconomic status tended to be stronger in women. For example, a 1 standard deviation (SD) higher BMI was associated with a £210 (€276; $300; 95% confidence interval £84 to £420; P=6 × 10(-3)) lower annual household income in men and a £1890 (£1680 to £2100; P=6 × 10(-15)) lower annual household income in women. Genetic analysis provided evidence that these associations were partly causal. A genetically determined 1 SD (6.3 cm) taller stature caused a 0.06 (0.02 to 0.09) year older age of completing full time education (P=0.01), a 1.12 (1.07 to 1.18) times higher odds of working in a skilled profession (P=6 × 10(-7)), and a £1130 (£680 to £1580) higher annual household income (P=4 × 10(-8)). Associations were stronger in men. A genetically determined 1 SD higher BMI (4.6 kg/m(2)) caused a £2940 (£1680 to £4200; P=1 × 10(-5)) lower annual household income and a 0.10 (0.04 to 0.16) SD (P=0.001) higher level of deprivation in women only. These data support evidence that height and BMI play an important partial role in determining several aspects of a person

  11. Intergenerational epigenetic inheritance in reef-building corals

    KAUST Repository

    Liew, Yi Jin

    2018-02-22

    The notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants and metazoans. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals). Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.

  12. Autosomal dominant inheritance of left ventricular outflow tract obstruction

    NARCIS (Netherlands)

    Wessels, Marjolein; Berger, Rudolphus; Frohn-Mulder, Ingrid M E; Roos-Hesselink, Jolien W; Hoogeboom, Jeanette J M; Mancini, Grazia S; Bartelings, Margot M; Krijger, Ronald de; Wladimiroff, Jury W; Niermeijer, Martinus F; Grossfeld, Paul; Willems, Patrick J

    2005-01-01

    Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction

  13. Autosomal dominant inheritance of left ventricular outflow tract obstruction.

    NARCIS (Netherlands)

    Wessels, M.W.; Berger, R.M.; Frohn-Mulder, I.M.; Roos-Hesselink, J.W.; Hoogeboom, J.J.; Mancini, G.S.; Bartelings, M.M.; Krijger, R.R. de; Wladimiroff, J.W.; Niermeijer, M.F.; Grossfeld, P.; Willems, P.J.

    2005-01-01

    Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction

  14. Interdisciplinary psychosocial care for families with inherited cardiovascular diseases.

    Science.gov (United States)

    Caleshu, Colleen; Kasparian, Nadine A; Edwards, Katharine S; Yeates, Laura; Semsarian, Christopher; Perez, Marco; Ashley, Euan; Turner, Christian J; Knowles, Joshua W; Ingles, Jodie

    2016-10-01

    Inherited cardiovascular diseases pose unique and complex psychosocial challenges for families, including coming to terms with life-long cardiac disease, risk of sudden death, grief related to the sudden death of a loved one, activity restrictions, and inheritance risk to other family members. Psychosocial factors impact not only mental health but also physical health and cooperation with clinical recommendations. We describe an interdisciplinary approach to the care of families with inherited cardiovascular disease, in which psychological care provided by specialized cardiac genetic counselors, nurses, and psychologists is embedded within the cardiovascular care team. We report illustrative cases and the supporting literature to demonstrate common scenarios, as well as practical guidance for clinicians working in the inherited cardiovascular disease setting. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. DNA analysis in inherited cardiomyopathies: Current status and clinical relevance

    NARCIS (Netherlands)

    van Spaendonck-Zwarts, Karin Y.; van den Berg, Maarten P.; van Tintelen, J. Peter

    2008-01-01

    Most hypertrophic cardiomyopathies and a subset of dilated and arrhythmogenic right ventricular cardiomyopathies are familial diseases. They generally show an autosomal dominant pattern of inheritance and have underlying mutations in genes encoding sarcomeric, cytoskeletal, nuclear envelope, and

  16. DNA analysis in inherited cardiomyopathies : Current status and clinical relevance

    NARCIS (Netherlands)

    Van Spaendonck-Zwarts, Karin Y.; Van den Berg, Maarten P.; Van Tintelen, J. Peter

    Most hypertrophic cardiomyopathies and a subset of dilated and arrhythmogenic right ventricular cardiomyopathies are familial diseases. They generally show an autosomal dominant pattern of inheritance and have underlying mutations in genes encoding sarcomeric, cytoskeletal, nuclear envelope, and

  17. Inheritance and identification of SCAR marker linked to bacterial wilt ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... Key word: Eggplant, bacterial wilt-resistance, molecular marker, inheritance. ... hundreds of plant species, including many crops such as tomato, potato ... rotation, adjusting the date of planting, cultural methods and soil ...

  18. Endocrine Disruptor Induction of Epigenetic Transgenerational Inheritance of Disease

    Science.gov (United States)

    Skinner, Michael K.

    2014-01-01

    Environmental exposures such as toxicants, nutrition and stress have been shown to promote the epigenetic transgenerational inheritance of disease susceptibility. Endocrine disruptors are one of the largest groups of specific toxicants shown to promote this form of epigenetic inheritance. These environmental compounds that interfere with normal endocrine signaling are one of the largest classes of toxicants we are exposed to on a daily level. The ability of ancestral exposures to promote disease susceptibility significantly increases the potential biohazards of these toxicants. Therefore, what your great-grandmother was exposed to during pregnancy may influence your disease development, even in the absence of any exposure, and you are going to pass this on to your grandchildren. This non-genetic form of inheritance significantly impacts our understanding of biology from the origins of disease to evolutionary biology. The current review will describe the previous studies and endocrine disruptors shown to promote the epigenetic transgenerational inheritance of disease. PMID:25088466

  19. Epigenetics and inheritance of phenotype variation in livestock

    OpenAIRE

    Triantaphyllopoulos, Kostas A; Ikonomopoulos, Ioannis; Bannister, Andrew J

    2016-01-01

    Epigenetic inheritance plays a crucial role in many biological processes, such as gene expression in early embryo development, imprinting and the silencing of transposons. It has recently been established that epigenetic effects can be inherited from one generation to the next. Here, we review examples of epigenetic mechanisms governing animal phenotype and behaviour, and we discuss the importance of these findings in respect to animal studies, and livestock in general. Epigenetic parameters ...

  20. Intercultural Communication in the Inheritance Urang Pulo the Myth

    OpenAIRE

    Hermawati, Euis

    2011-01-01

    Communication is an essential aspect fo Urang Pulo to preserve their mythical culture. One of the myth preserving method is to inherit in the myth to upcoming generation. The inheritance involves both interaction and communication among Urang Pulo s society. Who share similar cultural backgrounds, which called intracultural communication. This study defines intracultural communication within Urang Pulo society. In the myth preserving method. The society of Kampung Pulo is unique, they are Sun...

  1. Maternal inheritance of plastids in Encephalartos Lehm. (Zamiaceae, Cycadales).

    Science.gov (United States)

    Cafasso, D; Cozzolino, S; Caputo, P; De Luca, P

    2001-04-01

    The mode of inheritance of chloroplast DNA has been determined in Encephalartos by employing a restriction fragment length polymorphism analysis of chloroplast DNA. Artificial F1 hybrids were produced between a female specimen of E. natalensis and a male specimen of E. woodii. The hybridization patterns of all hybrids correspond, in all cases, with that of E. natalensis, and are different from that of E. woodii, thus indicating the maternal inheritance of cpDNA in cycads.

  2. Genetic testing and counselling in inherited eye disease

    DEFF Research Database (Denmark)

    Brøndum-Nielsen, Karen; Jensen, Hanne; Timshel, Susanne

    2013-01-01

    Advances in genetics have made genetic testing in patients with inherited eye disease increasingly accessible, and the initiation of clinical intervention trials makes it increasingly clinically relevant. Based on a multidisciplinary collaboration between ophthalmologists and clinical geneticists......, the extensive register of families with monogenic inherited eye diseases at the National Eye Clinic of the Kennedy Center in Denmark provides a valuable asset waiting to be exploited in the global effort to reduce blindness caused by genetic defects....

  3. Familial epilepsy in Algeria: Clinical features and inheritance profiles.

    Science.gov (United States)

    Chentouf, Amina; Dahdouh, Aïcha; Guipponi, Michel; Oubaiche, Mohand Laïd; Chaouch, Malika; Hamamy, Hanan; Antonarakis, Stylianos E

    2015-09-01

    To document the clinical characteristics and inheritance pattern of epilepsy in multigeneration Algerian families. Affected members from extended families with familial epilepsy were assessed at the University Hospital of Oran in Algeria. Available medical records, neurological examination, electroencephalography and imaging data were reviewed. The epilepsy type was classified according to the criteria of the International League Against Epilepsy and modes of inheritance were deduced from pedigree analysis. The study population included 40 probands; 23 male (57.5%) and 17 female subjects (42.5%). The mean age of seizure onset was 9.5 ± 6.1 years. According to seizure onset, 16 patients (40%) had focal seizures and 20 (50%) had generalized seizures. Seizure control was achieved for two patients (5%) for 10 years, while 28 (70%) were seizure-free for 3 months. Eleven patients (27.5%) had prior febrile seizures, 12 were diagnosed with psychiatric disorders and four families had syndromic epilepsy. The consanguinity rate among parents of affected was 50% with phenotypic concordance observed in 25 families (62.5%). Pedigree analysis suggested autosomal dominant (AD) inheritance with or without reduced penetrance in 18 families (45%), probable autosomal recessive (AR) inheritance in 14 families (35%), and an X-linked recessive inheritance in one family. This study reveals large Algerian families with multigenerational inheritance of epilepsy. Molecular testing such as exome sequencing would clarify the genetic basis of epilepsy in some of our families. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  4. Maternal inheritance of severe hypertriglyceridemia impairs glucose metabolism in offspring.

    Science.gov (United States)

    Ma, Ya-Hong; Yu, Caiguo; Kayoumu, Abudurexiti; Guo, Xin; Ji, Zhili; Liu, George

    2015-04-01

    Maternally inherited familial hypercholesterolemia (FH) impairs glucose metabolism and increases cardiovascular risks in the offspring to a greater degree than paternal inherited FH. However, it remains unknown whether hypertriglyceridemia affects glucose metabolism via inheritance. In this study, we sought to compare the impact of maternally and paternally inherited hypertriglyceridemia on glucose and lipid metabolism in mice. ApoCIII transgenic mice with severe hypertriglyceridemia were mated with non-transgenic control mice to obtain 4 types of offspring: maternal non-transgenic control and maternal transgenic offspring, and paternal control and paternal transgenic offspring. Plasma triglycerides (TG), total cholesterol (TC), fasting plasma glucose (FPG) and fasting insulin (FINS) were measured. ApoCIII overexpression caused severe hypertriglyceridemia, but the transgenic female mice had unaltered fertility with normal pregnancy and birth of pups. The 4 groups of offspring had similar birth weight and growth rate. The plasma TG of maternal and paternal transgenic offspring were nearly 40-fold higher than maternal and paternal control mice, but there was no difference in plasma TG between maternal and paternal transgenic offspring. Although the FPG of the 4 groups of animals had no difference, the maternal transgenic mice showed impaired glucose tolerance, increased FINS levels and higher homeostasis model assessment insulin resistance index (HOMA-IR) than the other 3 groups. In conclusion, maternally inherited hypertriglyceridemia in ApoCIII transgenic mice displayed impaired glucose tolerance, hyperinsulinemia and increased HOMA-R, while paternally inherited hypertriglyceridemia did not have such impacts.

  5. Mendelian breeding units versus standard sampling strategies: mitochondrial DNA variation in southwest Sardinia

    Directory of Open Access Journals (Sweden)

    Daria Sanna

    2011-01-01

    Full Text Available We report a sampling strategy based on Mendelian Breeding Units (MBUs, representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits.

  6. Stature and long-term labor market outcomes: Evidence using Mendelian randomization.

    Science.gov (United States)

    Böckerman, Petri; Viinikainen, Jutta; Vainiomäki, Jari; Hintsanen, Mirka; Pitkänen, Niina; Lehtimäki, Terho; Pehkonen, Jaakko; Rovio, Suvi; Raitakari, Olli

    2017-02-01

    We use the Young Finns Study (N=∼2000) on the measured height linked to register-based long-term labor market outcomes. The data contain six age cohorts (ages 3, 6, 9, 12, 15 and 18, in 1980) with the average age of 31.7, in 2001, and with the female share of 54.7. We find that taller people earn higher earnings according to the ordinary least squares (OLS) estimation. The OLS models show that 10cm of extra height is associated with 13% higher earnings. We use Mendelian randomization, with the genetic score as an instrumental variable (IV) for height to account for potential confounders that are related to socioeconomic background, early life conditions and parental investments, which are otherwise very difficult to fully account for when using covariates in observational studies. The IV point estimate is much lower and not statistically significant, suggesting that the OLS estimation provides an upward biased estimate for the height premium. Our results show the potential value of using genetic information to gain new insights into the determinants of long-term labor market success. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Methods for meta-analysis of individual participant data from Mendelian randomisation studies with binary outcomes.

    Science.gov (United States)

    Burgess, Stephen; Thompson, Simon G

    2016-02-01

    Mendelian randomisation is an epidemiological method for estimating causal associations from observational data by using genetic variants as instrumental variables. Typically the genetic variants explain only a small proportion of the variation in the risk factor of interest, and so large sample sizes are required, necessitating data from multiple sources. Meta-analysis based on individual patient data requires synthesis of studies which differ in many aspects. A proposed Bayesian framework is able to estimate a causal effect from each study, and combine these using a hierarchical model. The method is illustrated for data on C-reactive protein and coronary heart disease (CHD) from the C-reactive protein CHD Genetics Collaboration (CCGC). Studies from the CCGC differ in terms of the genetic variants measured, the study design (prospective or retrospective, population-based or case-control), whether C-reactive protein was measured, the time of C-reactive protein measurement (pre- or post-disease), and whether full or tabular data were shared. We show how these data can be combined in an efficient way to give a single estimate of causal association based on the totality of the data available. Compared to a two-stage analysis, the Bayesian method is able to incorporate data on 23% additional participants and 51% more events, leading to a 23-26% gain in efficiency. © The Author(s) 2012.

  8. Testing concordance of instrumental variable effects in generalized linear models with application to Mendelian randomization

    Science.gov (United States)

    Dai, James Y.; Chan, Kwun Chuen Gary; Hsu, Li

    2014-01-01

    Instrumental variable regression is one way to overcome unmeasured confounding and estimate causal effect in observational studies. Built on structural mean models, there has been considerale work recently developed for consistent estimation of causal relative risk and causal odds ratio. Such models can sometimes suffer from identification issues for weak instruments. This hampered the applicability of Mendelian randomization analysis in genetic epidemiology. When there are multiple genetic variants available as instrumental variables, and causal effect is defined in a generalized linear model in the presence of unmeasured confounders, we propose to test concordance between instrumental variable effects on the intermediate exposure and instrumental variable effects on the disease outcome, as a means to test the causal effect. We show that a class of generalized least squares estimators provide valid and consistent tests of causality. For causal effect of a continuous exposure on a dichotomous outcome in logistic models, the proposed estimators are shown to be asymptotically conservative. When the disease outcome is rare, such estimators are consistent due to the log-linear approximation of the logistic function. Optimality of such estimators relative to the well-known two-stage least squares estimator and the double-logistic structural mean model is further discussed. PMID:24863158

  9. The Causal Role of Alcohol Use in Adolescent Externalizing and Internalizing Problems: A Mendelian Randomization Study.

    Science.gov (United States)

    Chao, Miao; Li, Xinying; McGue, Matt

    2017-11-01

    The co-occurrence of alcohol use and externalizing/internalizing problems threatens adolescents' mental health. Research on whether alcohol use and these problems are causal and the direction of the potential causal relationships is needed to understand the mechanisms of the co-occurrence. A Mendelian randomization analysis was conducted in which the aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism was used as an instrumental variable for alcohol use phenotypes. In total, 1,608 Chinese adolescents (mean age 14.11 ± 1.83 years) were genotyped for the ALDH2 rs671 polymorphism. Three externalizing problems (aggression, delinquency, and attention problems) were measured with the Youth Self-Report inventory, and 2 internalizing problems (depression and anxiety) were measured with the self-reported Children's Depression Inventory and the Trait subscale of the State-Trait Anxiety Inventory. Alcohol use was positively associated with all 3 externalizing and 2 internalizing problems, and the ALDH2 polymorphism had a significant effect on alcohol use. Aggression and attention problems were also significantly affected by the ALDH2 polymorphism, whereas no significant association was observed between the ALDH2 polymorphism and delinquency, anxiety, or depression. The results suggest that alcohol use is a cause of adolescent aggression and attention problems but not adolescent delinquency, anxiety, or depression. Copyright © 2017 by the Research Society on Alcoholism.

  10. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies.

    Science.gov (United States)

    Rodriguez, Santiago; Gaunt, Tom R; Day, Ian N M

    2009-02-15

    Mendelian randomization (MR) permits causal inference between exposures and a disease. It can be compared with randomized controlled trials. Whereas in a randomized controlled trial the randomization occurs at entry into the trial, in MR the randomization occurs during gamete formation and conception. Several factors, including time since conception and sampling variation, are relevant to the interpretation of an MR test. Particularly important is consideration of the "missingness" of genotypes that can be originated by chance, genotyping errors, or clinical ascertainment. Testing for Hardy-Weinberg equilibrium (HWE) is a genetic approach that permits evaluation of missingness. In this paper, the authors demonstrate evidence of nonconformity with HWE in real data. They also perform simulations to characterize the sensitivity of HWE tests to missingness. Unresolved missingness could lead to a false rejection of causality in an MR investigation of trait-disease association. These results indicate that large-scale studies, very high quality genotyping data, and detailed knowledge of the life-course genetics of the alleles/genotypes studied will largely mitigate this risk. The authors also present a Web program (http://www.oege.org/software/hwe-mr-calc.shtml) for estimating possible missingness and an approach to evaluating missingness under different genetic models.

  11. Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study.

    LENUS (Irish Health Repository)

    Trompet, Stella

    2009-12-01

    Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

  12. Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies.

    Science.gov (United States)

    Palmer, Tom M; Holmes, Michael V; Keating, Brendan J; Sheehan, Nuala A

    2017-11-01

    Mendelian randomization studies use genotypes as instrumental variables to test for and estimate the causal effects of modifiable risk factors on outcomes. Two-stage residual inclusion (TSRI) estimators have been used when researchers are willing to make parametric assumptions. However, researchers are currently reporting uncorrected or heteroscedasticity-robust standard errors for these estimates. We compared several different forms of the standard error for linear and logistic TSRI estimates in simulations and in real-data examples. Among others, we consider standard errors modified from the approach of Newey (1987), Terza (2016), and bootstrapping. In our simulations Newey, Terza, bootstrap, and corrected 2-stage least squares (in the linear case) standard errors gave the best results in terms of coverage and type I error. In the real-data examples, the Newey standard errors were 0.5% and 2% larger than the unadjusted standard errors for the linear and logistic TSRI estimators, respectively. We show that TSRI estimators with modified standard errors have correct type I error under the null. Researchers should report TSRI estimates with modified standard errors instead of reporting unadjusted or heteroscedasticity-robust standard errors. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

  13. IDENTIFY CANCER DRIVER GENES THROUGH SHARED MENDELIAN DISEASE PATHOGENIC VARIANTS AND CANCER SOMATIC MUTATIONS.

    Science.gov (United States)

    Ma, Meng; Wang, Changchang; Glicksberg, Benjamin S; Schadt, Eric E; Li, Shuyu D; Chen, Rong

    2017-01-01

    Genomic sequencing studies in the past several years have yielded a large number of cancer somatic mutations. There remains a major challenge in delineating a small fraction of somatic mutations that are oncogenic drivers from a background of predominantly passenger mutations. Although computational tools have been developed to predict the functional impact of mutations, their utility is limited. In this study, we applied an alternative approach to identify potentially novel cancer drivers as those somatic mutations that overlap with known pathogenic mutations in Mendelian diseases. We hypothesize that those shared mutations are more likely to be cancer drivers because they have the established molecular mechanisms to impact protein functions. We first show that the overlap between somatic mutations in COSMIC and pathogenic genetic variants in HGMD is associated with high mutation frequency in cancers and is enriched for known cancer genes. We then attempted to identify putative tumor suppressors based on the number of distinct HGMD/COSMIC overlapping mutations in a given gene, and our results suggest that ion channels, collagens and Marfan syndrome associated genes may represent new classes of tumor suppressors. To elucidate potentially novel oncogenes, we identified those HGMD/COSMIC overlapping mutations that are not only highly recurrent but also mutually exclusive from previously characterized oncogenic mutations in each specific cancer type. Taken together, our study represents a novel approach to discover new cancer genes from the vast amount of cancer genome sequencing data.

  14. Assessing the Genetic Predisposition of Education on Myopia: A Mendelian Randomization Study.

    Science.gov (United States)

    Cuellar-Partida, Gabriel; Lu, Yi; Kho, Pik Fang; Hewitt, Alex W; Wichmann, H-Erich; Yazar, Seyhan; Stambolian, Dwight; Bailey-Wilson, Joan E; Wojciechowski, Robert; Wang, Jie Jin; Mitchell, Paul; Mackey, David A; MacGregor, Stuart

    2016-01-01

    Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two-step least squares instrumental-variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta-analysis of the three cohorts, using the PGRS as an IV, we estimated that each z-score increase in education (approximately 2 years of education) results in a reduction of 0.92 ± 0.29 diopters (P = 1.04 × 10(-3) ). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 ± 0.03 diopters reduction per education z-score [∼2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error. © 2015 WILEY PERIODICALS, INC.

  15. "What Programmers Do with Inheritance in Java" Replicated on Source Code

    NARCIS (Netherlands)

    C. Aytekin (Cigdem)

    2014-01-01

    htmlabstractInheritance is an important mechanism in object oriented languages. Quite some research effort is invested in inheritance until now. Most of the research work about inheritance (if not all) is done about the inheritance relationship between the types (namely, classes and interfaces).

  16. Simple Machine Junk Cars

    Science.gov (United States)

    Herald, Christine

    2010-01-01

    During the month of May, the author's eighth-grade physical science students study the six simple machines through hands-on activities, reading assignments, videos, and notes. At the end of the month, they can easily identify the six types of simple machine: inclined plane, wheel and axle, pulley, screw, wedge, and lever. To conclude this unit,…

  17. Long Oskar Controls Mitochondrial Inheritance in Drosophila melanogaster.

    Science.gov (United States)

    Hurd, Thomas Ryan; Herrmann, Beate; Sauerwald, Julia; Sanny, Justina; Grosch, Markus; Lehmann, Ruth

    2016-12-05

    Inherited mtDNA mutations cause severe human disease. In most species, mitochondria are inherited maternally through mechanisms that are poorly understood. Genes that specifically control the inheritance of mitochondria in the germline are unknown. Here, we show that the long isoform of the protein Oskar regulates the maternal inheritance of mitochondria in Drosophila melanogaster. We show that, during oogenesis, mitochondria accumulate at the oocyte posterior, concurrent with the bulk streaming and churning of the oocyte cytoplasm. Long Oskar traps and maintains mitochondria at the posterior at the site of primordial germ cell (PGC) formation through an actin-dependent mechanism. Mutating long oskar strongly reduces the number of mtDNA molecules inherited by PGCs. Therefore, Long Oskar ensures germline transmission of mitochondria to the next generation. These results provide molecular insight into how mitochondria are passed from mother to offspring, as well as how they are positioned and asymmetrically partitioned within polarized cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Minireview: Transgenerational Epigenetic Inheritance: Focus on Endocrine Disrupting Compounds

    Science.gov (United States)

    Rissman, Emilie F.

    2014-01-01

    The idea that what we eat, feel, and experience influences our physical and mental state and can be transmitted to our offspring and even to subsequent generations has been in the popular realm for a long time. In addition to classic gene mutations, we now recognize that some mechanisms for inheritance do not require changes in DNA. The field of epigenetics has provided a new appreciation for the variety of ways biological traits can be transmitted to subsequent generations. Thus, transgenerational epigenetic inheritance has emerged as a new area of research. We have four goals for this minireview. First, we describe the topic and some of the nomenclature used in the literature. Second, we explain the major epigenetic mechanisms implicated in transgenerational inheritance. Next, we examine some of the best examples of transgenerational epigenetic inheritance, with an emphasis on those produced by exposing the parental generation to endocrine-disrupting compounds (EDCs). Finally, we discuss how whole-genome profiling approaches can be used to identify aberrant epigenomic features and gain insight into the mechanism of EDC-mediated transgenerational epigenetic inheritance. Our goal is to educate readers about the range of possible epigenetic mechanisms that exist and encourage researchers to think broadly and apply multiple genomic and epigenomic technologies to their work. PMID:24885575

  19. Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study.

    Science.gov (United States)

    Dimitrakopoulou, Vasiliki I; Tsilidis, Konstantinos K; Haycock, Philip C; Dimou, Niki L; Al-Dabhani, Kawthar; Martin, Richard M; Lewis, Sarah J; Gunter, Marc J; Mondul, Alison; Shui, Irene M; Theodoratou, Evropi; Nimptsch, Katharina; Lindström, Sara; Albanes, Demetrius; Kühn, Tilman; Key, Timothy J; Travis, Ruth C; Vimaleswaran, Karani Santhanakrishnan; Kraft, Peter; Pierce, Brandon L; Schildkraut, Joellen M

    2017-10-31

    Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol

  20. INHERITANCE OF QUANTITATIVE TRAITS IN DRY PEA (Pisum sativum L.

    Directory of Open Access Journals (Sweden)

    Ranko Gantner

    2012-12-01

    Full Text Available The research was conducted with six parental genotypes: varieties Anno, Gold, Joel, Junior, PF-G1 and Shawnee with aim to improve the dry pea breeding for higher grain yield. Objectives of the research were to investigate: a the inheritance of grain yield per plant and its components; b to determination of the combining ability of parents and their cross-combinations; c the interrelationships among grain yield, its components and morphological traits; d choosing the primary selection criteria; e choosing the best cross-combinations in order to achieve the highest selection response of grain yield; f simple and digenic epistatic gene-effects in the chosen cross-combinations which determ the trait chosen as a primary selection criterion; g the genetic components of variation in the chosen cross-combinations of the trait chosen as a primary selection criterion; h the anticipation of genetic gain of grain yield per plant of the chosen cross-combinations. The research was conducted on experimental fields and laboratories of the Agricultural Institute Osijek. Parental lines were chosen in 2006, the first series of crossings in a diallel fashion were performed in 2007, and the second series in 2008, in a diallel fashion plus back-crossing. The obtained generation material (P1, P2, F1, F2, BC1 i BC2 of 15 biparental combinations was seeded in the field trial in 2009. Measurement of the yield, its components and morfological traits was done at the end of vegetation. The inheritance of investigated traits was estimated using Hayman’s approach to diallel analysis, combining abilities were determined using Griffing’s approach to diallel analysis, interrelationships among investigated traits were determined using correlation analysis, the primary selection criterion was chosen according to the inheritance of the investigated traits and their interrelationships, best cross-combinations were chosen upon Griffing’s analysis results and two principles: a

  1. Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis.

    Science.gov (United States)

    Nüesch, Eveline; Dale, Caroline; Palmer, Tom M; White, Jon; Keating, Brendan J; van Iperen, Erik Pa; Goel, Anuj; Padmanabhan, Sandosh; Asselbergs, Folkert W; Verschuren, W M; Wijmenga, C; Van der Schouw, Y T; Onland-Moret, N C; Lange, Leslie A; Hovingh, G K; Sivapalaratnam, Suthesh; Morris, Richard W; Whincup, Peter H; Wannamethe, Goya S; Gaunt, Tom R; Ebrahim, Shah; Steel, Laura; Nair, Nikhil; Reiner, Alexander P; Kooperberg, Charles; Wilson, James F; Bolton, Jennifer L; McLachlan, Stela; Price, Jacqueline F; Strachan, Mark Wj; Robertson, Christine M; Kleber, Marcus E; Delgado, Graciela; März, Winfried; Melander, Olle; Dominiczak, Anna F; Farrall, Martin; Watkins, Hugh; Leusink, Maarten; Maitland-van der Zee, Anke H; de Groot, Mark Ch; Dudbridge, Frank; Hingorani, Aroon; Ben-Shlomo, Yoav; Lawlor, Debbie A; Amuzu, A; Caufield, M; Cavadino, A; Cooper, J; Davies, T L; Drenos, F; Engmann, J; Finan, C; Giambartolomei, C; Hardy, R; Humphries, S E; Hypponen, E; Kivimaki, M; Kuh, D; Kumari, M; Ong, K; Plagnol, V; Power, C; Richards, M; Shah, S; Shah, T; Sofat, R; Talmud, P J; Wareham, N; Warren, H; Whittaker, J C; Wong, A; Zabaneh, D; Davey Smith, George; Wells, Jonathan C; Leon, David A; Holmes, Michael V; Casas, Juan P

    2016-12-01

    We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index ( P  < 0.001), triglycerides ( P  < 0.001), non high-density (non-HDL) cholesterol ( P  < 0.001), C-reactive protein ( P  = 0.042), and systolic blood pressure ( P  = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity ( P  < 0.001 for both). Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

  2. Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer.

    Science.gov (United States)

    Rodriguez-Broadbent, Henry; Law, Philip J; Sud, Amit; Palin, Kimmo; Tuupanen, Sari; Gylfe, Alexandra; Hänninen, Ulrika A; Cajuso, Tatiana; Tanskanen, Tomas; Kondelin, Johanna; Kaasinen, Eevi; Sarin, Antti-Pekka; Ripatti, Samuli; Eriksson, Johan G; Rissanen, Harri; Knekt, Paul; Pukkala, Eero; Jousilahti, Pekka; Salomaa, Veikko; Palotie, Aarno; Renkonen-Sinisalo, Laura; Lepistö, Anna; Böhm, Jan; Mecklin, Jukka-Pekka; Al-Tassan, Nada A; Palles, Claire; Martin, Lynn; Barclay, Ella; Farrington, Susan M; Timofeeva, Maria N; Meyer, Brian F; Wakil, Salma M; Campbell, Harry; Smith, Christopher G; Idziaszczyk, Shelley; Maughan, Timothy S; Kaplan, Richard; Kerr, Rachel; Kerr, David; Passarelli, Michael N; Figueiredo, Jane C; Buchanan, Daniel D; Win, Aung K; Hopper, John L; Jenkins, Mark A; Lindor, Noralane M; Newcomb, Polly A; Gallinger, Steven; Conti, David; Schumacher, Fred; Casey, Graham; Aaltonen, Lauri A; Cheadle, Jeremy P; Tomlinson, Ian P; Dunlop, Malcolm G; Houlston, Richard S

    2017-06-15

    While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia. © 2017 UICC.

  3. Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis.

    Science.gov (United States)

    May-Wilson, Sebastian; Sud, Amit; Law, Philip J; Palin, Kimmo; Tuupanen, Sari; Gylfe, Alexandra; Hänninen, Ulrika A; Cajuso, Tatiana; Tanskanen, Tomas; Kondelin, Johanna; Kaasinen, Eevi; Sarin, Antti-Pekka; Eriksson, Johan G; Rissanen, Harri; Knekt, Paul; Pukkala, Eero; Jousilahti, Pekka; Salomaa, Veikko; Ripatti, Samuli; Palotie, Aarno; Renkonen-Sinisalo, Laura; Lepistö, Anna; Böhm, Jan; Mecklin, Jukka-Pekka; Al-Tassan, Nada A; Palles, Claire; Farrington, Susan M; Timofeeva, Maria N; Meyer, Brian F; Wakil, Salma M; Campbell, Harry; Smith, Christopher G; Idziaszczyk, Shelley; Maughan, Timothy S; Fisher, David; Kerr, Rachel; Kerr, David; Passarelli, Michael N; Figueiredo, Jane C; Buchanan, Daniel D; Win, Aung K; Hopper, John L; Jenkins, Mark A; Lindor, Noralane M; Newcomb, Polly A; Gallinger, Steven; Conti, David; Schumacher, Fred; Casey, Graham; Aaltonen, Lauri A; Cheadle, Jeremy P; Tomlinson, Ian P; Dunlop, Malcolm G; Houlston, Richard S

    2017-10-01

    While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10-3; ORPOA = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10-4; ORAA = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10-4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01-1.35, P = 0.041). Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  4. Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.

    Science.gov (United States)

    Hägg, Sara; Fall, Tove; Ploner, Alexander; Mägi, Reedik; Fischer, Krista; Draisma, Harmen H M; Kals, Mart; de Vries, Paul S; Dehghan, Abbas; Willems, Sara M; Sarin, Antti-Pekka; Kristiansson, Kati; Nuotio, Marja-Liisa; Havulinna, Aki S; de Bruijn, Renée F A G; Ikram, M Arfan; Kuningas, Maris; Stricker, Bruno H; Franco, Oscar H; Benyamin, Beben; Gieger, Christian; Hall, Alistair S; Huikari, Ville; Jula, Antti; Järvelin, Marjo-Riitta; Kaakinen, Marika; Kaprio, Jaakko; Kobl, Michael; Mangino, Massimo; Nelson, Christopher P; Palotie, Aarno; Samani, Nilesh J; Spector, Tim D; Strachan, David P; Tobin, Martin D; Whitfield, John B; Uitterlinden, André G; Salomaa, Veikko; Syvänen, Ann-Christine; Kuulasmaa, Kari; Magnusson, Patrik K; Esko, Tõnu; Hofman, Albert; de Geus, Eco J C; Lind, Lars; Giedraitis, Vilmantas; Perola, Markus; Evans, Alun; Ferrières, Jean; Virtamo, Jarmo; Kee, Frank; Tregouet, David-Alexandre; Arveiler, Dominique; Amouyel, Philippe; Gianfagna, Francesco; Brambilla, Paolo; Ripatti, Samuli; van Duijn, Cornelia M; Metspalu, Andres; Prokopenko, Inga; McCarthy, Mark I; Pedersen, Nancy L; Ingelsson, Erik

    2015-04-01

    Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22,193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

  5. Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns.

    Science.gov (United States)

    Allard, C; Desgagné, V; Patenaude, J; Lacroix, M; Guillemette, L; Battista, M C; Doyon, M; Ménard, J; Ardilouze, J L; Perron, P; Bouchard, L; Hivert, M F

    2015-01-01

    Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (β = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P = 7.8 × 10(-11); N = 467). A higher GRS10 was associated with lower methylation levels at cg12083122 located near LEP (β = -0.072 unit per additional risk allele; SE = 0.04; P = 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (β = -0.17 log of cord blood leptin per unit; SE = 0.07; P = 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

  6. Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis.

    Science.gov (United States)

    Nead, Kevin T; Sharp, Stephen J; Thompson, Deborah J; Painter, Jodie N; Savage, David B; Semple, Robert K; Barker, Adam; Perry, John R B; Attia, John; Dunning, Alison M; Easton, Douglas F; Holliday, Elizabeth; Lotta, Luca A; O'Mara, Tracy; McEvoy, Mark; Pharoah, Paul D P; Scott, Rodney J; Spurdle, Amanda B; Langenberg, Claudia; Wareham, Nicholas J; Scott, Robert A

    2015-09-01

    Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer. We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants. Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10(-6)). This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk. © The Author 2015. Published by Oxford University Press.

  7. Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study.

    Science.gov (United States)

    Thomsen, Mette; Varbo, Anette; Tybjærg-Hansen, Anne; Nordestgaard, Børge G

    2014-05-01

    Increased nonfasting plasma triglycerides marking increased amounts of cholesterol in remnant lipoproteins are important risk factors for cardiovascular disease, but whether lifelong reduced concentrations of triglycerides on a genetic basis ultimately lead to reduced all-cause mortality is unknown. We tested this hypothesis. Using individuals from the Copenhagen City Heart Study in a mendelian randomization design, we first tested whether low concentrations of nonfasting triglycerides were associated with reduced all-cause mortality in observational analyses (n = 13 957); second, whether genetic variants in the triglyceride-degrading enzyme lipoprotein lipase, resulting in reduced nonfasting triglycerides and remnant cholesterol, were associated with reduced all-cause mortality (n = 10 208). During a median 24 and 17 years of 100% complete follow-up, 9991 and 4005 individuals died in observational and genetic analyses, respectively. In observational analyses compared to individuals with nonfasting plasma triglycerides of 266-442 mg/dL (3.00-4.99 mmol/L), multivariably adjusted hazard ratios for all-cause mortality were 0.89 (95% CI 0.78-1.02) for 177-265 mg/dL (2.00-2.99 mmol/L), 0.74 (0.65-0.84) for 89-176 mg/dL (1.00-1.99 mmol/L), and 0.59 (0.51-0.68) for individuals with nonfasting triglycerides triglycerides was 0.50 (0.30-0.82), with a corresponding observational hazard ratio of 0.87 (0.85-0.89). Also, the odds ratio for a genetically derived 50% lower concentration in nonfasting triglycerides was 0.43 (0.23-0.80), with a corresponding observational hazard ratio of 0.73 (0.70-0.77). Genetically reduced concentrations of nonfasting plasma triglycerides are associated with reduced all-cause mortality, likely through reduced amounts of cholesterol in remnant lipoproteins.

  8. Dissecting Causal Pathways Using Mendelian Randomization with Summarized Genetic Data: Application to Age at Menarche and Risk of Breast Cancer.

    Science.gov (United States)

    Burgess, Stephen; Thompson, Deborah J; Rees, Jessica M B; Day, Felix R; Perry, John R; Ong, Ken K

    2017-10-01

    Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor, keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI), and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly available data to better understand causal mechanisms. Copyright © 2017 by the Genetics Society of America.

  9. [Current status and future perspective in inherited cardiac arrhythmias].

    Science.gov (United States)

    Shimizu, Wataru

    2014-03-01

    Some patients with inherited cardiac arrhythmias such as congenital long QT syndrome (LQTS), Brugada syndrome, and early repolarization syndrome (ERS) have a link to mutations in genes encoding for ion channels or other membrane components. The diagnosis and management for inherited cardiac arrhythmias have been updated in recently published HRS/EHRA/APHRS Expert Consensus Statement. More recently, an exome study or whole genome study by using next generation sequencer as well as a genome-wide association study (GWAS) by using a gene array have been introduced to identify a new responsible gene or to explore the role of common genetic variants (polymorphisms) as a susceptible or modifier gene in inherited cardiac arrhythmias.

  10. Inheriting the past: Exploring historical consciousness across generations

    Directory of Open Access Journals (Sweden)

    Anna Clark

    2014-06-01

    Full Text Available Despite significant research into the meaning and operation of historical consciousness, there is still much to be understood about its hereditary function. For example, what does historical inheritance look like? How does it influence our individual and collective historical consciousnesses? And, just as critically, what happens to historical consciousness when history is deliberately withheld, when that inheritance is suspended or severed? As a way into some of these questions about passing on the past, this paper draws on a qualitative research project into historical consciousness in Australia to explore how so-called ‘ordinary people’ see themselves as part of a historical narrative. It reveals that historical inheritance is critical to our historical consciousness, and it notes the profound impact of forgetting on participants, raising important questions about the role of ‘silence’ and ‘absence’ in the formation of historical consciousness.

  11. Using Types and Inheritance in Object-Oriented Languages

    Science.gov (United States)

    Halbert, Daniel C.; O'Brien, Patrick D.

    If the object-oriented style of programming hopes to live up to its potential as an improved methodology for software programming, a clear understanding of how to use types and inheritance is essential. Our experiences with using object-oriented languages and teaching object-oriented techniques to other programmers have shown that effective use of types and inheritance may be problematic. There are no concrete guidelines to assist programmers, and the existing aphorisms often create interpretation problems for novice object-oriented programmers. In this paper we look at how types, subtyping, and inheritance are used in object-oriented languages. We discuss the different ways that types and type hierarchies can be used to structure programs. We illustrate appropriate use of these concepts through examples and develop guidelines to assist programmers in using the object-oriented methodology effectively.

  12. Selected aspects of transgenerational epigenetic inheritance and resetting in plants.

    Science.gov (United States)

    Paszkowski, Jerzy; Grossniklaus, Ueli

    2011-04-01

    Transgenerational epigenetic inheritance (TEI), which is the inheritance of expression states and thus traits that are not determined by the DNA sequence, is often postulated but the molecular mechanisms involved are only rarely verified. This especially applies to the heritability of environmentally induced traits, which have gained interest over the last years. Here we will discuss selected examples of epigenetic inheritance in plants and artificially divide them according to the occurrence of inter-generational resetting. The decision which epigenetic marks are reset and which ones are not is crucial for the understanding of TEI. We will consider examples of epialleles found in natural populations and epialleles induced by genetic and/or environmental factors used in experimental setups. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Inherited secondary nephrogenic diabetes insipidus: concentrating on humans.

    Science.gov (United States)

    Bockenhauer, D; Bichet, D G

    2013-04-15

    The study of human physiology is paramount to understanding disease and developing rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentration and identified the vasopressin receptor AVPR2, as well as the water channel aquaporin-2 (AQP2), as key players in water reabsorption in the collecting duct. Yet, there are also secondary forms of NDI, for instance as a complication of lithium treatment. The focus of this review is secondary NDI associated with inherited human diseases, such as Bartter syndrome or apparent mineralocorticoid excess. Currently, the underlying pathophysiology of this inherited secondary NDI is unclear, but there appears to be true AQP2 deficiency. To better understand the underlying mechanism(s), collaboration between clinical and experimental physiologists is essential to further investigate these observations in appropriate experimental models.

  14. RNA-mediated transgenerational inheritance in ciliates and plants.

    Science.gov (United States)

    Neeb, Zachary T; Nowacki, Mariusz

    2017-12-11

    In the age of next-generation sequencing (NGS) and with the availability of whole sequenced genomes and epigenomes, some attention has shifted from purely sequence-based studies to those of heritable epigenetic modifications. Transgenerational inheritance can be defined as heritable changes to the state of DNA that may be passed on to subsequent generations without alterations to the underlying DNA sequence. Although this phenomenon has been extensively studied in many systems, studies of transgenerational inheritance in mammals and other higher-level eukaryotes may be complicated by the fact that many epigenetic marks are reprogrammed during sexual reproduction. This, by definition, may obscure our interpretation of what is in fact truly transgenerational. Therefore, in this mini review, we discuss what is currently known in the field about transgenerational epigenetic inheritance in ciliates and plants, with a particular emphasis on RNA-mediated processes and changes in chromatin states.

  15. C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization

    DEFF Research Database (Denmark)

    Timpson, N J; Nordestgaard, B G; Harbord, R M

    2011-01-01

    Context:The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed.Objective:Using reciprocal Mendelian...... randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique.Participants and methods:The study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609...

  16. Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium.

    Science.gov (United States)

    Taylor, Amy E; Fluharty, Meg E; Bjørngaard, Johan H; Gabrielsen, Maiken Elvestad; Skorpen, Frank; Marioni, Riccardo E; Campbell, Archie; Engmann, Jorgen; Mirza, Saira Saeed; Loukola, Anu; Laatikainen, Tiina; Partonen, Timo; Kaakinen, Marika; Ducci, Francesca; Cavadino, Alana; Husemoen, Lise Lotte N; Ahluwalia, Tarunveer Singh; Jacobsen, Rikke Kart; Skaaby, Tea; Ebstrup, Jeanette Frost; Mortensen, Erik Lykke; Minica, Camelia C; Vink, Jacqueline M; Willemsen, Gonneke; Marques-Vidal, Pedro; Dale, Caroline E; Amuzu, Antoinette; Lennon, Lucy T; Lahti, Jari; Palotie, Aarno; Räikkönen, Katri; Wong, Andrew; Paternoster, Lavinia; Wong, Angelita Pui-Yee; Horwood, L John; Murphy, Michael; Johnstone, Elaine C; Kennedy, Martin A; Pausova, Zdenka; Paus, Tomáš; Ben-Shlomo, Yoav; Nohr, Ellen A; Kuh, Diana; Kivimaki, Mika; Eriksson, Johan G; Morris, Richard W; Casas, Juan P; Preisig, Martin; Boomsma, Dorret I; Linneberg, Allan; Power, Chris; Hyppönen, Elina; Veijola, Juha; Jarvelin, Marjo-Riitta; Korhonen, Tellervo; Tiemeier, Henning; Kumari, Meena; Porteous, David J; Hayward, Caroline; Romundstad, Pål R; Smith, George Davey; Munafò, Marcus R

    2014-10-07

    To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety. Published by the BMJ Publishing Group

  17. The Effect of Iron Status on Risk of Coronary Artery Disease: A Mendelian Randomization Study-Brief Report.

    Science.gov (United States)

    Gill, Dipender; Del Greco M, Fabiola; Walker, Ann P; Srai, Surjit K S; Laffan, Michael A; Minelli, Cosetta

    2017-09-01

    Iron status is a modifiable trait that has been implicated in cardiovascular disease. This study uses the Mendelian randomization technique to investigate whether there is any causal effect of iron status on risk of coronary artery disease (CAD). A 2-sample Mendelian randomization approach is used to estimate the effect of iron status on CAD risk. Three loci (rs1800562 and rs1799945 in the HFE gene and rs855791 in TMPRSS6) that are each associated with serum iron, transferrin saturation, ferritin, and transferrin in a pattern suggestive of an association with systemic iron status are used as instruments. SNP (single-nucleotide polymorphism)-iron status association estimates are based on a genome-wide association study meta-analysis of 48 972 individuals. SNP-CAD estimates are derived by combining the results of a genome-wide association study meta-analysis of 60 801 CAD cases and 123 504 controls with those of a meta-analysis of 63 746 CAD cases and 130 681 controls obtained from Metabochip and genome-wide association studies. Combined Mendelian randomization estimates are obtained for each marker by pooling results across the 3 instruments. We find evidence of a protective effect of higher iron status on CAD risk (iron odds ratio, 0.94 per SD unit increase; 95% confidence interval, 0.88-1.00; P=0.039; transferrin saturation odds ratio, 0.95 per SD unit increase; 95% confidence interval, 0.91-0.99; P=0.027; log-transformed ferritin odds ratio, 0.85 per SD unit increase; 95% confidence interval, 0.73-0.98; P=0.024; and transferrin odds ratio, 1.08 per SD unit increase; 95% confidence interval, 1.01-1.16; P=0.034). This Mendelian randomization study supports the hypothesis that higher iron status reduces CAD risk. These findings may highlight a therapeutic target. © 2017 American Heart Association, Inc.

  18. Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

    Science.gov (United States)

    Taylor, Amy E; Fluharty, Meg E; Bjørngaard, Johan H; Gabrielsen, Maiken Elvestad; Skorpen, Frank; Marioni, Riccardo E; Campbell, Archie; Engmann, Jorgen; Mirza, Saira Saeed; Loukola, Anu; Laatikainen, Tiina; Partonen, Timo; Kaakinen, Marika; Ducci, Francesca; Cavadino, Alana; Husemoen, Lise Lotte N; Ahluwalia, Tarunveer Singh; Jacobsen, Rikke Kart; Skaaby, Tea; Ebstrup, Jeanette Frost; Mortensen, Erik Lykke; Minica, Camelia C; Vink, Jacqueline M; Willemsen, Gonneke; Marques-Vidal, Pedro; Dale, Caroline E; Amuzu, Antoinette; Lennon, Lucy T; Lahti, Jari; Palotie, Aarno; Räikkönen, Katri; Wong, Andrew; Paternoster, Lavinia; Wong, Angelita Pui-Yee; Horwood, L John; Murphy, Michael; Johnstone, Elaine C; Kennedy, Martin A; Pausova, Zdenka; Paus, Tomáš; Ben-Shlomo, Yoav; Nohr, Ellen A; Kuh, Diana; Kivimaki, Mika; Eriksson, Johan G; Morris, Richard W; Casas, Juan P; Preisig, Martin; Boomsma, Dorret I; Linneberg, Allan; Power, Chris; Hyppönen, Elina; Veijola, Juha; Jarvelin, Marjo-Riitta; Korhonen, Tellervo; Tiemeier, Henning; Kumari, Meena; Porteous, David J; Hayward, Caroline; Romundstad, Pål R; Smith, George Davey; Munafò, Marcus R

    2014-01-01

    Objectives To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Design Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Participants Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Primary outcome measures Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. Results The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Conclusions Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the

  19. A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality.

    Science.gov (United States)

    Buckley, Bethany A; Burkhart, Kirk B; Gu, Sam Guoping; Spracklin, George; Kershner, Aaron; Fritz, Heidi; Kimble, Judith; Fire, Andrew; Kennedy, Scott

    2012-09-20

    Epigenetic information is frequently erased near the start of each new generation. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance). A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.

  20. Transgenerational epigenetic inheritance: focus on soma to germline information transfer.

    Science.gov (United States)

    Sharma, Abhay

    2013-12-01

    In trangenerational epigenetic inheritance, phenotypic information not encoded in DNA sequence is transmitted across generations. In germline-dependent mode, memory of environmental exposure in parental generation is transmitted through gametes, leading to appearance of phenotypes in the unexposed future generations. The memory is considered to be encoded in epigenetic factors like DNA methylation, histone modifications and regulatory RNAs. Environmental exposure may cause epigenetic modifications in the germline either directly or indirectly through primarily affecting the soma. The latter possibility is most intriguing because it contradicts the established dogma that hereditary information flows only from germline to soma, not in reverse. As such, identification of the factor(s) mediating soma to germline information transfer in transgenerational epigenetic inheritance would be pathbreaking. Regulatory RNAs and hormone have previously been implicated or proposed to play a role in soma to germline communication in epigenetic inheritance. This review examines the recent examples of gametogenic transgenerational inheritance in plants and animals in order to assess if evidence of regulatory RNAs and hormones as mediators of information transfer is supported. Overall, direct evidence for both mobile regulatory RNAs and hormones is found to exist in plants. In animals, although involvement of mobile RNAs seems imminent, direct evidence of RNA-mediated soma to germline information transfer in transgenerational epigenetic inheritance is yet to be obtained. Direct evidence is also lacking for hormones in animals. However, detailed examination of recently reported examples of transgenerational inheritance reveals circumstantial evidence supporting a role of hormones in information transmission. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Environmentally Induced Epigenetic Transgenerational Inheritance of Disease Susceptibility

    Science.gov (United States)

    Nilsson, Eric E.; Skinner, Michael K.

    2014-01-01

    Environmental insults, such as exposure to toxicants or nutritional abnormalities, can lead to epigenetic changes that are in turn related to increased susceptibility to disease. The focus of this review is on the transgenerational inheritance of such epigenetic abnormalities (epimutations), and how it is that these inherited epigenetic abnormalities can lead to increased disease susceptibility, even in the absence of continued environmental insult. Observations of environmental toxicant specificity and exposure specific disease susceptibility are discussed. How epimutations are transmitted across generations and how epigenetic changes in the germline are translated into an increased disease susceptibility in the adult is reviewed in regards to disease etiology. PMID:24657180

  2. A Unification of Inheritance and Automatic Program Specialization

    DEFF Research Database (Denmark)

    Schultz, Ulrik Pagh

    2004-01-01

    to be structured appropriately for specialization and is yet another new concept for the programmer to understand and apply. We have unified automatic program specialization and inheritance into a single concept, and implemented this approach in a modified version of Java named JUST. When programming in JUST......, inheritance is used to control the automatic application of program specialization to class members during compilation to obtain an efficient implementation. This paper presents the language JUST, which integrates object-oriented concepts, block structure, and techniques from automatic program specialization...

  3. Herencia de la retinosis pigmentaria en la provincia Camagüey Inheritance of retinitis pigmentosa in the province of Camagüey

    Directory of Open Access Journals (Sweden)

    Elisa Dyce Gordon

    1999-06-01

    Full Text Available Con el objetivo de clasificar a los pacientes con Retinosis Pigmentaria y a sus respectivas familias según la herencia y exponer el valor de dicha clasificación, se realizó un estudio descriptivo con 354 individuos afectados, distribuidos en 191 familias camagüeyanas. A través de entrevistas y la confección e interpretación del árbol genealógico se obtuvieron los datos necesarios. Se realizó estadística descriptiva con pruebas de chi-cuadrado y de probabilidad estadística. El 36,65 % de las familias estuvieron representadas por los casos con herencia no definida (simple seguidas por las herencias autosómica recesiva (27,75 % y autosómica dominante (24,60 %, esta última con el 87 % de penetrancia. Estadísticamente significativa fue la asociación de la consanguinidad con las herencias recesivas ( p A descriptive study of 354 affected individuals distributed in 190 families from Camagüey was conducted aimed at classifying those patients with retinitis pigmentosa and their families according to inheritance and at showing the value of such classification. The necessary data were obtained by interviews and genealogical analysis. A descriptive statistics was presented based on chi square test and statistical probability test. 36,65 % of the families were represent by the cases with indefinite (simple inheritance followed by recessive autosomal inheritances (27,75 % and dominant autosomal inheritance (24,60 %. The latter with 87 % of penetrance. The association of consanguinity with the recesive inheritances was statistically significant (p < ,005. 231 new diagnosis (39,75 % were made among the 581 patients who were examined. Knowing the ways of inheritance of retinis pigmentosa of each patient and this family is very important for screening the affected individuals and for preventing the disease

  4. Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses.

    Science.gov (United States)

    Mukherjee, Shubhabrata; Walter, Stefan; Kauwe, John S K; Saykin, Andrew J; Bennett, David A; Larson, Eric B; Crane, Paul K; Glymour, M Maria

    2015-12-01

    Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.96 (0.87-1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  5. Autosomal-recessive inheritance of benign recurrent intrahepatic cholestasis

    NARCIS (Netherlands)

    De Koning, T J; Sandkuijl, L A; De Schryver, J E; Hennekam, E A; Beemer, F A; Houwen, R H

    1995-01-01

    Benign recurrent intrahepatic cholestasis (BRIC) is a rare disorder characterized by recurrent episodes of cholestasis without permanent liver damage. Familial and sporadic cases have been described. Based on existing evidence, both autosomal-recessive and autosomal-dominant inheritance have been

  6. Darwin's Invention: Inheritance & the "Mad Dream" of Pangenesis

    Science.gov (United States)

    McComas, William F.

    2012-01-01

    This article recounts the story of the development of pangenesis, a principle proposed by Charles Darwin to describe the rules of inheritance and the source of new variation, two concepts vital to his proposal of evolution by natural selection. Historical accounts such as this are infrequently included in texts and classroom discussions but can…

  7. 3. Pattern of Inheritance of Autosome and Sex. Chromosome Linked ...

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 4; Issue 10. Teaching and Learning Genetics with Drosophila – Pattern of Inheritance of Autosome and Sex Chro-mosome Linked Genes/Characters. H A Ranganath M T Tanuja. Classroom Volume 4 Issue 10 October 1999 pp 78-87 ...

  8. Inherited bleeding disorders | Alli | South African Medical Journal

    African Journals Online (AJOL)

    Abnormal bleeding is a common clinical presentation in general practice, and a rational approach to this problem is therefore required. Investigation of a suspected bleeding disorder necessitates a comprehensive history, thorough physical examination and systematic laboratory work-up. Inherited bleeding disorders (IBDs) ...

  9. RAPD inheritance and diversity in pawpaw (Asimina triloba)

    Science.gov (United States)

    Hongwen Huang; Desmond R. Layne; Thomas L. Kubisiak

    2000-01-01

    Twelve, 10-base primers amplified a total of 20 intense and easily scorable polymorphic bands in an interspecific cross of PPFl-5 pawpaw (Asimina triloba (L.) Dunal.) x RET (Asimina reticulata Shuttlew.). In this cross, all bands scored were present in, and inherited from, the A. triloba ...

  10. Illusions of controlling the future: Risk and genetic inheritance.

    Science.gov (United States)

    Finkler, Kaja

    2003-01-01

    The aim of this paper is to analyse the implications of current beliefs that human beings can control the risk of inheriting a genetic disease and influence their present and future health. To accomplish this goal, materials will be drawn from disparate literatures bearing on concepts of probability, risk and genetic inheritance, and on empirical data gathered on cancer survivors and healthy persons with a family history of cancer. The concept of risk has been theorised on a grand scale but, as Lupton (1999, Introduction, Risk and Sociological Theory , Cambridge University Press) correctly observes, there has been very little empirical work done on how people experience risk as part of their lived world. In this paper, notions of probabilities and risk will be examined as applied to beliefs in genetic inheritance that are shaped by historical and cultural forces and in turn how they shape people's lives. It will be proposed that the belief that knowledge of one's genetic inheritance can control one's future health and disease is an illusion, and also replicates in part a religious notion of predestination.

  11. inheritance of resistance to common bacterial blight in common

    African Journals Online (AJOL)

    Prof. Adipala Ekwamu

    INHERITANCE OF RESISTANCE TO COMMON BACTERIAL BLIGHT IN. COMMON BEAN. B.Y.E. CHATAIKA, J.M. ... common bacterial blight caused by Xanthomonas axonopodis pv phaseoli (Xap). Effective breeding for resistance ... (2004) reported great genetic diversity and co- evolution for Xap across geographic ...

  12. CAMFAK syndrome: a demyelinating inherited disease similar to Cockayne syndrome.

    Science.gov (United States)

    Talwar, D; Smith, S A

    1989-10-01

    CAMFAK syndrome is an inherited disease characterized by congenital cataracts, microcephaly, failure to thrive, and kyphoscoliosis with onset in early infancy. Its pathogenesis has not been clearly defined. We report on a patient with this syndrome and present evidence that it is a neurologic disease characterized by peripheral and central demyelination similar to that seen in Cockayne syndrome.

  13. inheritance of resistance to angular leaf spot in yellow beans ...

    African Journals Online (AJOL)

    Prof. Adipala Ekwamu

    African Crop Science Journal, Vol. 19, No. 4, pp. ... Department of Plant Science and Crop Protection, University of Nairobi, P. O. Box 30197-00100,. Nairobi ..... Colombia. Santos-Filho, H.P., Ferraz, H.P. and Vieira, C. 1976. Inheritance of resistance to angular leaf spot in Phaseolus vulgaris L. Annual Report of the Bean ...

  14. Inherited and de novo variation in human genomes

    NARCIS (Netherlands)

    Francioli, L.C.

    2015-01-01

    Most human traits, ranging from physical appearance to behavior and disease susceptibility, are in part inherited through genetic material. Whole-genome sequencing has enabled the complete characterization of human genetic variation. While most of common DNA sequence variation has been observed in

  15. The Right to Property and Inheritance in the Old Testament

    Directory of Open Access Journals (Sweden)

    Adrian Vasile

    2016-01-01

    Inheritance has for ever played an important part in human societies and it still does in certainareas of the world. The Jewish right to succession had some features that derived from thepatriarchal family, which had been thoroughly established even before the age of stateconsolidation.

  16. [Erythropoietic protoporphyria. A rare inherited metabolic disorder with skin symptoms.

    DEFF Research Database (Denmark)

    Dam, Claus; Bathum, Lise; Sommerlund, Mette

    2008-01-01

    Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder, resulting from a deficiency of a specific enzyme, ferrochelatase, in the haem biosynthesis pathway. Early and late skin symptoms in EPP are demonstrated by three case stories. Diagnosis depends on characteristic skin...

  17. Inheritance of infertility | Tsuari | Obstetrics and Gynaecology Forum

    African Journals Online (AJOL)

    Patients with idiopathic infertility, family history of infertility, with a known congenital abnormality, in a consanguineous marriage, as well as advanced parental age should be offered genetic counselling, physical evaluation of dysmorphology as well as cytogenic studies as part of management of infertility. Inheritance of ...

  18. Several methods to detect the inheritance and resistance to the ...

    African Journals Online (AJOL)

    Majority of the transgenic plants had only a single copy of the inserted CryIA(c) gene. Leaf section bioassays showed that resistance against larvae of diamondback moth in CryIA(c) transgenic cabbage was significantly enhanced. The inheritance patterns of the transgene in T1 offspring of transgenic cabbage were ...

  19. Concepts of Kinship Relations and Inheritance in Childhood and Adolescence

    Science.gov (United States)

    Williams, Joanne M.; Smith, Lesley A.

    2010-01-01

    This paper examines the development and consistency of children's (4, 7, 10, and 14 years) naive concepts of inheritance using three tasks. A modified adoption task asked participants to distinguish between biological and social parentage in their predictions and explanations of the origins of different feature types (physical characteristics,…

  20. Mortality in inherited cardiac diseases: directing care in affected families

    NARCIS (Netherlands)

    Nannenberg, E.A.

    2014-01-01

    Many patients with an inherited cardiac disease face a substantial mortality risk, due to arrhythmias (sudden cardiac death), heart failure or embolic stroke. Knowledge about the mortality of diseases can help doctors and patients to make decisions on (timing of) treatment, screening strategies,

  1. Challenges identified in the management of patients with inherited ...

    African Journals Online (AJOL)

    Background: Pakistan is the sixth most populous country in the World. High rates of consanguinity and inter caste marriages have resulted in a substantial burden of inherited metabolic disorders (IMDs). Despite this load, there is a dearth of both medical genetic and clinical metabolic services in Pakistan. There are ...

  2. PHENYLKETONURIA, AN INHERITED METABOLIC DISORDER ASSOCIATED WITH MENTAL RETARDATION.

    Science.gov (United States)

    CENTERWALL, WILLARD R.; CENTERWALL, SIEGRIED A.

    ADDRESSED TO PUBLIC HEALTH WORKERS AND PHYSICIANS IN GENERAL PRACTICE, THE PAMPHLET INTRODUCES METHODS OF DETECTING AND MANAGING PHENYLKETONURIA, AN INHERITED METABOLIC DISORDER ASSOCIATED WITH MENTAL RETARDATION. INFORMATION, UPDATED FROM THE 1961 EDITION, IS INCLUDED ON THE INCIDENCE AND GENETICS, BIOCHEMISTRY, AND CLINICAL COURSE OF THE…

  3. Inheritance of plant height in two Ethiopian castor varieties | Alemaw ...

    African Journals Online (AJOL)

    Castor varieties are tall in plant height which makes them difficult for harvesting. A study was carried out to investigate the inheritance of plant height among two tall Castor varieties Hiruy and Abaro and one dwarf experimental line MD-1 during 2012 to 2014 at Melkassa. The F1 from reciprocal crosses of Abaro and Hiruy ...

  4. Elucidation of the molecular genetic basis of inherited hearing impairment

    NARCIS (Netherlands)

    Luijendijk, Mirjam Wilhelmina Johanna

    2006-01-01

    Hearing loss is the most common sensory disorder in the human population. It affects 0.1% of all young children and by the age of 70, 30% of the population suffers from hearing loss greater than 40 dB. When early onset hearing loss is inherited, 70% is classified as nonsyndromic and 30% as

  5. Genetic adaptability of inheritance of resistance to biotic and abiotic ...

    African Journals Online (AJOL)

    Moreover, generation means analysis of several traits assessed in diverse environmental conditions revealed that the mode of inheritance of each trait varied with the biotic or abiotic stress level. With less stress level, only additive and dominance effects was found significant. In contrast with moderate and higher stress level ...

  6. Performance of parental genotypes and inheritance of Angular Leaf ...

    African Journals Online (AJOL)

    Two studies, one on performance of six common bean parental genotypes and another on inheritance of resistance to Phaeosariopsis griseola (Pg) in the common bean were carried out in Malawi. Common bean entries namely; Chimbamba, Nasaka, RC 15, CAL 143 and Mexico 54 were evaluated on station in the ...

  7. Evolutionary origin and consequences of uniparental mitochondrial inheritance

    NARCIS (Netherlands)

    Hoekstra, R.F.

    2000-01-01

    In the great majority of sexual organisms, cytoplasmic genomes such as the mitochondrial genome are inherited (almost) exclusively through only one, usually the maternal, parent. This rule probably evolved to minimize the potential spread of selfish cytoplasmic genomic mutations through a species.

  8. A basic investigation for inherited metabolic diseases: indication for ...

    African Journals Online (AJOL)

    A basic investigation for inherited metabolic diseases: indication for genomic approach. ... All subjects were subjected to Benedicts reaction, the Ferric Chloride (FeC13) test, clinstix, and the ninhydrin reactions. ... The FeC13 test and the ninhydrin reactions were negative in both the handicapped and controls subjects.

  9. Transgenerational epigenetic inheritance in mammals: how good is the evidence?

    Science.gov (United States)

    van Otterdijk, Sanne D; Michels, Karin B

    2016-07-01

    Epigenetics plays an important role in orchestrating key biologic processes. Epigenetic marks, including DNA methylation, histones, chromatin structure, and noncoding RNAs, are modified throughout life in response to environmental and behavioral influences. With each new generation, DNA methylation patterns are erased in gametes and reset after fertilization, probably to prevent these epigenetic marks from being transferred from parents to their offspring. However, some recent animal studies suggest an apparent resistance to complete erasure of epigenetic marks during early development, enabling transgenerational epigenetic inheritance. Whether there are similar mechanisms in humans remains unclear, with the exception of epigenetic imprinting. Nevertheless, a distinctly different mechanism-namely, intrauterine exposure to environmental stressors that may affect establishment of the newly composing epigenetic patterns after fertilization-is often confused with transgenerational epigenetic inheritance. In this review, we delineate the definition of and requirement for transgenerational epigenetic inheritance, differentiate it from the consequences of intrauterine exposure, and discuss the available evidence in both animal models and humans.-Van Otterdijk, S. D., Michels, K. B. Transgenerational epigenetic inheritance in mammals: how good is the evidence? © FASEB.

  10. Rare inherited kidney diseases: challenges, opportunities, and perspectives.

    NARCIS (Netherlands)

    Devuyst, O.; Knoers, N.V.A.M.; Remuzzi, G.; Schaefer, F.; Bindels, R.J.

    2014-01-01

    At least 10% of adults and nearly all children who receive renal-replacement therapy have an inherited kidney disease. These patients rarely die when their disease progresses and can remain alive for many years because of advances in organ-replacement therapy. However, these disorders substantially

  11. Inheritance and segregation of exogenous genes in transgenic cotton

    Indian Academy of Sciences (India)

    Three transgenic cotton varieties (lines) were chosen for the study of inheritance and segregation of foreign Bt (Bacillus thuringiensis toxin) and tfdA genes in cotton. The transformed cotton varieties CCRI 30 and NewCott 33B expressing the Bt cryIA gene, and cotton line TFD expressing the tfdA gene were crossed with ...

  12. Inheritance and segregation of exogenous genes in transgenic cotton

    Indian Academy of Sciences (India)

    Three transgenic cotton varieties (lines) were chosen for the study of inheritance and segregation of foreign Bt (Bacillus thuringiensis toxin) and tfdA genes in cotton. The transformed cotton varieties CCRI 30 and NewCott 33B expressing the Bt. cryIA gene, and cotton line TFD expressing the tfdA gene were crossed with ...

  13. Safeguarding inheritance and enhancing the resilience of orphaned ...

    African Journals Online (AJOL)

    This article explores the resilience of orphaned young people in safeguarding physical assets (land and property) inherited from their parents and sustaining their households without a co-resident adult relative. Drawing on the concept of resilience and the sustainable livelihoods framework, the article analyses the findings ...

  14. Sexual behaviour and inheritance rights among HIV- positive ...

    African Journals Online (AJOL)

    In developing countries, culture favours males for economic ventures more than females. There is evidence that allowing HIV positive women inheritance rights will mitigate negative economic consequences of HIV/AIDS and other related risks. This study aimed to examine the extent to which HIV positive women have ...

  15. Dominantly inherited microcephaly, short stature and normal intelligence

    NARCIS (Netherlands)

    Hennekam, R. C.; van Rhijn, A.; Hennekam, F. A.

    1992-01-01

    A large family is reported in which microcephaly and short stature is segregating as a probably autosomal dominantly inherited trait. Some affected members also show a delayed onset of puberty. No other clinical or radiological symptoms are present, and psychomotor development is normal. This short

  16. The inheritance of dynamic and deontic integrity constraints

    NARCIS (Netherlands)

    Wieringa, Roelf J.; Weigand, H.; Meyer, J.J.C.; Dignum, F.P.M.

    1991-01-01

    In [18,23], we presented a language for the specification of static, dynamic and deontic integrity constraints (IC's) for conceptual models (CM's). An important problem not discussed in that paper is how IC's are inherited in a taxonomic network of types. For example, if students are permitted to

  17. Cystinuria AA (B): digenic inheritance with three mutations in two ...

    Indian Academy of Sciences (India)

    1Faculty of Medicine, University Children's Hospital, Skopje 1000, Republic of Macedonia. 2Macedonian Academy of Sciences and Arts, ... 8% of children suffering from kidney stones have cystinuria. (Rosenberg 1966). Historically the biochemical ... inheritance; three mutations; SLC3A1; SLC7A9. Journal of Genetics, Vol.

  18. genetics and inheritance of seed dormancy inflicted by seed

    African Journals Online (AJOL)

    Mgina

    reference to its genetic factors. Bull. Inst. Res. Tohoku University 14:1-. 879 (J). Takahashi T 1997 Inheritance of seed germination and dormancy. In. Science of the Rice Plant Genetics. Vol. 3. Eds. T Matsao et al (1997). FAO Policy Center, Tokyo. Tomar JB 1984 Genetics of grain dormancy in rice (Oryza sativa L.) Genetica.

  19. Inheritance and identification of SCAR marker linked to bacterial wilt ...

    African Journals Online (AJOL)

    In the present work, the combinations (F1) were crossed between highly resistant and susceptible to bacterial wilt eggplant parents and its F2, BC1 segregation population plants were inoculated with race1 of Ralstonia solanacearum in greenhouse. In this paper, we reported that the inheritance of bacterial wilt resistance in ...

  20. A conserved function for Inp2 in peroxisome inheritance

    NARCIS (Netherlands)

    Saraya, Ruchi; Cepinska, Malgorzata N.; Kiel, Jan A. K. W.; Veenhuis, Marten; van der Klei, Ida J.; Cepińska, Małgorzata N.

    In budding yeast Saccharomyces cerevisiae, the peroxisomal protein Inp2 is required for inheritance of peroxisomes to the bud, by connecting the organelles to the motor protein Myo2 and the actin cytoskeleton. Recent data suggested that the function of Inp2 may not be conserved in other yeast

  1. Several methods to detect the inheritance and resistance to the ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-06-17

    Jun 17, 2009 ... Majority of the transgenic plants had only a single copy of the inserted CryIA(c) gene. Leaf section bioassays showed that resistance against larvae of diamondback moth in CryIA(c) transgenic cabbage was significantly enhanced. The inheritance patterns of the transgene in T1 offspring of transgenic.

  2. Vena porta thrombosis in patient with inherited factor VII deficiency

    DEFF Research Database (Denmark)

    Klovaite, Jolanta; Friis-Hansen, Lennart Jan; Larsen, Fin S

    2010-01-01

    with inherited FVII deficiency and chronic vena porta thrombosis. She presented at 32 weeks of gestation with spontaneously increased international normalized ratio, severe thrombocytopenia and very few unspecific symptoms. The extensive examination of the patient revealed cavernous transformation of the portal...

  3. An inherited cataract in New Zealand Romney sheep.

    Science.gov (United States)

    Brooks, H V; Jolly, R D; West, D M; Bruere, A N

    1982-08-01

    A bilateral cataract was noted to occur in sheep on a New Zealand Romney stud. Extensive breeding trials showed that this defect was inherited as an autosomal dominant. As such this form of cataract is of minimal importance to the sheep industry as control is merely by culling affected individuals.

  4. A review of ocular genetics and inherited eye diseases

    Directory of Open Access Journals (Sweden)

    S. D. Mathebula

    2012-12-01

    Full Text Available During the past twenty years, there has been an exponential increase in the knowledge and under-standing of ocular genetic diseases and syndromes. The number of human eye diseases that have a known genetic or hereditary component continues to increase. In addition, genetic diseases are the most common cause of blindness in infants and children in developed countries. Optometrists are likely to encounter patients with inherited eye disorders. They may be the first clinician the patient consults. Inherited eye diseases may be isolated (only affecting the eye or part of a complicated syndrome. Both isolated eye diseases and genetic syndromes can have identifiable gene mutation known to cause the disease.Knowledge of the clinical and molecular features of ocular genetics and inherited eye diseases is important for appropriate diagnosis and patient management. This article reviews the current information on ocular genetics and inherited eye diseases.The ocular conditions described in the review have significant visual impairment and blindness consequences. Therefore, optometrists (as the mostly likely first line of consultation should be able todiagnose the condition appropriately first before they could make any management, care or referralplan. Visual aids are, of course, one of the management options for such patients with visual impairment. (S Afr Optom 2012 71(4 178-189

  5. Assessing causality in the association between child adiposity and physical activity levels: a Mendelian randomization analysis.

    Directory of Open Access Journals (Sweden)

    Rebecca C Richmond

    2014-03-01

    Full Text Available Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose-response association with body mass index (BMI has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects.The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity. In observational analysis, a 3.3 kg/m² (one standard deviation higher BMI was associated with 22.3 (95% CI, 17.0, 27.6 movement counts/min less total physical activity (p = 1.6×10⁻¹⁶, 2.6 (2.1, 3.1 min/d less moderate-to-vigorous-intensity activity (p = 3.7×10⁻²⁹, and 3.5 (1.5, 5.5 min/d more sedentary time (p = 5.0×10⁻⁴. In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9 movement counts/min less total physical activity (p = 0.04 (∼5.3% of the mean counts/minute, 2.8 (0.1, 5.5 min/d less moderate-to-vigorous-intensity activity (p = 0.04, and 13.2 (1.3, 25.2 min/d more sedentary time (p = 0.03. There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI.Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to

  6. Effect of Bile Acid Sequestrants on the Risk of Cardiovascular Events: A Mendelian Randomization Analysis.

    Science.gov (United States)

    Ross, Stephanie; D'Mello, Matthew; Anand, Sonia S; Eikelboom, John; Stewart, Alexandre F R; Samani, Nilesh J; Roberts, Robert; Paré, Guillaume

    2015-08-01

    Statins lower low-density lipoprotein cholesterol (LDL-C) and risk of coronary artery disease (CAD), but they may be ineffective or not tolerated. Bile acid sequestrants (BAS) reduce LDL-C, yet their clinical efficacy on CAD remains controversial. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of cholestyramine and colesevelam. We then used Mendelian randomization to estimate the effect of BAS on reducing the risk of CAD. First, we quantified the effect of rs4299376 (ABCG5/ABCG8), which affects the intestinal cholesterol absorption pathway targeted by BAS and then we used these estimates to predict the effect of BAS on CAD. Nineteen randomized controlled trials with a total of 7021 study participants were included. Cholestyramine 24 g/d was associated with a reduction in LDL-C of 23.5 mg/dL (95% confidence interval [CI] -26.8,-20.2; N=3806) and a trend toward reduced risk of CAD (odds ratio 0.81, 95% CI 0.70-1.02; P=0.07; N=3806), whereas colesevelam 3.75 g/d was associated with a reduction in LDL-C of 22.7 mg/dL (95% CI -28.3, -17.2; N=759). Based on the findings that rs4299376 was associated with a 2.75 mg/dL decrease in LDL-C and a 5% decrease in risk of CAD outcomes, we estimated that cholestyramine was associated with an odds ratio for CAD of 0.63 (95% CI 0.52-0.77; P=6.3×10(-6)) and colesevelam with an odds ratio of 0.64 (95% CI 0.52-0.79, P=4.3×10(-5)), which were not statistically different from BAS clinical trials (P>0.05). The cholesterol lowering effect of BAS may translate into a clinically relevant reduction in CAD. © 2015 American Heart Association, Inc.

  7. Elevated remnant cholesterol in 25-hydroxyvitamin D deficiency in the general population: Mendelian randomization study.

    Science.gov (United States)

    Ooi, Esther M; Afzal, Shoaib; Nordestgaard, Børge G

    2014-10-01

    Low plasma 25-hydroxyvitamin D [25(OH)D] levels are associated with high cardiovascular risk. This may be because that low 25(OH)D levels are associated with high levels of atherogenic lipoproteins, but whether these 2 risk factors are genetically associated is unknown. We tested this hypothesis. Using a Mendelian randomization approach, potential genetic associations between plasma levels of atherogenic lipoproteins and 25(OH)D were examined in ≤85,868 white, Danish individuals in whom we genotyped for variants affecting plasma levels of 25(OH)D, nonfasting remnant cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Lipoprotein levels were measured in all and 25(OH)D levels in 31,435. A doubling in nonfasting remnant cholesterol levels was observationally and genetically associated with -6.0%(95% confidence interval [CI], -6.5% to -5.5%) and -8.9% (95% CI, -15% to -2.3%) lower plasma 25(OH)D levels. For low-density lipoprotein-cholesterol levels, corresponding values were -4.6% (95% CI, -5.4% to -3.7%) observationally and -11% (95% CI, -29% to +6.9%) genetically. In contrast, a halving in high-density lipoprotein-cholesterol levels was observationally associated with -1.5% (95% CI, -2.2% to -0.7%) lower but genetically associated with +20% (95% CI, +7.4% to +34%) higher plasma 25(OH)D levels. Plasma levels of lipoprotein(a) and 25(OH)D did not associate. Finally, low 25(OH)D levels did not associate genetically with levels of remnant and low-density lipoprotein-cholesterol. Genetically elevated nonfasting remnant cholesterol is associated with low 25(OH)D levels, whereas genetically reduced high-density lipoprotein-cholesterol is not associated with low 25(OH)D levels. These findings suggest that low 25(OH)D levels observationally is simply a marker for elevated atherogenic lipoproteins and question a role for vitamin D supplementation in the prevention of cardiovascular disease. © 2014 American Heart Association, Inc.

  8. Assessing causality in the association between child adiposity and physical activity levels: a Mendelian randomization analysis.

    Science.gov (United States)

    Richmond, Rebecca C; Davey Smith, George; Ness, Andy R; den Hoed, Marcel; McMahon, George; Timpson, Nicholas J

    2014-03-01

    Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose-response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects. The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity. In observational analysis, a 3.3 kg/m² (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6×10⁻¹⁶), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7×10⁻²⁹), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0×10⁻⁴). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (∼5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI. Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase

  9. Inflammation, insulin resistance, and diabetes--Mendelian randomization using CRP haplotypes points upstream.

    Directory of Open Access Journals (Sweden)

    Eric J Brunner

    2008-08-01

    Full Text Available Raised C-reactive protein (CRP is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study. Homeostasis model assessment-insulin resistance (HOMA-IR and hemoglobin A1c (HbA1c were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52-0.92. The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007-0.11. Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25-0.88. Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls using three SNPs in tight linkage disequilibrium with our

  10. Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

    Science.gov (United States)

    Carreras-Torres, Robert; Johansson, Mattias; Haycock, Philip C; Wade, Kaitlin H; Relton, Caroline L; Martin, Richard M; Davey Smith, George; Albanes, Demetrius; Aldrich, Melinda C; Andrew, Angeline; Arnold, Susanne M; Bickeböller, Heike; Bojesen, Stig E; Brunnström, Hans; Manjer, Jonas; Brüske, Irene; Caporaso, Neil E; Chen, Chu; Christiani, David C; Christian, W Jay; Doherty, Jennifer A; Duell, Eric J; Field, John K; Davies, Michael P A; Marcus, Michael W; Goodman, Gary E; Grankvist, Kjell; Haugen, Aage; Hong, Yun-Chul; Kiemeney, Lambertus A; van der Heijden, Erik H F M; Kraft, Peter; Johansson, Mikael B; Lam, Stephen; Landi, Maria Teresa; Lazarus, Philip; Le Marchand, Loïc; Liu, Geoffrey; Melander, Olle; Park, Sungshim L; Rennert, Gad; Risch, Angela; Haura, Eric B; Scelo, Ghislaine; Zaridze, David; Mukeriya, Anush; Savić, Milan; Lissowska, Jolanta; Swiatkowska, Beata; Janout, Vladimir; Holcatova, Ivana; Mates, Dana; Schabath, Matthew B; Shen, Hongbing; Tardon, Adonina; Teare, M Dawn; Woll, Penella; Tsao, Ming-Sound; Wu, Xifeng; Yuan, Jian-Min; Hung, Rayjean J; Amos, Christopher I; McKay, James; Brennan, Paul

    2017-01-01

    Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

  11. Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D.

    Directory of Open Access Journals (Sweden)

    Diane J Berry

    Full Text Available Mendelian randomization (MR studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies.We evaluated genetic markers that index differences in 25-hydroxyvitamin D (25(OHD as instruments for MR studies on vitamin D.We used data from up-to 6,877 participants in the 1958 British birth cohort with information on genetic markers and 25(OHD. As potential instruments, we selected 20 single nucleotide polymorphisms (SNP which are located in the vitamin D metabolism pathway or affect skin pigmentation/tanning, including 4 SNPs from genome-wide association (GWA meta-analyses on 25(OHD. We analyzed SNP associations with 25(OHD and evaluated the use of allele scores dividing genes to those affecting 25(OHD synthesis (DHCR7, CYP2R1 and metabolism (GC, CYP24A1, CYP27B1. In addition to the GWA SNPs, only two SNPs (CYP27B1, OCA2 showed evidence for association with 25(OHD, with the OCA2 association abolished after lifestyle adjustment. Per allele differences varied between -0.02 and -0.08 nmol/L (P≤0.02 for all, with a 6.1 nmol/L and a 10.2 nmol/L difference in 25(OHD between individuals with highest compared lowest number of risk alleles in synthesis and metabolism allele scores, respectively. Individual SNPs but not allele scores showed associations with lifestyle factors. An exception was geographical region which was associated with synthesis score. Illustrative power calculations (80% power, 5% alpha suggest that approximately 80,000 participants are required to establish a causal effect of vitamin D on blood pressure using the synthesis allele score.Combining SNPs into allele scores provides a more powerful instrument for MR analysis than a single SNP in isolation. Population stratification and the potential for pleiotropic effects need to be considered in MR

  12. Neo-sex chromosome inheritance across species in Silene hybrids.

    Science.gov (United States)

    Weingartner, L A; Delph, L F

    2014-07-01

    Neo-sex chromosomes, which form through the major restructuring of ancestral sex chromosome systems, have evolved in various taxa. Such restructuring often consists of the fusion of an autosome to an existing sex chromosome, resulting in novel sex chromosome formations (e.g. X1X2Y or XY1Y2.). Comparative studies are often made between restructured sex chromosome systems of closely related species, and here we evaluate the consequences of variable sex chromosome systems to hybrids. If neo-sex chromosomes are improperly inherited across species, this could lead to aberrant development and reproductive isolation. In this study, we examine the fate of neo-sex chromosomes in hybrids of the flowering plants Silene diclinis and Silene latifolia. Silene diclinis has a neo-sex chromosome system (XY1Y2) that is thought to have evolved from an ancestral XY system that is still present in S. latifolia. These species do not hybridize naturally, and improper sex chromosome inheritance could contribute to reproductive isolation. We investigated whether this major restructuring of sex chromosomes prevents their proper inheritance in a variety of hybrid crosses, including some F2 - and later-generation hybrids, with sex chromosome-linked, species-specific, polymorphic markers and chromosome squashes. We discovered that despite the differences in sex chromosomes that exist between these two species, proper segregation had occurred in hybrids that made it to flowering, including later-generation hybrids, indicating that neo-sex chromosome formation alone does not result in complete reproductive isolation between these two species. Additionally, hybrids with aberrant sex expression (e.g. neuter, hermaphrodite) also inherited the restructured sex chromosomes properly, highlighting that issues with sexual development in hybrids can be caused by intrinsic genetic incompatibility rather than improper sex chromosome inheritance. © 2014 The Authors. Journal of Evolutionary Biology © 2014

  13. Simple guide to Skype

    CERN Document Server

    Winter, Rick

    2013-01-01

    Simple Guides give you Just the Facts Get up to speed with Skypefast! Simple Guides: get you started quickly. No extra clutter, no extra reading. Learn how to set up Skype, as well as how to add and set up all your friends, family, and other contacts. Find out about all the features of Skype, how to change views, set your status and conduct video and audio only calls. Learn about all the different things you can do to contact your friends and family on Skype for free, and start having fun!

  14. Droids Made Simple

    CERN Document Server

    Mazo, Gary

    2011-01-01

    If you have a Droid series smartphone - Droid, Droid X, Droid 2, or Droid 2 Global - and are eager to get the most out of your device, Droids Made Simple is perfect for you. Authors Martin Trautschold, Gary Mazo and Marziah Karch guide you through all of the features, tips, and tricks using their proven combination of clear instructions and detailed visuals. With hundreds of annotated screenshots and step-by-step directions, Droids Made Simple will transform you into a Droid expert, improving your productivity, and most importantly, helping you take advantage of all of the cool features that c

  15. Excel 2010 Made Simple

    CERN Document Server

    Katz, Abbott

    2011-01-01

    Get the most out of Excel 2010 with Excel 2010 Made Simple - learn the key features, understand what's new, and utilize dozens of time-saving tips and tricks to get your job done. Over 500 screen visuals and clear-cut instructions guide you through the features of Excel 2010, from formulas and charts to navigating around a worksheet and understanding Visual Basic for Applications (VBA) and macros. Excel 2010 Made Simple takes a practical and highly effective approach to using Excel 2010, showing you the best way to complete your most common spreadsheet tasks. You'll learn how to input, format,

  16. Mendelian Randomisation Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes

    DEFF Research Database (Denmark)

    Yaghootkar, Hanieh; Lamina, Claudia; Scott, Robert A

    2013-01-01

    Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes but its causal role remains controversial. We used a Mendelian randomisation approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic varian...

  17. Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes

    NARCIS (Netherlands)

    H. Yaghootkar (Hanieh); C. Lamina (Claudia); R.A. Scott (Robert); Z. Dastani (Zari); M.-F. Hivert (Marie-France); L.L. Warren (Liling); A. Stancáková (Alena); S.G. Buxbaum (Sarah); L.-P. Lyytikäinen (Leo-Pekka); P. Henneman (Peter); Y. Wu (Ying); C.Y.Y. Cheung (Chloe); J.S. Pankow (James); A.U. Jackson (Anne); S. Gustafsson (Stefan); J.H. Zhao (Jing Hua); C. Ballantyne (Christie); W. Xie (Weijia); R.N. Bergman (Richard); M. Boehnke (Michael); F. El Bouazzaoui (Fatiha); F.S. Collins (Francis); S.H. Dunn (Sandra); J. Dupuis (Josée); N.G. Forouhi (Nita); C.J. Gillson (Christopher); A.T. Hattersley (Andrew); J. Hong (Jaeyoung); M. Kähönen (Mika); J. Kuusisto (Johanna); L. Kedenko (Lyudmyla); F. Kronenberg (Florian); A. Doria (Andrea); T.L. Assimes (Themistocles); E. Ferrannini (Ele); T. Hansen (Torben); K. Hao (Ke); H. Häring (Hans); J.W. Knowles (Joshua); C.M. Lindgren (Cecilia); J.J. Nolan (John); J. Paananen (Jussi); O. Pedersen (Oluf); T. Quertermous (Thomas); U. Smith (Ulf); T. Lehtimäki (Terho); C.-T. Liu (Ching-Ti); R.J.F. Loos (Ruth); M.I. McCarthy (Mark); A.D. Morris (Andrew); R.S. Vasan (Ramachandran Srini); T.D. Spector (Timothy); T.M. Teslovich (Tanya); J. Tuomilehto (Jaakko); J.A.P. Willems van Dijk (Ko); J. Viikari (Jorma); N. Zhu (Na); C. Langenberg (Claudia); E. Ingelsson (Erik); R.K. Semple (Robert); A. Sinaiko (Alan); C.N.A. Palmer (Colin); M. Walker (Mark); K.S.L. Lam (Karen); B. Paulweber (Bernhard); K.L. Mohlke (Karen); C.M. van Duijn (Cornelia); O. Raitakari (Olli); A. Bidulescu (Aurelian); N.J. Wareham (Nick); M. Laakso (Markku); D. Waterworth (Dawn); D.A. Lawlor (Debbie); J.B. Meigs (James); J.B. Richards (Brent); T.M. Frayling (Timothy)

    2013-01-01

    textabstractAdiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used

  18. Discovering the genetic cause of Mendelian disorders in the age of genomics : the evolving capability of next-generation DNA sequencing

    NARCIS (Netherlands)

    Monroe, G.R.|info:eu-repo/dai/nl/413967476

    2017-01-01

    The research presented in this thesis identifies the genetic cause of a diverse range of Mendelian disorders using next generation sequencing. This work reflects the extremely rapid development of NGS, beginning with target gene panel sequencing in a research setting (Chapters 2 and 3) and only 4

  19. A Simple Hydrogen Electrode

    Science.gov (United States)

    Eggen, Per-Odd

    2009-01-01

    This article describes the construction of an inexpensive, robust, and simple hydrogen electrode, as well as the use of this electrode to measure "standard" potentials. In the experiment described here the students can measure the reduction potentials of metal-metal ion pairs directly, without using a secondary reference electrode. Measurements…

  20. (3) Simple processing method

    African Journals Online (AJOL)

    Adeyinka Odunsi

    Simple Processing Method for Recycling Poultry Waste into. Animal Feed Ingredient. *Komolafe, A. A. and Sonaiya, E. B. ... recycled and become consumables to livestock, thus entering the human food chain. Poultry waste is not ... on the concrete roof (20.5 m high) of the Faculty of Agriculture, Obafemi. Awolowo University ...

  1. Environmental epigenetic inheritance through gametes and implications for human reproduction.

    Science.gov (United States)

    Wei, Yanchang; Schatten, Heide; Sun, Qing-Yuan

    2015-01-01

    Traditional studies focused on DNA as the heritable information carrier that passes the phenotype from parents to offspring. However, increasing evidence suggests that information, that is independent of the DNA sequence, termed epigenetic information, can be inherited between generations. Recently, in our lab, we found that prediabetes in fathers increases the susceptibility to diabetes in offspring through gametic cytosine methylation changes. Paternal prediabetes changed overall methylation patterns in sperm, and a large portion of differentially methylated loci can be transmitted to pancreatic islets of offspring up to the second generation. In this review, we survey the extensive examples of environmentally induced epigenetic inheritance in various species, ranging from Caenorhabditis elegans to humans. We focus mainly on elucidating the molecular basis of environmental epigenetic inheritance through gametes, which is an emerging theme and has important implications for explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases, which is also important for understanding the influence of environmental exposures on reproductive and overall health in offspring. For this review, we included relevant data and information obtained through a PubMed database search for all English language articles published up to August 2014 which included the term 'environmental epigenetic inheritance' and 'transgenerational epigenetic inheritance'. We focused on research papers using animal models including Drosophila, C. elegans, mouse and rat. Human data were also included. Evidence from animal models suggests that environmental epigenetic inheritance through gametes exists in various species. Extensive molecular evidence suggests that epigenetic information carriers including DNA methylation, non-coding RNAs and chromatin proteins in gametes play important roles in the transmission of phenotypes from parents to offspring. Given the large number

  2. Effect of Inherited Breast Cancer Susceptibility on Treatment Outcomes After Conservative Surgery and Radiation Therapy

    National Research Council Canada - National Science Library

    Nixon, Asa

    1998-01-01

    The recent ability to test for an inherited susceptibility to breast cancer raises questions about the use of radiation therapy in patients with inherited mutations in BRCA1, BRCA2, or other breast...

  3. Maternal inheritance of mitochondrial DNA by diverse mechanisms to eliminate paternal mitochondrial DNA

    National Research Council Canada - National Science Library

    Sato, Miyuki; Sato, Ken

    2013-01-01

    .... This pattern of mtDNA inheritance is well known as "maternal inheritance." However, how the paternal mitochondria and mtDNA are eliminated from the cytoplasm of gametes or zygotes remains an enigma...

  4. Inherited unbalanced structural chromosome abnormalities at prenatal chromosome analysis are rarely ascertained through recurrent miscarriage

    NARCIS (Netherlands)

    Franssen, M. T. M.; Korevaar, J. C.; Tjoa, W. M.; Leschot, N. J.; Bossuyt, P. M. M.; Knegt, A. C.; Suykerbuyk, R. F.; Hochstenbach, R.; van der Veen, F.; Goddijn, M.

    2008-01-01

    OBJECTIVE: To determine the mode of ascertainment of inherited unbalanced structural chromosome abnormalities detected at prenatal chromosome analysis. METHODS: From the databases of three centres for clinical genetics in the Netherlands, all cases of inherited unbalanced structural chromosome

  5. Inherited unbalanced structural chromosome abnormalities at prenatal chromosome analysis are rarely ascertained through recurrent miscarriage

    NARCIS (Netherlands)

    Franssen, M. T. M.; Korevaar, J. C.; Tjoa, W. M.; Leschot, N. J.; Bossuyt, P. M. M.; Knegt, A. C.; Suykerbuyk, R. F.; Hochstenbach, R.; van der Veen, F.; Goddijn, M.

    Objective To determine the mode of ascertainment of inherited unbalanced structural chromosome abnormalities detected at prenatal chromosome analysis. Methods From the databases of three centres for clinical genetics in the Netherlands, all cases of inherited unbalanced structural chromosome

  6. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

    Directory of Open Access Journals (Sweden)

    Yan Guo

    2016-08-01

    Full Text Available Observational epidemiological studies have shown that high body mass index (BMI is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC (cases  =  46,325, controls  =  42,482. We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10. The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8 and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8. This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7. Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs in association with breast cancer risk at p < 0.05; for 16 of them, the

  7. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

    Science.gov (United States)

    Guo, Yan; Warren Andersen, Shaneda; Shu, Xiao-Ou; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Garcia-Closas, Montserrat; Milne, Roger L.; Schmidt, Marjanka K.; Chang-Claude, Jenny; Dunning, Allison; Bojesen, Stig E.; Ahsan, Habibul; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bogdanova, Natalia V.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brand, Judith; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Casey, Graham; Chenevix-Trench, Georgia; Couch, Fergus J.; Cross, Simon S.; Czene, Kamila; Dörk, Thilo; Dumont, Martine; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gammon, Marilie; Giles, Graham G.; Guénel, Pascal; Haiman, Christopher A.; Hamann, Ute; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jasmine, Farzana; Jenkins, Mark; John, Esther M.; Johnson, Nichola; Jones, Michael E.; Kabisch, Maria; Knight, Julia A.; Koppert, Linetta B.; Kosma, Veli-Matti; Kristensen, Vessela; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lindblom, Annika; Lubinski, Jan; Malone, Kathi E.; Mannermaa, Arto; Margolin, Sara; McLean, Catriona; Meindl, Alfons; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olson, Janet E.; Perez, Jose I. A.; Perkins, Barbara; Phillips, Kelly-Anne; Pylkäs, Katri; Rudolph, Anja; Santella, Regina; Sawyer, Elinor J.; Schmutzler, Rita K.; Seynaeve, Caroline; Shah, Mitul; Shrubsole, Martha J.; Southey, Melissa C.; Swerdlow, Anthony J.; Toland, Amanda E.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Ursin, Giske; Van Der Luijt, Rob B.; Verhoef, Senno; Whittemore, Alice S.; Winqvist, Robert; Zhao, Hui; Zhao, Shilin; Hall, Per; Simard, Jacques; Kraft, Peter; Hunter, David; Easton, Douglas F.; Zheng, Wei

    2016-01-01

    Background Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31–0.62, p  =  9.91 × 10−8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46–0.71, p  =  1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60–0.84, p   =   1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p

  8. Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis.

    Science.gov (United States)

    Zhang, Ge; Bacelis, Jonas; Lengyel, Candice; Teramo, Kari; Hallman, Mikko; Helgeland, Øyvind; Johansson, Stefan; Myhre, Ronny; Sengpiel, Verena; Njølstad, Pål Rasmus; Jacobsson, Bo; Muglia, Louis

    2015-08-01

    Observational epidemiological studies indicate that maternal height is associated with gestational age at birth and fetal growth measures (i.e., shorter mothers deliver infants at earlier gestational ages with lower birth weight and birth length). Different mechanisms have been postulated to explain these associations. This study aimed to investigate the casual relationships behind the strong association of maternal height with fetal growth measures (i.e., birth length and birth weight) and gestational age by a Mendelian randomization approach. We conducted a Mendelian randomization analysis using phenotype and genome-wide single nucleotide polymorphism (SNP) data of 3,485 mother/infant pairs from birth cohorts collected from three Nordic countries (Finland, Denmark, and Norway). We constructed a genetic score based on 697 SNPs known to be associated with adult height to index maternal height. To avoid confounding due to genetic sharing between mother and infant, we inferred parental transmission of the height-associated SNPs and utilized the haplotype genetic score derived from nontransmitted alleles as a valid genetic instrument for maternal height. In observational analysis, maternal height was significantly associated with birth length (p = 6.31 × 10-9), birth weight (p = 2.19 × 10-15), and gestational age (p = 1.51 × 10-7). Our parental-specific haplotype score association analysis revealed that birth length and birth weight were significantly associated with the maternal transmitted haplotype score as well as the paternal transmitted haplotype score. Their association with the maternal nontransmitted haplotype score was far less significant, indicating a major fetal genetic influence on these fetal growth measures. In contrast, gestational age was significantly associated with the nontransmitted haplotype score (p = 0.0424) and demonstrated a significant (p = 0.0234) causal effect of every 1 cm increase in maternal height resulting in ~0.4 more gestational

  9. Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis.

    Directory of Open Access Journals (Sweden)

    Ge Zhang

    2015-08-01

    Full Text Available Observational epidemiological studies indicate that maternal height is associated with gestational age at birth and fetal growth measures (i.e., shorter mothers deliver infants at earlier gestational ages with lower birth weight and birth length. Different mechanisms have been postulated to explain these associations. This study aimed to investigate the casual relationships behind the strong association of maternal height with fetal growth measures (i.e., birth length and birth weight and gestational age by a Mendelian randomization approach.We conducted a Mendelian randomization analysis using phenotype and genome-wide single nucleotide polymorphism (SNP data of 3,485 mother/infant pairs from birth cohorts collected from three Nordic countries (Finland, Denmark, and Norway. We constructed a genetic score based on 697 SNPs known to be associated with adult height to index maternal height. To avoid confounding due to genetic sharing between mother and infant, we inferred parental transmission of the height-associated SNPs and utilized the haplotype genetic score derived from nontransmitted alleles as a valid genetic instrument for maternal height. In observational analysis, maternal height was significantly associated with birth length (p = 6.31 × 10-9, birth weight (p = 2.19 × 10-15, and gestational age (p = 1.51 × 10-7. Our parental-specific haplotype score association analysis revealed that birth length and birth weight were significantly associated with the maternal transmitted haplotype score as well as the paternal transmitted haplotype score. Their association with the maternal nontransmitted haplotype score was far less significant, indicating a major fetal genetic influence on these fetal growth measures. In contrast, gestational age was significantly associated with the nontransmitted haplotype score (p = 0.0424 and demonstrated a significant (p = 0.0234 causal effect of every 1 cm increase in maternal height resulting in ~0.4 more

  10. Congenital vocal cord paralysis with possible autosomal recessive inheritance: Case report and review of the literature

    Energy Technology Data Exchange (ETDEWEB)

    Koppel, R.; Friedman, S.; Fallet, S. [Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY (United States)

    1996-08-23

    We describe an infant with congenital vocal cord paralysis born to consanguineous parents. While autosomal dominant and X-linked inheritance have been previously reported in this condition, we conclude that the degree of parental consanguinity in this case strongly suggests autosomal recessive inheritance. Although we cannot exclude X-linked inheritance, evidence from animal studies demonstrates autosomal recessive inheritance and provides a possible molecular basis for congenital vocal cord paralysis. 14 refs., 1 fig.

  11. No actual conflict over colony inheritance despite high potential conflict in the social wasp Polistes dominulus

    OpenAIRE

    Monnin, Thibaud; Cini, Alessandro; Lecat, Vincent; Fédérici, Pierre; Doums, Claudie

    2009-01-01

    Social insect societies are outstanding examples of cooperation and conflict. Individuals work together, yet seek to increase their inclusive fitness at each others' expense. One such conflict is over colony inheritance, when a queen inherits the colony following the death of the previous queen. Colony inheritance is common in the social wasp Polistes dominulus, and it can have dramatic fitness consequences. The subordinate inheriting the colony is often unrelated to the initial foundress (al...

  12. Inheritance for software reuse: The good, the bad, and the ugly

    Science.gov (United States)

    Sitaraman, Murali; Eichmann, David A.

    1992-01-01

    Inheritance is a powerful mechanism supported by object-oriented programming languages to facilitate modifications and extensions of reusable software components. This paper presents a taxonomy of the various purposes for which an inheritance mechanism can be used. While some uses of inheritance significantly enhance software reuse, some others are not as useful and in fact, may even be detrimental to reuse. The paper discusses several examples, and argues for a programming language design that is selective in its support for inheritance.

  13. Big Missing Data: are scientific memes inherited differently from gendered authorship?

    OpenAIRE

    Araújo, Tanya; Fontainha, Elsa

    2017-01-01

    This paper seeks to build upon the previous literature on gender aspects in research collaboration and knowledge diffusion. Our approach adds the meme inheritance notion to traditional citation analysis, as we investigate if scientific memes are inherited differently from gendered authorship. Since authors of scientific papers inherit knowledge from their cited authors, once authorship is gendered we are able to characterize the inheritance process with respect to the frequencies of memes and...

  14. Role of T1 Mapping in Inherited Cardiomyopathies.

    Science.gov (United States)

    Swoboda, Peter P; McDiarmid, Adam K; Page, Stephen P; Greenwood, John P; Plein, Sven

    2016-01-01

    T1 mapping by cardiovascular magnetic resonance is a rapidly evolving method for the quantitative assessment of tissue characteristics in cardiac disease. The myocardial T1 time can be measured without contrast (native T1) or following the administration of intravenous gadolinium-based contrast agent (post-contrast T1). By combining both of these measures, the myocardial extracellular volume fraction can be approximated. This value has been validated histologically in various inherited cardiomyopathies. Due to overlapping phenotypes, the diagnosis of inherited cardiomyopathy can at times be challenging. In this article we discuss when T1 mapping may be a useful tool in the differential diagnosis of cardiomyopathy. We also present evidence of when T1 mapping provides incremental risk stratification over other biomarkers.

  15. Epigenetics and inheritance of phenotype variation in livestock.

    Science.gov (United States)

    Triantaphyllopoulos, Kostas A; Ikonomopoulos, Ioannis; Bannister, Andrew J

    2016-01-01

    Epigenetic inheritance plays a crucial role in many biological processes, such as gene expression in early embryo development, imprinting and the silencing of transposons. It has recently been established that epigenetic effects can be inherited from one generation to the next. Here, we review examples of epigenetic mechanisms governing animal phenotype and behaviour, and we discuss the importance of these findings in respect to animal studies, and livestock in general. Epigenetic parameters orchestrating transgenerational effects, as well as heritable disorders, and the often-overlooked areas of livestock immunity and stress, are also discussed. We highlight the importance of nutrition and how it is linked to epigenetic alteration. Finally, we describe how our understanding of epigenetics is underpinning the latest cancer research and how this can be translated into directed efforts to improve animal health and welfare.

  16. Tomato plant inheritance of antixenotic resistance to tomato leafminer

    Directory of Open Access Journals (Sweden)

    Adilson de Castro Antônio

    2011-01-01

    Full Text Available The objective of this work was to determine the inheritance of resistance by antixenosis in tomato plants (Lycopersicon esculentum to tomato leafminer [Tuta absoluta (Lepidoptera: Gelechiidae]. Evaluations were performed for tomato plants of the generations P1, P2, F1, F2, RC1 and RC2. The measured characteristic in the parents, BGH-1497 (P2 male and 'Santa Clara' (P1 female, and in the F1, F2, RC1 and RC2 generations was the number of eggs per plant. This number was converted to the oviposition nonpreference index. The inheritance of antixenosis resistance of genotype BGH-1497 is ruled by a gene of greater effect and polygenes in epistatic interactions, with a phenotypic proportion of 13:3 between susceptible and resistant genotypes, respectively.

  17. Genetic manipulation for inherited neurodegenerative diseases: myth or reality?

    Science.gov (United States)

    Yu-Wai-Man, Patrick

    2016-10-01

    Rare genetic diseases affect about 7% of the general population and over 7000 distinct clinical syndromes have been described with the majority being due to single gene defects. This review will provide a critical overview of genetic strategies that are being pioneered to halt or reverse disease progression in inherited neurodegenerative diseases. This field of research covers a vast area and only the most promising treatment paradigms will be discussed with a particular focus on inherited eye diseases, which have paved the way for innovative gene therapy paradigms, and mitochondrial diseases, which are currently generating a lot of debate centred on the bioethics of germline manipulation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  18. A thirty million year-old inherited heteroplasmy.

    Directory of Open Access Journals (Sweden)

    Vincent Doublet

    Full Text Available Due to essentially maternal inheritance and a bottleneck effect during early oogenesis, newly arising mitochondrial DNA (mtDNA mutations segregate rapidly in metazoan female germlines. Consequently, heteroplasmy (i.e. the mixture of mtDNA genotypes within an organism is generally resolved to homoplasmy within a few generations. Here, we report an exceptional transpecific heteroplasmy (predicting an alanine/valine alloacceptor tRNA change that has been stably inherited in oniscid crustaceans for at least thirty million years. Our results suggest that this heteroplasmy is stably transmitted across generations because it occurs within mitochondria and therefore escapes the mtDNA bottleneck that usually erases heteroplasmy. Consistently, at least two oniscid species possess an atypical trimeric mitochondrial genome, which provides an adequate substrate for the emergence of a constitutive intra-mitochondrial heteroplasmy. Persistence of a mitochondrial polymorphism on such a deep evolutionary timescale suggests that balancing selection may be shaping mitochondrial sequence evolution in oniscid crustaceans.

  19. Environmentally Induced Epigenetic Transgenerational Inheritance of Ovarian Disease

    Science.gov (United States)

    Nilsson, Eric; Larsen, Ginger; Manikkam, Mohan; Guerrero-Bosagna, Carlos; Savenkova, Marina I.; Skinner, Michael K.

    2012-01-01

    The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology. PMID:22570695

  20. Dynamic Inheritance and Static Analysis can be Reconciled

    DEFF Research Database (Denmark)

    Ernst, Erik

    1998-01-01

    In the area of object-orientation there is a long-standingschism between the rigid but safe statically typed languages, and theexpressive and exible but less safe \\typeless" languages. Many e ortshave aimed at combining the best of both. This paper presents a lan-guage mechanism which enhances...... the exibility and expressivity of staticlanguages while preserving the safety properties. It is an inheritancemechanism, with standard single inheritance as a special case. It al-lows both compile-time and run-time construction of new classes. More-over, it supports specialization of existing objects at run....... With dynamic inheritance, pre-methoding becomesmore expressive, supporting control structures as rst class values whichmay be constructed and combined dynamically. Even though the conceptof pre-methoding is missing from most other languages, the basic ideacould be applied to any statically typed object...

  1. Ten inherited disorders in purebred dogs by functional breed groupings

    OpenAIRE

    Oberbauer, A. M.; Belanger, J. M.; Bellumori, T.; BANNASCH, D. L.; Famula, T R

    2015-01-01

    Background Analysis of 88,635 dogs seen at the University of California, Davis Veterinary Medical Teaching Hospital from 1995 to 2010 identified ten inherited conditions having greater prevalence within the purebred dog population as compared to the mixed-breed dog population: aortic stenosis, atopy/allergic dermatitis, gastric dilatation volvulus (GDV), early onset cataracts, dilated cardiomyopathy, elbow dysplasia, epilepsy, hypothyroidism, intervertebral disk disease (IVDD), and hepatic po...

  2. Encoding Lexicalized Tree Adjoining Grammars with a Nonmonotonic Inheritance Hierarchy

    CERN Document Server

    Evans, R; Weir, D; Evans, Roger; Gazdar, Gerald; Weir, David

    1995-01-01

    This paper shows how DATR, a widely used formal language for lexical knowledge representation, can be used to define an LTAG lexicon as an inheritance hierarchy with internal lexical rules. A bottom-up featural encoding is used for LTAG trees and this allows lexical rules to be implemented as covariation constraints within feature structures. Such an approach eliminates the considerable redundancy otherwise associated with an LTAG lexicon.

  3. Inheritance of Arabica Coffee Resistance to Radopholus similisCobb.

    Directory of Open Access Journals (Sweden)

    Retno Hulupi

    2007-05-01

    Full Text Available A research to get inheritance of Arabica coffee resistance to Radopholus similisnematode was done in screen house and laboratory of Indonesian Coffee and Cocoa Research Institute, also at endemic area of coffee plantation, using F1, F1 R and F2 crossing between BP 542 A(resistant x Andungsari 1 (susceptible with their reciprocal, and BP 542 A x Kartika 1. The purpose of this study that was conducted at seedling stage is to formulate a Strategy for Arabica coffee breeding to get resistant varieties to nematode. As the variables of resistance were weight of seedling biomass, percent of root weight deviation, number of root nematodes, number of soil nematodes, reproduction and percent of necrotic root. Using discriminant analysis and fastclus, those data variables were analyzed for genetic of resistance with Statistical Analysis System programme version 8. Genetic study on the inheritance of resistance to R. similiswas started with evaluation of homozigosity of BP 542 A was resistant parent. The result showed that BP 542 A was heterozygous. Therefore, segregation test could not be suggested with segregation pattern principals as Mendel proposed. Segregation test on BP 542 A showed that it was heterozygote and the resistance was controlled by single gene with complete dominant effect, so the progeny segregated in 75% resistant and 25% susceptible. The result of the test showed the absence of maternal effect for root weight deviation and percentage of necrotic root variables, which meant that no cytoplasmic inheritance was involved. Based on the test of segregation ratio, almost all of the resistance was not appropriate for monogenic and or digenic segregation pattern as expected due to non allelic gene interaction that caused epistasis. Key words: Inheritance, resistance, Arabica coffee, Radopholus similis.

  4. Development of Cultural Management and Inheritance by Community Participation

    OpenAIRE

    Pichayapol Nguanthaisong; Souneth Phothisane; Sastra Laoakka

    2011-01-01

    Problem statement: Museums were places where all collections, which indicated values of arts and cultural heritages that were useful for learning, were kept. Establishment of museums was successful by having development, systematic management, cultural inheritance, knowledge transferring, participation and support. Approach: This study aimed to study backgrounds of museum development in temples in the area of the lower northeastern, to study current conditions and problems about museum manage...

  5. Heritability, combining ability and inheritance of storage root dry ...

    African Journals Online (AJOL)

    Significant (p<0.001) mean squares for general combining ability (GCA), and specific combining ability (SCA) were observed in F1 and F2 generations, demonstrating additive and non-additive genetic inheritance of RDM. High Baker's ratio in F1 (0.76) and F2 (0.78), and large σ2GCA/σ2SCA (3.13) indicate predominance ...

  6. Inheriting, marrying, and founding farms: women's place on the land.

    Science.gov (United States)

    Osterud, Grey

    2011-01-01

    This article considers rural women's place on the land in south-central New York during the first half of the twentieth century. Based on a community history and ethnographic study conducted during the 1980s, the article draws on women's oral narratives to explore the connections between women's sense of agency and their relationship to the land through descent and inheritance, marriage into a landowning family, founding a farm in partnership, and the experience of dispossession.

  7. Leber’s Inherited Optic Neuropathy: A Large Family

    Directory of Open Access Journals (Sweden)

    Taylan Pekoz

    2012-04-01

    Full Text Available Leber's hereditary optic neuropathy characterized by loss of central vision is often seen in men and a maternally inherited disease. Here, admitted to our clinic with complaints of unilateral visual loss was diagnosed as Leber's hereditary optic neuropathy which was confirmed by the presence of a mutation at 3460G>A position. [Cukurova Med J 2012; 37(2.000: 121-124

  8. Maintaining Epigenetic Inheritance During DNA Replication in Plants

    OpenAIRE

    Francisco M Iglesias; Cerdán, Pablo D.

    2016-01-01

    Biotic and abiotic stresses alter the pattern of gene expression in plants. Depending on the frequency and duration of stress events, the effects on the transcriptional state of genes are “remembered” temporally or transmitted to daughter cells and, in some instances, even to offspring (transgenerational epigenetic inheritance). This “memory” effect, which can be found even in the absence of the original stress, has an epigenetic basis, through molecular mechanisms that take place at the chro...

  9. Maintaining epigenetic inheritance during DNA replication in plants

    OpenAIRE

    Francisco eIglesias; Pablo eCerdan

    2016-01-01

    Biotic and abiotic stresses alter the pattern of gene expression in plants. Depending on the frequency and duration of stress events, the effects on the transcriptional state of genes are remembered temporally or transmitted to daughter cells and, in some instances, even to offspring (transgenerational epigenetic inheritance). This memory effect, which can be found even in the absence of the original stress, has an epigenetic basis, through molecular mechanisms that take place at the chromati...

  10. Clinical and inheritance profiles of Kallmann syndrome in Jordan

    Directory of Open Access Journals (Sweden)

    Shegem Nadima S

    2004-10-01

    Full Text Available Abstract Background Proper management of patients with Kallmann syndrome (KS allows them to attain a normal reproductive health. The purpose of this study is to demonstrate the presentation modalities, phenotypes and the modes of inheritance among 32 patients with Kallmann syndrome in Jordan. Recognition of the syndrome allows for prompt proper management and provision of genetic counselling. Subjects Over a period of five years (1999–2004, the clinical and inheritance profiles of 26 male and 6 female patients with Kallmann syndrome from 12 families were evaluated at the National Center for Diabetes, Endocrinology and Genetics in Jordan. Results The patients belonged to twelve Jordanian and Palestinian families and their age at presentation ranged from 4 – 46 years. Nine boys aged 4–14 years presented with cryptorchidism and microphallus, all other males presented with delayed puberty, hypogonadism and/or infertility. The main presentation among six female patients was primary amenorrhea. Intrafamilial variability in clinical phenotype was specifically evident for renal abnormalities and sensorineural hearing impairment. Familial KS was diagnosed in 27 patients belonging to five families with the X-linked mode of inheritance and two families with the autosomal recessive mode of inheritance. Conclusions (1 the majority of cases in this study represented the X-linked form of KS, which might point to a high prevalence of Kal 1 gene in the population. (2 Genetic counselling helps these families to reach a diagnosis at an early age and to decide about their reproductive options. (3 Children presenting with cryptorchidism and microphallus in our population should be investigated for KS.

  11. Immunoglobulin levels in chickens with inherited muscular distrophy.

    Science.gov (United States)

    Abplanalp, H; Benedict, A A

    1978-12-01

    Blood serum levels of 7S Ig appear to be a highly heritable (h(2)=0.76) trait. A possibly weak association of high 7S Ig with the phenotype of inherited muscular dystrophy is noted. In contrast to a previous study (Sanders and Kline 1977), our survey of 4 comparisons in paired lines showed dystrophics with slightly elevated 7S Ig levels and no differences in IgM levels when compared to controls.

  12. Genetic hearing impairment : a clinical study of various dominant inherited types

    NARCIS (Netherlands)

    Ensink, Robbert Jan Herman

    2000-01-01

    In this thesis a presentation is given of different patterns of inheritance, present in the cochlea or in the auditory chain of ossicles. Presentation and diagnosis of hereditary hearing loss is reviewed. A rare pattern of inheritance is the so called mitochondrial or maternal inheritance. In this

  13. Modern mathematics made simple

    CERN Document Server

    Murphy, Patrick

    1982-01-01

    Modern Mathematics: Made Simple presents topics in modern mathematics, from elementary mathematical logic and switching circuits to multibase arithmetic and finite systems. Sets and relations, vectors and matrices, tesselations, and linear programming are also discussed.Comprised of 12 chapters, this book begins with an introduction to sets and basic operations on sets, as well as solving problems with Venn diagrams. The discussion then turns to elementary mathematical logic, with emphasis on inductive and deductive reasoning; conjunctions and disjunctions; compound statements and conditional

  14. The simple complex numbers

    OpenAIRE

    Zalesny, Jaroslaw

    2008-01-01

    A new simple geometrical interpretation of complex numbers is presented. It differs from their usual interpretation as points in the complex plane. From the new point of view the complex numbers are rather operations on vectors than points. Moreover, in this approach the real, imaginary and complex numbers have similar interpretation. They are simply some operations on vectors. The presented interpretation is simpler, more natural, and better adjusted to possible applications in geometry and ...

  15. Information technology made simple

    CERN Document Server

    Carter, Roger

    1991-01-01

    Information Technology: Made Simple covers the full range of information technology topics, including more traditional subjects such as programming languages, data processing, and systems analysis. The book discusses information revolution, including topics about microchips, information processing operations, analog and digital systems, information processing system, and systems analysis. The text also describes computers, computer hardware, microprocessors, and microcomputers. The peripheral devices connected to the central processing unit; the main types of system software; application soft

  16. DNA methylation and epigenetic inheritance during plant gametogenesis.

    Science.gov (United States)

    Takeda, Shin; Paszkowski, Jerzy

    2006-02-01

    In plants, newly acquired epigenetic states of transcriptional gene activity are readily transmitted to the progeny. This is in contrast to mammals, where only rare cases of transgenerational inheritance of new epigenetic traits have been reported (FASEB J 12:949-957, 1998; Nat Genet 23:314-318, 1999; Proc Natl Acad Sci U S A 100:2538-2543, 2003). Epigenetic inheritance in plants seems to rely on cytosine methylation maintained through meiosis and postmeiotic mitoses, giving rise to gametophytes. In particular, maintenance of CpG methylation ((m)CpG) appears to play a central role, guiding the distribution of other epigenetic signals such as histone H3 methylation and non-CpG DNA methylation. The evolutionarily conserved DNA methyltransferase MET1 is responsible for copying (m)CpG patterns through DNA replication in the gametophytic phase. The importance of gametophytic MET1 activity is illustrated by the phenotypes of met1 mutants that are severely compromised in the accuracy of epigenetic inheritance during gametogenesis. This includes elimination of imprinting at paternally silent loci such as FWA or MEDEA (MEA). The importance of DNA methylation in gametophytic imprinting has been reinforced by the discovery of DEMETER (DME), encoding putative DNA glycosylase involved in the removal of (m)C. DME opposes transcriptional silencing associated with imprinting activities of the MEA/FIE polycomb group complex.

  17. Inherited and acquired alterations in development of breast cancer

    Directory of Open Access Journals (Sweden)

    Rizzolo P

    2011-11-01

    Full Text Available Piera Rizzolo, Valentina Silvestri, Mario Falchetti, Laura OttiniDepartment of Molecular Medicine, "La Sapienza" University of Rome, Rome, ItalyAbstract: Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In contrast, breast cancer is a rare disease in men, accounting for less than 1% of all cancers. Up to 10% of all breast cancers are hereditary forms, caused by inherited germ-line mutations in "high-penetrance," "moderate-penetrance," and "low-penetrance" breast cancer susceptibility genes. The remaining 90% of breast cancers are due to acquired somatic genetic and epigenetic alterations. A heterogeneous set of somatic alterations, including mutations and gene amplification, are reported to be involved in the etiology of breast cancer. Promoter hypermethylation of genes involved in DNA repair and hormone-mediated cell signaling, as well as altered expression of micro RNAs predicted to regulate key breast cancer genes, play an equally important role as genetic factors in development of breast cancer. Elucidation of the inherited and acquired genetic and epigenetic alterations involved in breast cancer may not only clarify molecular pathways involved in the development and progression of breast cancer itself, but may also have an important clinical and therapeutic impact on improving the management of patients with the disease.Keywords: breast cancer, inherited susceptibility, acquired alterations, epigenetics

  18. Inherited disorders of brain neurotransmitters: pathogenesis and diagnostic approach.

    Science.gov (United States)

    Szymańska, Krystyna; Kuśmierska, Katarzyna; Demkow, Urszula

    2015-01-01

    Neurotransmitters (NTs) play a central role in the efficient communication between neurons necessary for normal functioning of the nervous system. NTs can be divided into two groups: small molecule NTs and larger neuropeptide NTs. Inherited disorders of NTs result from a primary disturbance of NTs metabolism or transport. This group of disorders requires sophisticated diagnostic procedures. In this review we discuss disturbances in the metabolism of tetrahydrobiopterin, biogenic amines, γ-aminobutyric acid, foliate, pyridoxine-dependent enzymes, and also the glycine-dependent encephalopathy. We point to pathologic alterations of proteins involved in synaptic neurotransmission that may cause neurological and psychiatric symptoms. We postulate that synaptic receptors and transporter proteins for neurotransmitters should be investigated in unresolved cases. Patients with inherited neurotransmitters disorders present various clinical presentations such as mental retardation, refractory seizures, pyramidal and extrapyramidal syndromes, impaired locomotor patterns, and progressive encephalopathy. Every patient with suspected inherited neurotransmitter disorder should undergo a structured interview and a careful examination including neurological, biochemical, and imaging.

  19. Epigenetic transgenerational inheritance of somatic transcriptomes and epigenetic control regions.

    Science.gov (United States)

    Skinner, Michael K; Manikkam, Mohan; Haque, Md M; Zhang, Bin; Savenkova, Marina I

    2012-10-03

    Environmentally induced epigenetic transgenerational inheritance of adult onset disease involves a variety of phenotypic changes, suggesting a general alteration in genome activity. Investigation of different tissue transcriptomes in male and female F3 generation vinclozolin versus control lineage rats demonstrated all tissues examined had transgenerational transcriptomes. The microarrays from 11 different tissues were compared with a gene bionetwork analysis. Although each tissue transgenerational transcriptome was unique, common cellular pathways and processes were identified between the tissues. A cluster analysis identified gene modules with coordinated gene expression and each had unique gene networks regulating tissue-specific gene expression and function. A large number of statistically significant over-represented clusters of genes were identified in the genome for both males and females. These gene clusters ranged from 2-5 megabases in size, and a number of them corresponded to the epimutations previously identified in sperm that transmit the epigenetic transgenerational inheritance of disease phenotypes. Combined observations demonstrate that all tissues derived from the epigenetically altered germ line develop transgenerational transcriptomes unique to the tissue, but common epigenetic control regions in the genome may coordinately regulate these tissue-specific transcriptomes. This systems biology approach provides insight into the molecular mechanisms involved in the epigenetic transgenerational inheritance of a variety of adult onset disease phenotypes.

  20. Imperative part of the Law on Kosovo Inheritance (Comparative view

    Directory of Open Access Journals (Sweden)

    MSc. Shpresa Ibrahimi

    2013-12-01

    Full Text Available Making a testament seems to be one of the available freedoms, and most significant of the law subjects. Testament, as final declaration of the testator’s will, is considered to be one of the most significant freedoms of the same, since by declaring his will, determines the fate of his/her property heritage, earned with lots of efforts throughout life. Freedom of compiling the testament, in the Constitution of the Republic of Kosovo is guaranteed by the Law on Inheritance in Kosovo but also by the international Conventions. However, every subjective right has its limits.  Such limitation comes as a result of the care toward subjective rights of other persons, sometimes the best of the society, but the purpose of limiting such freedom in terms of inheritance, comes as result of common marital life, as a result of the care toward children and parents. Quota of the obligatory part is part of heritage that shall not be deprived, since it is guaranteed with imperative norms. This inheritance quota is presented as object for analyses and study in relation to testamentary freedom, always in a comparative view in the region and broader.

  1. Islamic Inheritance Law (Faraid and Its Economic Implication

    Directory of Open Access Journals (Sweden)

    Adelina Zuleika

    2014-03-01

    Full Text Available Objective - This paper attempts to discuss the Islamic law of inheritance (Faraid, its existence and its systematic impact to humankind. Faraid plays a fundamental role as an impetus behind the development of science, which has a great economic impact to the development of social welfare. This paper aims to increase the awareness towards the importance of Islamic law of Inheritance for knowledge development, and social prosperity of humankind. Secondly, to reveal the hikmah behind the rules set in Faraid and their economic implications. Thirdly is to emerge the consciousness for being Sharia’ compliance by revealing the secret behind His rules and its benefit for humankind.Method - Employing a qualitative method and literature reviewResult - This paper shows that from the macroeconomic perspective, Faraid systematically ensures the redistribution of wealth, and spreads the concentration of wealth in every generation. Literature reviews and information collected are employed in order to analyze and make further inferences. The literature review clarifies the magnificence of Faraid and its real contribution to human development; in economics and in other disciplines. Faraid keeps the justice in wealth distribution, protects property rights, empowers women to be involved in economic activities and as a whole, Faraid also encourages economic growth.Conclusion - Conclusively, by commissioning Faraid, the wealth is generated and returned to the factors production through many hands of who deserve it after the absence of deceased.Keywords : Islamic Inheritance Law; Faraid; Property  Rights; Distribution of Wealth

  2. Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis

    DEFF Research Database (Denmark)

    Taylor, Amy E; Martin, Richard M; Geybels, Milan S

    2017-01-01

    Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee...... consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic...... with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage...

  3. Plasma apolipoprotein E levels and risk of dementia-A Mendelian randomization study of 106,562 individuals

    DEFF Research Database (Denmark)

    Rasmussen, Katrine L; Tybjærg-Hansen, Anne; Nordestgaard, Børge G

    2017-01-01

    INTRODUCTION: In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established. METHODS: Using a Mendelian randomization approach, we studied 106,562 and 75,260 individuals...... from the general population in observational and genetic analyses, respectively. RESULTS: In observational analyses risk of Alzheimer disease and all dementia increased stepwise as a function of stepwise lower apoE levels (P for trend, 2 × 10(-17) and 9 × 10(-21)). APOE-weighted allele scores were...... associated with stepwise decreases in apoE (P for trend, genetically determined lower apoE were 1.41 (1.27-1.57) for Alzheimer disease and 1.33 (1.25-1.43) for all dementia (F-statistics = 3821). DISCUSSION: Genetic...

  4. Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomisation

    DEFF Research Database (Denmark)

    Danesh, J.; Hingorani, A.; Wensley, F.

    2008-01-01

    Many prospective studies have reported associations between circulating C-reactive protein (CRP) levels and risk of coronary heart disease (CHD), but causality remains uncertain. Studies of CHD are being conducted that involve measurement of common polymorphisms of the CRP gene known...... to be associated with circulating concentrations, thereby utilising these variants as proxies for circulating CRP levels. By analysing data from several studies examining the association between relevant CRP polymorphisms and CHD risk, the present collaboration will undertake a Mendelian randomisation analysis...... to help assess the likelihood of any causal relevance of CRP levels to CHD risk. A central database is being established containing individual data on CRP polymorphisms, circulating CRP levels, and major coronary outcomes as well as age, sex and other relevant characteristics. Associations between CRP...

  5. Moderate alcohol drinking in pregnancy increases risk for children's persistent conduct problems: causal effects in a Mendelian randomisation study.

    Science.gov (United States)

    Murray, Joseph; Burgess, Stephen; Zuccolo, Luisa; Hickman, Matthew; Gray, Ron; Lewis, Sarah J

    2016-05-01

    Heavy alcohol use during pregnancy can cause considerable developmental problems for children, but effects of light-moderate drinking are uncertain. This study examined possible effects of moderate drinking in pregnancy on children's conduct problems using a Mendelian randomisation design to improve causal inference. A prospective cohort study (ALSPAC) followed children from their mother's pregnancy to age 13 years. Analyses were based on 3,544 children whose mothers self-reported either not drinking alcohol during pregnancy or drinking up to six units per week without binge drinking. Children's conduct problem trajectories were classified as low risk, childhood-limited, adolescence-onset or early-onset-persistent, using six repeated measures of the Strengths and Difficulties Questionnaire between ages 4-13 years. Variants of alcohol-metabolising genes in children were used to create an instrumental variable for Mendelian randomisation analysis. Children's genotype scores were associated with early-onset-persistent conduct problems (OR = 1.29, 95% CI = 1.04-1.60, p = .020) if mothers drank moderately in pregnancy, but not if mothers abstained from drinking (OR = 0.94, CI = 0.72-1.25, p = .688). Children's genotype scores did not predict childhood-limited or adolescence-onset conduct problems. This quasi-experimental study suggests that moderate alcohol drinking in pregnancy contributes to increased risk for children's early-onset-persistent conduct problems, but not childhood-limited or adolescence-onset conduct problems. © 2015 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.

  6. Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration.

    Science.gov (United States)

    Burgess, Stephen; Davey Smith, George

    2017-08-01

    Undertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk. Two-sample Mendelian randomization investigation using published data. A total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium. We consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison. Diagnosis of AMD. We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD. Some genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk

  7. Investigating causal associations between use of nicotine, alcohol, caffeine, and cannabis: A two-sample bidirectional Mendelian randomization study.

    Science.gov (United States)

    Verweij, Karin J H; Treur, Jorien L; Vink, Jacqueline M

    2018-01-15

    Epidemiological studies consistently show co-occurrence of use of different addictive substances. Whether these associations are causal or due to overlapping underlying influences remains an important question in addiction research. Methodological advances have made it possible to use published genetic associations to infer causal relationships between phenotypes. In this exploratory study, we used Mendelian randomization (MR) to examine the causality of well-established associations between nicotine, alcohol, caffeine, and cannabis use. Two-sample MR was employed to estimate bi-directional causal effects between four addictive substances: nicotine (smoking initiation and cigarettes smoked per day), caffeine (cups of coffee per day), alcohol (units per week), and cannabis (initiation). Based on existing genome-wide association results we selected genetic variants associated with the exposure measure as an instrument to estimate causal effects. Where possible we applied sensitivity analyses (MR-Egger and weighted median) more robust to horizontal pleiotropy. Most MR tests did not reveal causal associations. There was some weak evidence for a causal positive effect of genetically instrumented alcohol use on smoking initiation and of cigarettes per day on caffeine use, but these did not hold up with the sensitivity analyses. There was also some suggestive evidence for a positive effect of alcohol use on caffeine use (only with MR-Egger) and smoking initiation on cannabis initiation (only with weighted median). None of the suggestive causal associations survived corrections for multiple testing. Two-sample Mendelian randomization analyses found little evidence for causal relationships between nicotine, alcohol, caffeine, and cannabis use. This article is protected by copyright. All rights reserved.

  8. No Causal Association between 25-Hydroxyvitamin D and Features of Skin Aging: Evidence from a Bidirectional Mendelian Randomization Study.

    Science.gov (United States)

    Noordam, Raymond; Hamer, Merel A; Pardo, Luba M; van der Nat, Tamara; Kiefte-de Jong, Jessica C; Kayser, Manfred; Slagboom, P Eline; Uitterlinden, André; Zillikens, M Carola; Beekman, Marian; Nijsten, Tamar; van Heemst, Diana; Gunn, David A

    2017-11-01

    Data from in vitro experiments suggest that vitamin D reduces the rate of skin aging, whereas population studies suggest the opposite, most likely due to confounding by UV exposure. We investigated whether there are causal associations between 25-hydroxyvitamin D concentrations and features of skin aging in a bidirectional Mendelian randomization study. In the Rotterdam Study (N = 3,831; 58.2% women, median age 66.5 years) and Leiden Longevity Study (N = 661; 50.5% women, median age 63.1 years), facial skin aging features (perceived age, wrinkling, pigmented spots) were assessed either manually or digitally. Associations between 25-hydroxyvitamin D and skin aging features were tested by multivariable linear regression. Mendelian randomization analyses were performed using single nucleotide polymorphisms identified from previous genome-wide association studies. After meta-analysis of the two cohorts, we observed that higher serum 25-hydroxyvitamin D was associated with a higher perceived age (P-value = 3.6 × 10-7), more skin wrinkling (P-value = 2.6 × 10-16), but not with more pigmented spots (P-value = 0.30). In contrast, a genetically determined 25-hydroxyvitamin D concentration was not associated with any skin aging feature (P-values > 0.05). Furthermore, a genetically determined higher degree of pigmented spots was not associated with higher 25-hydroxyvitamin D (P-values > 0.05). Our study did not indicate that associations between 25-hydroxyvitamin D and features of skin aging are causal. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population.

    Science.gov (United States)

    Liu, Yan-Ping; Gu, Yu-Mei; Thijs, Lutgarde; Knapen, Marjo H J; Salvi, Erika; Citterio, Lorena; Petit, Thibault; Carpini, Simona Delli; Zhang, Zhenyu; Jacobs, Lotte; Jin, Yu; Barlassina, Cristina; Manunta, Paolo; Kuznetsova, Tatiana; Verhamme, Peter; Struijker-Boudier, Harry A; Cusi, Daniele; Vermeer, Cees; Staessen, Jan A

    2015-02-01

    Matrix Gla-protein is a vitamin K-dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP). The risk associated with dp-ucMGP in the population is unknown. In a Flemish population study, we measured circulating dp-ucMGP at baseline (1996-2011), genotyped MGP, recorded adverse health outcomes until December 31, 2012, and assessed the multivariable-adjusted associations of adverse health outcomes with dp-ucMGP. We applied a Mendelian randomization analysis using MGP genotypes as instrumental variables. Among 2318 participants, baseline dp-ucMGP averaged 3.61 μg/L. Over 14.1 years (median), 197 deaths occurred, 58 from cancer and 70 from cardiovascular disease; 85 participants experienced a coronary event. The risk of death and non-cancer mortality curvilinearly increased (P≤0.008) by 15.0% (95% confidence interval, 6.9-25.3) and by 21.5% (11.1-32.9) for a doubling of the nadir (1.43 and 0.97 μg/L, respectively). With higher dp-ucMGP, cardiovascular mortality log-linearly increased (hazard ratio for dp-ucMGP doubling, 1.14 [1.01-1.28]; P=0.027), but coronary events log-linearly decreased (0.93 [0.88-0.99]; P=0.021). dp-ucMGP levels were associated (P≤0.001) with MGP variants rs2098435, rs4236, and rs2430692. For non-cancer mortality and coronary events (P≤0.022), but not for total and cardiovascular mortality (P≥0.13), the Mendelian randomization analysis suggested causality. Higher dp-ucMGP predicts total, non-cancer and cardiovascular mortality, but lower coronary risk. For non-cancer mortality and coronary events, these associations are likely causal. © 2014 American Heart Association, Inc.

  10. Studying Simple and Complex Traits Using Pedigrees Produced From a Large Database

    Directory of Open Access Journals (Sweden)

    Cheryld L. Emmons

    2010-11-01

    Full Text Available Students in genetics classes become familiar with interpreting pedigrees for modes of inheritance of single-gene traits. Non-majors’ genetics courses often have students produce pedigrees of their own families. This exercise provides students with an extensive database, including over 50 families, from which they are asked to produce pedigrees as evidence in support of or refuting suggested models of inheritance for simple traits. Students are also asked to propose modes of inheritance for complex human traits based on pedigrees that they produce from the database. The people in the database are real and include their own families. This makes the exercise more real and personal for the students.

  11. The Non-Mendelian Green Cotyledon Gene in Soybean Encodes a Small Subunit of Photosystem II.

    Science.gov (United States)

    Kohzuma, Kaori; Sato, Yutaka; Ito, Hisashi; Okuzaki, Ayako; Watanabe, Mai; Kobayashi, Hideki; Nakano, Michiharu; Yamatani, Hiroshi; Masuda, Yu; Nagashima, Yumi; Fukuoka, Hiroyuki; Yamada, Tetsuya; Kanazawa, Akira; Kitamura, Keisuke; Tabei, Yutaka; Ikeuchi, Masahiko; Sakamoto, Wataru; Tanaka, Ayumi; Kusaba, Makoto

    2017-04-01

    Chlorophyll degradation plays important roles in leaf senescence including regulation of degradation of chlorophyll-binding proteins. Although most genes encoding enzymes of the chlorophyll degradation pathway have been identified, the regulation of their activity has not been fully understood. Green cotyledon mutants in legume are stay-green mutants, in which chlorophyll degradation is impaired during leaf senescence and seed maturation. Among them, the soybean (Glycine max) green cotyledon gene cytG is unique because it is maternally inherited. To isolate cytG, we extensively sequenced the soybean chloroplast genome, and detected a 5-bp insertion causing a frame-shift in psbM, which encodes one of the small subunits of photosystem II. Mutant tobacco plants (Nicotiana tabacum) with a disrupted psbM generated using a chloroplast transformation technique had green senescent leaves, confirming that cytG encodes PsbM. The phenotype of cytG was very similar to that of mutant of chlorophyll b reductase catalyzing the first step of chlorophyll b degradation. In fact, chlorophyll b-degrading activity in dark-grown cytG and psbM-knockout seedlings was significantly lower than that of wild-type plants. Our results suggest that PsbM is a unique protein linking photosynthesis in presenescent leaves with chlorophyll degradation during leaf senescence and seed maturation. Additionally, we discuss the origin of cytG, which may have been selected during domestication of soybean. © 2017 American Society of Plant Biologists. All Rights Reserved.

  12. Simple chain grammars and languages

    NARCIS (Netherlands)

    Nijholt, Antinus

    1979-01-01

    A subclass of the LR(0)-grammars, the class of simple chain grammars is introduced. Although there exist simple chain grammars which are not LL(k) for any k>0, this new class of grammars is very closely related to the LL(1) and simple LL(1) grammars. In fact it can be shown that every simple chain

  13. Data processing made simple

    CERN Document Server

    Wooldridge, Susan

    2013-01-01

    Data Processing: Made Simple, Second Edition presents discussions of a number of trends and developments in the world of commercial data processing. The book covers the rapid growth of micro- and mini-computers for both home and office use; word processing and the 'automated office'; the advent of distributed data processing; and the continued growth of database-oriented systems. The text also discusses modern digital computers; fundamental computer concepts; information and data processing requirements of commercial organizations; and the historical perspective of the computer industry. The

  14. Applied mathematics made simple

    CERN Document Server

    Murphy, Patrick

    1982-01-01

    Applied Mathematics: Made Simple provides an elementary study of the three main branches of classical applied mathematics: statics, hydrostatics, and dynamics. The book begins with discussion of the concepts of mechanics, parallel forces and rigid bodies, kinematics, motion with uniform acceleration in a straight line, and Newton's law of motion. Separate chapters cover vector algebra and coplanar motion, relative motion, projectiles, friction, and rigid bodies in equilibrium under the action of coplanar forces. The final chapters deal with machines and hydrostatics. The standard and conte

  15. Theory of simple liquids

    CERN Document Server

    Hansen, Jean-Pierre

    1986-01-01

    This book gives a comprehensive and up-to-date treatment of the theory of ""simple"" liquids. The new second edition has been rearranged and considerably expanded to give a balanced account both of basic theory and of the advances of the past decade. It presents the main ideas of modern liquid state theory in a way that is both pedagogical and self-contained. The book should be accessible to graduate students and research workers, both experimentalists and theorists, who have a good background in elementary mechanics.Key Features* Compares theoretical deductions with experimental r

  16. Beyond Simple Headquarters Configurations

    DEFF Research Database (Denmark)

    Dellestrand, Henrik; Kappen, Philip; Nell, Phillip Christopher

    .e., an innovation that is important for the firm beyond the divisional boundaries, drives dual headquarters involvement in innovation development. Contrary to expectations, on average, a non-significant effect of cross-divisional embeddedness on dual headquarters involvement is found. Yet, both cross......-divisional importance and embeddedness effects are contingent on the overall complexity of the innovation project as signified by the size of the development network. The results lend support for the notion that parenting in complex structures entails complex headquarters structures and that we need to go beyond simple...

  17. Simple Driving Techniques

    DEFF Research Database (Denmark)

    Rosendahl, Mads

    2002-01-01

    Driving was introduced as a program transformation technique by Valentin Turchin in some papers around 1980. It was intended for the programming language REFAL and used in metasystem transitions based on super compilation. In this paper we present one version of driving for a more conventional lisp......-like language. Our aim is to extract a simple notion of driving and show that even in this tamed form it has much of the power of more general notions of driving. Our driving technique may be used to simplify functional programs which use function composition and will often be able to remove intermediate data...

  18. ASP made simple

    CERN Document Server

    Deane, Sharon

    2003-01-01

    ASP Made Simple provides a brief introduction to ASP for the person who favours self teaching and/or does not have expensive computing facilities to learn on. The book will demonstrate how the principles of ASP can be learned with an ordinary PC running Personal Web Server, MS Access and a general text editor like Notepad.After working through the material readers should be able to:* Write ASP scripts that can display changing information on a web browser* Request records from a remote database or add records to it* Check user names & passwords and take this knowledge forward, either for their

  19. Inheritance of Resistance to Sorghum Shoot Fly, Atherigona soccata in Sorghum, Sorghum bicolor (L. Moench

    Directory of Open Access Journals (Sweden)

    Mohammed eRiyazaddin

    2016-04-01

    glossy score and plant vigor score with high σ2g, additive variance, predictability ratio, and GCA/SCA showed predominance of additive type of gene action indicating importance of heterosis breeding followed by simple selection in breeding shoot fly-resistant sorghums. Most of the traits exhibited high broadsense heritability, indicating high inheritance of shoot fly resistance traits.

  20. The magmatic budget of Atlantic type rifted margins: is it related to inheritance?

    Science.gov (United States)

    Manatschal, Gianreto; Tugend, Julia; Picazo, Suzanne; Müntener, Othmar

    2016-04-01

    In the past, Atlantic type rifted margins were either classified as volcanic or non-volcanic. An increasing number of high quality reflection and refraction seismic surveys and drill hole data show a divergent style of margin architecture and an evolution in which the quantity and distribution of syn-rift magmatism is variable, independently of the amount of extension. Overgeneralized classifications and models assuming simple relations between magmatic and extensional systems are thus inappropriate to describe the formation of rifted margins. More recent studies show that the magmatic evolution of rifted margins is complex and cannot be characterized based on the volume of observed magma alone. On the one hand, so-called "non-volcanic" margins are not necessarily amagmatic, as shown by the results of ODP drilling along the Iberia-Newfoundland rifted margins. On the other hand, magma-rich margins, such as the Norwegian, NW Australian or the Namibia rifted margins show evidence for hyper-extension prior to breakup. These observations suggest that the magmatic budget does not only depend on extension rates but also on the composition and temperature of the decompressing mantle. Moreover, the fact that the magmatic budget may change very abruptly along strike and across the margin is difficult to reconcile with the occurrence of plumes or other deep-seated large-scale mantle phenomena only. These overall observations result in questions on how magmatic and tectonic processes are interacting during rifting and lithospheric breakup and on how far inheritance may control the magmatic budget during rifting. In our presentation we will review results from the South and North Atlantic and the Alpine Tethys domain and will discuss the structural and magmatic evolution of so-called magma-rich and magma-poor rifted margins. In particular, we will try to define when, where and how much magma forms during rifting and lithospheric breakup. The key questions that we aim to address