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Search Results: 1 - 10 of 407476 matches for " Benjamin M Neale "
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The IMAGE project: methodological issues for the molecular genetic analysis of ADHD
Jonna Kuntsi, Benjamin M Neale, Wai Chen, Stephen V Faraone, Philip Asherson
Behavioral and Brain Functions , 2006, DOI: 10.1186/1744-9081-2-27
Abstract: With the identification of genes associated with ADHD, the goal of ADHD genetics is now shifting from gene discovery towards gene functionality – the study of intermediate phenotypes ('endophenotypes'). We discuss methodological issues relating to quantitative genetic data from twin and family studies on candidate endophenotypes and how such data can inform attempts to link molecular genetic data to cognitive, affective and motivational processes in ADHD.The International Multi-centre ADHD Gene (IMAGE) project exemplifies current collaborative research efforts on the genetics of ADHD. This European multi-site project is well placed to take advantage of the resources that are emerging following the sequencing of the human genome and the development of international resources for whole genome association analysis. As a result of IMAGE and other molecular genetic investigations of ADHD, we envisage a rapid increase in the number of identified genetic variants and the promise of identifying novel gene systems that we are not currently investigating, opening further doors in the study of gene functionality.Research into the etiology of attention deficit hyperactivity disorder (ADHD) exemplifies the way that inter-disciplinary research fosters collaboration and opens up new avenues of investigation. International research has established that there is a strong genetically inherited contribution to ADHD and the genetic mechanisms involved are being sorted with considerable success by several centres worldwide. Recent review and meta-analyses of available data demonstrate an emerging set of findings that confirm prior hypotheses about the role of genetic variation within genes involved in the regulation of catecholamine neurotransmitters in susceptibility to ADHD [1,2]. Despite the importance of these findings, uncertainties remain due to the very small effect sizes that are observed, with average odds ratios in the range of 1.1 to 1.5. Under simple additive multi-gene mode
Cross-phenotype meta-analysis reveals large-scale trans-eQTLs mediating patterns of transcriptional co-regulation
Boel Brynedal,Towfique Raj,Barbara E Stranger,Robert Bjornson,Benjamin M Neale,Benjamin F Voight,Chris Cotsapas
Quantitative Biology , 2014,
Abstract: Genetic variation affecting gene regulation is a central driver of phenotypic differences between individuals and can be used to uncover how biological processes are organized in a cell. Although detecting cis-eQTLs is now routine, trans-eQTLs have proven more challenging to find due to the modest variance explained and the multiple tests burden of testing millions of SNPs for association to thousands of transcripts. Here, we successfully map trans-eQTLs with the complementary approach of looking for SNPs associated to the expression of multiple genes simultaneously. We find 732 trans- eQTLs that replicate across two continental populations; each trans-eQTL controls large groups of target transcripts (regulons), which are part of interacting networks controlled by transcription factors. We are thus able to uncover co-regulated gene sets and begin describing the cell circuitry of gene regulation.
The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis
M. Neale Weitzmann
Scientifica , 2013, DOI: 10.1155/2013/125705
Abstract:
The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis
M. Neale Weitzmann
Scientifica , 2013, DOI: 10.1155/2013/125705
Abstract: Although it has long been recognized that inflammation, a consequence of immune-driven processes, significantly impacts bone turnover, the degree of centralization of skeletal and immune functions has begun to be dissected only recently. It is now recognized that formation of osteoclasts, the bone resorbing cells of the body, is centered on the key osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL). Although numerous inflammatory cytokines are now recognized to promote osteoclast formation and skeletal degradation, with just a few exceptions, RANKL is now considered to be the final downstream effector cytokine that drives osteoclastogenesis and regulates osteoclastic bone resorption. The biological activity of RANKL is moderated by its physiological decoy receptor, osteoprotegerin (OPG). New discoveries concerning the sources and regulation of RANKL and OPG in physiological bone turnover as well as under pathological (osteoporotic) conditions continue to be made, opening a window to the complex regulatory processes that control skeletal integrity and the depth of integration of the skeleton within the immune response. This paper will examine the interconnection between bone turnover and the immune system and the implications thereof for physiological and pathological bone turnover. 1. Introduction Mineralized bone consists of a protein matrix comprising predominantly, but not exclusively, collagen type I fibers that are layered down in oriented linear bundles. This protein matrix scaffold is coated with a layer of mineral, predominantly calcium phosphate in the form of crystals of hydroxyapatite [1]. The skeleton forms in early life, mainly through endochondral ossification in which bone is initially patterned in mineralized cartilage followed by replacement of the cartilage template by mineralized bone. Some skeletal components including certain bones of the skull such as the calvaria are formed without a cartilage intermediate through direct matrix and mineralization deposition, a process referred to as intramembranous ossification [2]. The skeleton achieves its final shape and ultimate form through bone modeling, a process involving the coordinated activity of bone synthesizing osteoblasts and bone resorbing osteoclasts. This process of selective bone deposition and removal sculpts the skeleton to achieve final shape and optimal load bearing capacity [3, 4]. Bone modeling continues until early adulthood in humans at which time peak bone mineral density (BMD) and bone size are achieved. Thereafter, the skeleton undergoes a process
Testing for an Unusual Distribution of Rare Variants
Benjamin M. Neale equal contributor ,Manuel A. Rivas equal contributor,Benjamin F. Voight,David Altshuler,Bernie Devlin,Marju Orho-Melander,Sekar Kathiresan,Shaun M. Purcell,Kathryn Roeder ? ,Mark J. Daly ?
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001322
Abstract: Technological advances make it possible to use high-throughput sequencing as a primary discovery tool of medical genetics, specifically for assaying rare variation. Still this approach faces the analytic challenge that the influence of very rare variants can only be evaluated effectively as a group. A further complication is that any given rare variant could have no effect, could increase risk, or could be protective. We propose here the C-alpha test statistic as a novel approach for testing for the presence of this mixture of effects across a set of rare variants. Unlike existing burden tests, C-alpha, by testing the variance rather than the mean, maintains consistent power when the target set contains both risk and protective variants. Through simulations and analysis of case/control data, we demonstrate good power relative to existing methods that assess the burden of rare variants in individuals.
Pervasive Sharing of Genetic Effects in Autoimmune Disease
Chris Cotsapas equal contributor,Benjamin F. Voight equal contributor,Elizabeth Rossin,Kasper Lage,Benjamin M. Neale,Chris Wallace,Gon?alo R. Abecasis,Jeffrey C. Barrett,Timothy Behrens,Judy Cho,Philip L. De Jager,James T. Elder,Robert R. Graham,Peter Gregersen,Lars Klareskog,Katherine A. Siminovitch,David A. van Heel,Cisca Wijmenga,Jane Worthington,John A. Todd,David A. Hafler,Stephen S. Rich,Mark J. Daly ,on behalf of the FOCiS Network of Consortia
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002254
Abstract: Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases—as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple—but not all—immune-mediated diseases (SNP-wise PCPMA<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.
Online Biodiversity Resources - Principles for Usability
Sophie Neale,M. R. Pull,M. F. Watson
Biodiversity Informatics , 2007,
Abstract: Online biodiversity portals and databases enabling access to large volumes of biological information represent a potentially extensive set of resources for a variety of user groups. However, in order for these resources to live up to their promise they need to be both useful and easy to use. We discuss a number of principles for designing systems for usability, examine how these have been applied to the development of online biodiversity resources and compare this with a portal project developed by the Astrophysics community. We highlight a lack of user involvement and formalised requirements analysis by biodiversity projects resulting in a poor understanding of both the users and their tasks. We suggest a change in the way large biodiversity portal projects are structured, that is by providing infrastructure and supporting user groups developing individual interfaces.
Cloning and Sequencing of Protein Kinase cDNA from Harbor Seal (Phoca vitulina) Lymphocytes
Jennifer C. C. Neale,Thomas P. Kenny,M. Eric Gershwin
Clinical and Developmental Immunology , 2004, DOI: 10.1080/10446670410001722195
Abstract: Protein kinases (PKs) play critical roles in signal transduction and activation of lymphocytes. The identification of PK genes provides a tool for understanding mechanisms of immunotoxic xenobiotics. As part of a larger study investigating persistent organic pollutants in the harbor seal and their possible immunomodulatory actions, we sequenced harbor seal cDNA fragments encoding PKs. The procedure, using degenerate primers based on conserved motifs of human protein tyrosine kinases (PTKs), successfully amplified nine phocid PK gene fragments with high homology to human and rodent orthologs. We identified eight PTKs and one dual (serine/threonine and tyrosine) kinase. Among these were several PKs important in early signaling events through the B- and T-cell receptors (FYN, LYN, ITK and SYK) and a MAP kinase involved in downstream signal transduction. V-FGR, RET and DDR2 were also expressed. Sequential activation of protein kinases ultimately induces gene transcription leading to the proliferation and differentiation of lymphocytes critical to adaptive immunity. PKs are potential targets of bioactive xenobiotics, including persistent organic pollutants of the marine environment; characterization of these molecules in the harbor seal provides a foundation for further research illuminating mechanisms of action of contaminants speculated to contribute to large-scale die-offs of marine mammals via immunosuppression.
Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae
Jennifer K. Lowe,Julian B. Maller,Itsik Pe'er,Benjamin M. Neale,Jacqueline Salit,Eimear E. Kenny,Jessica L. Shea,Ralph Burkhardt,J. Gustav Smith,Weizhen Ji,Martha Noel,Jia Nee Foo,Maude L. Blundell,Vita Skilling,Laura Garcia,Marcia L. Sullivan,Heather E. Lee,Anna Labek,Hope Ferdowsian,Steven B. Auerbach,Richard P. Lifton,Christopher Newton-Cheh,Jan L. Breslow,Markus Stoffel,Mark J. Daly,David M. Altshuler ,Jeffrey M. Friedman
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000365
Abstract: It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.
Job Satisfaction of Employees Undergoing Public Sector Reform in Fiji  [PDF]
Gurmeet Singh, Neale J. Slack
Theoretical Economics Letters (TEL) , 2016, DOI: 10.4236/tel.2016.62035
Abstract: This study analyses job satisfaction in the Maritime Safety Authority of Fiji (MSAF), a public sector entity undergoing reform. Results of this study determine that the level of MSAF employee job satisfaction by dimension was predominantly low; employees had a low level of intrinsic satisfaction, an average level of extrinsic satisfaction, and a low level of general satisfaction; and employees’ level of job satisfaction was significantly lower than the reference group. This research makes its theoretical contribution primarily to the literature on public service job satisfaction, and to the scarce theoretical strands relating to public service safety organisations. A practical outcome of this research is its contribution towards ongoing public sector reforms in Fiji in general and MSAF and the maritime industry in particular.
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