DOCSLIB.ORG

1 Uganda Genome Resource Enables Insights

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1 Uganda Genome Resource Enables Insights Uganda Genome Resource enables insights into population history and genomic discovery in Africa Gurdasani D.*1, Carstensen T.2* , Fatumo S.* 3,4,5, Chen G.*6, Franklin CS.*2, Prado-Martinez J.* 2, Bouman H.* 2, Abascal F. 2 , Haber M. 2, Tachmazidou I. 2, Mathieson I.7, Ekoru K.8, DeGorter MK. 9, Nsubuga RN.8, Finan C. 2, Wheeler E. 2, Chen L.2, Cooper DN.10, Schiffels S.11, Chen Y. 2, Ritchie GRS.2, Pollard MO. 2, Fortune MD. 2, Mentzer AJ.12, Garrison E. 2, Bergström A.2, Hatzikotoulas K.2, Adebowale A. 6, Doumatey A. 4, Elding H. 2, Wain LV.13,14, Ehret G.15,16, Auer PL.17, Kooperberg CL.18 , Reiner AP.19,20, Franceschini N.21, Maher DP.6, Montgomery SB.7,22, Kadie C.23, Widmer C.24, Xue Y.2, Seeley J. 6,3 , Asiki G. 8 , Kamali A. 8, Young EH. 25,2, Pomilla C. 25, Soranzo N. 2,26,27, Zeggini E. 28, Pirie F.29, Morris AP.30,12, Heckerman D.24, Tyler-Smith C2‡, Motala A.29‡ , Rotimi C6‡, Kaleebu P. ‡3,4,8, Barroso I.‡31,2, Sandhu MS.23 ‡ *these authors contributed equally ‡ these authors contributed equally Lead Contact: Manjinder Sandhu [email protected] 1 William Harvey Research Institute, Queen Mary’s University of London, London, UK 2 Wellcome Sanger Institute, Hinxton, Cambridge, UK 3 London School of Hygiene and Tropical Medicine, London, UK 4 Uganda Medical Informatics Centre (UMIC), MRC/UVRI and LSHTM (Uganda Research Unit), Entebbe-Uganda 5 H3Africa Bioinformatics Network (H3ABioNet) Node, Center for Genomics Research and Innovation (CGRI)/ National Biotechnology Development Agency CGRI/NABDA, Abuja, Nigeria 6 Center for Research on Genomics and Global Health, National Institute of Health, USA 7 Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA 8 Medical Research Council/Uganda Virus Research Institute (MRC/UVRI) Uganda Research Unit on AIDS, Uganda 9 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA 10 Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK 11 Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena, Germany 12 The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK 13 Department of Health Sciences, University of Leicester, Leicester, UK 14 National Institute for Health Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK 15 McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD, USA 16 Geneva University Hospitals, Rue Gabrielle-Perret-Gentil,41211 Genève 14, Switzerland 17 Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee WI, USA 18 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle WA, USA 19 Department of Epidemiology, University of Washington, Seattle WA, USA 20 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle WA, USA 21 Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA 22 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA 23 Microsoft Research, Redmond, CA, USA 24 Microsoft Research, Los Angeles, CA, USA 25 Department of Medicine, University of Cambridge, Cambridge, UK 26 Department of Haematology, University of Cambridge, Cambridge, UK 27 The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, UK 28 Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany 29 Department of Diabetes and Endocrinology, University of KwaZulu-Natal, Durban, South Africa 30 Department of Biostatistics, University of Liverpool, Liverpool, UK 31 MRC Epidemiology Unit, University of Cambridge, Cambridge, UK 1 Corresponding authors: Manjinder Sandhu [email protected] Inês Barroso [email protected] Charles Rotimi [email protected] Ayesha Motala [email protected] Chris Tyler-Smith [email protected] Pontiano Kaleebu [email protected] 2 Abstract Genomic studies in African populations provide unique opportunities to understand disease aetiology, human diversity and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals, and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically-correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans is best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, haematological, lipid and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region. Introduction Africa is central to our understanding of human origins, genetic diversity and disease susceptibility.(Tishkoff et al., 2009) The marked genomic diversity and allelic differentiation among populations in Africa, in combination with the substantially lower linkage disequilibrium (correlation) among genetic variants, has the potential to provide new opportunities to understand disease aetiology relevant to African populations but also globally.(Tishkoff et al., 2009, Gurdasani D., 2014) Consequently, there is a clear scientific and public health need to develop large-scale efforts that examine disease susceptibility across diverse populations within the African continent. Such efforts will need to be fully integrated with research-capacity-building initiatives across the region.(Consortium, 2014) Countries in Africa are undergoing epidemiological transitions—with a high burden of endemic infectious disease and growing prevalence of non-communicable diseases.(Organisation, 2015) Importantly, because of varying environments, population history, and adaptive evolution, the distribution of risk factors for a broad range of cardiometabolic and infectious diseases, and their individual contributions, may differ among populations globally.(Campbell and Tishkoff, 2010) Differences in allele frequencies among populations, due to either selection or genetic drift provide unique opportunities to identify novel disease susceptibility loci; highlighting the value of conducting such studies in African populations. However, while there has been a recent increase in genetic studies of cardiometabolic traits including African-Americans,(Peprah et al., 2015, Lanktree et al., 2015) there have been relatively few investigations of population diversity or the genetic determinants of cardiometabolic or infectious traits and diseases across the continent. To conduct genetic studies in diverse populations across Africa, appropriate study designs that account for population structure, admixture and genetic relatedness (overt and cryptic), as well as the development of genetic tools to capture variation in African genomes, are needed.(Gurdasani D., 2014) To leverage the relative benefits of different strategies, we undertook a combined approach of genotyping and low coverage whole-genome sequencing (WGS) in a population-based study of 6,400 individuals from a geographically defined rural community in South-West Uganda (Figure 1a, STAR Methods, Figure 1, Figure S1 and Table S1). We present data from 4,778 individuals with genotypes for ~2.2 million SNPs from the Uganda genome-wide association study (UGWAS) resource (STAR 3 Methods), and sequence data (STAR Methods, Table S1.1) on up to 1,978 individuals including 41.5M SNPs and 4.5M indels (UG2G) (Figure S1, Table S1.1, and STAR Methods). Collectively, these data represent the Uganda Genome Resource (UGR). To enhance trait-associated locus discovery, we also include collective data on up to 14,126 individuals from across the African continent for genome wide association analysis (STAR Methods). Using these resources, we conducted a series of analyses to: 1) understand the population structure, admixture and demographic history in a geographically-defined population from Uganda (STAR Methods); 2) describe the spectrum of disease-causing mutations in the UG2G cohort (STAR Methods); and 3) highlight the value of the UG2G sequence panel as an imputation resource (STAR Methods). 4) refine estimates of heritability of 34 complex traits, accounting for environmental correlation among individuals (STAR Methods); and 5) assess the spectrum of genetic variants associated with cardiometabolic and other complex traits in populations from sub-Saharan Africa (STAR Methods). Importantly, the UGR was designed to help develop local resources for public health and genomic research, including building research capacity, training and collaboration across the region. We envisage that data from these studies will provide a global resource for researchers, as well as facilitate genetic studies in African populations. Results A history of Ugandan ethnic diversity Uganda has a diverse and complex history of extensive historical migration from surrounding regions over several hundred years. Migration has included economic migration for labour, as well as migration due to conflict in surrounding regions. Uganda is home to several
Load more

Recommended publications
  • A New Genetic Method for Isolating Functionally Interacting Genes
    Copyright 2000 by the Genetics Society of America A New Genetic Method for Isolating Functionally Interacting Genes: High plo1؉-Dependent Mutants and Their Suppressors De®ne Genes in Mitotic and Septation Pathways in Fission Yeast C. Fiona Cullen,*,² Karen M. May,* Iain M. Hagan,³ David M. Glover²,§ and Hiroyuki Ohkura*,² *Institute of Cell and Molecular Biology, The University of Edinburgh, Edinburgh EH9 3JR, United Kingdom, ²Department of Anatomy and Physiology, Medical Sciences Institute, The University of Dundee, Dundee DD1 4HN, United Kingdom, ³School of Biological Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom and §Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom Manuscript received February 2, 2000 Accepted for publication April 10, 2000 ABSTRACT We describe a general genetic method to identify genes encoding proteins that functionally interact with and/or are good candidates for downstream targets of a particular gene product. The screen identi®es mutants whose growth depends on high levels of expression of that gene. We apply this to the plo1ϩ gene that encodes a ®ssion yeast homologue of the polo-like kinases. plo1ϩ regulates both spindle formation and septation. We have isolated 17 high plo1ϩ-dependent (pld) mutants that show defects in mitosis or septation. Three mutants show a mitotic arrest phenotype. Among the 14 pld mutants with septation defects, 12 mapped to known loci: cdc7, cdc15, cdc11 spg1, and sid2. One of the pld mutants, cdc7-PD1, was selected for suppressor analysis. As multicopy suppressors, we isolated four known genes involved in septation in ®ssion yeast: spg1ϩ, sce3ϩ, cdc8ϩ, and rho1ϩ, and two previously uncharacterized genes, mpd1ϩ and mpd2ϩ.
    [Show full text]
  • HERV-K(HML7) Integrations in the Human Genome: Comprehensive Characterization and Comparative Analysis in Non-Human Primates
    biology Article HERV-K(HML7) Integrations in the Human Genome: Comprehensive Characterization and Comparative Analysis in Non-Human Primates Nicole Grandi 1,* , Maria Paola Pisano 1 , Eleonora Pessiu 1, Sante Scognamiglio 1 and Enzo Tramontano 1,2 1 Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Cagliari, Italy; [email protected] (M.P.P.); [email protected] (E.P.); [email protected] (S.S.); [email protected] (E.T.) 2 Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), 09042 Monserrato, Cagliari, Italy * Correspondence: [email protected] Simple Summary: The human genome is not human at all, but it includes a multitude of sequences inherited from ancient viral infections that affected primates’ germ line. These elements can be seen as the fossils of now-extinct retroviruses, and are called Human Endogenous Retroviruses (HERVs). View as “junk DNA” for a long time, HERVs constitute 4 times the amount of DNA needed to produce all cellular proteins, and growing evidence indicates their crucial role in primate brain evolution, placenta development, and innate immunity shaping. HERVs are also intensively studied for a pathological role, even if the incomplete knowledge about their exact number and genomic position has thus far prevented any causal association. Among possible relevant HERVs, the HERV-K Citation: Grandi, N.; Pisano, M.P.; supergroup is of particular interest, including some of the oldest (HML5) as well as youngest (HML2) Pessiu, E.; Scognamiglio, S.; integrations. Among HERV-Ks, the HML7 group still lack a detailed description, and the present Tramontano, E.
    [Show full text]
  • Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle
    animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest.
    [Show full text]
  • Multiple Hits for the Association of Uterine Fibroids on Human Chromosome 1Q43
    Multiple Hits for the Association of Uterine Fibroids on Human Chromosome 1q43 Brahim Aissani1*, Howard Wiener1, Kui Zhang2 1 Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America, 2 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America Abstract Uterine leiomyomas (or fibroids) are the most common tumors in women of reproductive age. Early studies of two familial cancer syndromes, the multiple cutaneous and uterine leiomyomatosis (MCUL1), and the hereditary leiomyomatosis and renal cell cancer (HLRCC), implicated FH, a gene on chromosome 1q43 encoding the tricarboxylic acid cycle fumarate hydratase enzyme. The role of this metabolic housekeeping gene in tumorigenesis is still a matter of debate and pseudo- hypoxia has been suggested as a pathological mechanism. Inactivating FH mutations have rarely been observed in the nonsyndromic and common form of fibroids; however, loss of heterozygosity across FH appeared as a significant event in the pathogenesis of a subset of these tumors. To assess the role of FH and the linked genes in nonsyndromic uterine fibroids, we explored a two-megabase interval spanning FH in the NIEHS Uterine fibroid study, a cross-sectional study of fibroids in 1152 premenopausal women. Association mapping with a dense set of single nucleotide polymorphisms revealed several peaks of association (p = 1022–8.1025) with the risk and/or growth of fibroids. In particular, genes encoding factors suspected (cytosolic FH) or known (EXO1 - exonuclease 1) to be involved in DNA mismatch repair emerged as candidate susceptibility genes whereas those acting in the autophagy/apoptosis (MAP1LC3C - microtubule-associated protein) or signal transduction (RGS7 - Regulator of G-protein and PLD5– Phospoholipase D) appeared to affect tumor growth.
    [Show full text]
  • T-Scan: a Genome-Wide Method for the Systematic Discovery of T Cell Epitopes
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Cell. Author Manuscript Author manuscript; Manuscript Author available in PMC 2020 January 02. Published in final edited form as: Cell. 2019 August 08; 178(4): 1016–1028.e13. doi:10.1016/j.cell.2019.07.009. T-Scan: A Genome-wide Method for the Systematic Discovery of T Cell Epitopes Tomasz Kula1,2, Mohammad H. Dezfulian1,2, Charlotte I. Wang1,2,3, Nouran S. Abdelfattah1,2, Zachary C. Hartman4, Kai W. Wucherpfennig5, Herbert Kim Lyerly6, Stephen J. Elledge1,2,7,* 1Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women’s Hospital, Boston, MA 02115, USA 2Department of Genetics, Harvard University Medical School, Boston, MA, USA 3Department of Pathology, Massachusetts General Hospital, Boston, MA, USA 4Departments of Surgery and Pathology, Duke University Medical Center, 571 Research Drive, Suite 433, Box 2606, Durham, NC 27710, USA 5Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Department of Immunobiology, Harvard Medical School, Boston, MA 02115, USA 6Departments of Surgery, Immunology, and Pathology, Duke University Medical Center, 571 Research Drive, Suite 433, Box 2606, Durham, NC 27710, USA 7Lead Contact SUMMARY T cell recognition of specific antigens mediates protection from pathogens and controls neoplasias, but can also cause autoimmunity. Our knowledge of T cell antigens and their implications for human health is limited by the technical limitations of T cell profiling technologies. Here, we present T-Scan, a high-throughput platform for identification of antigens productively recognized by T cells. T-Scan uses lentiviral delivery of antigen libraries into cells for endogenous processing and presentation on major histocompatibility complex (MHC) molecules.
    [Show full text]
  • Analysis of the Indacaterol-Regulated Transcriptome in Human Airway
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/04/13/jpet.118.249292.DC1 1521-0103/366/1/220–236$35.00 https://doi.org/10.1124/jpet.118.249292 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:220–236, July 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the s Adverse and Therapeutic Effects of b2-Adrenoceptor Agonists Dong Yan, Omar Hamed, Taruna Joshi,1 Mahmoud M. Mostafa, Kyla C. Jamieson, Radhika Joshi, Robert Newton, and Mark A. Giembycz Departments of Physiology and Pharmacology (D.Y., O.H., T.J., K.C.J., R.J., M.A.G.) and Cell Biology and Anatomy (M.M.M., R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Received March 22, 2018; accepted April 11, 2018 Downloaded from ABSTRACT The contribution of gene expression changes to the adverse and activity, and positive regulation of neutrophil chemotaxis. The therapeutic effects of b2-adrenoceptor agonists in asthma was general enriched GO term extracellular space was also associ- investigated using human airway epithelial cells as a therapeu- ated with indacaterol-induced genes, and many of those, in- tically relevant target. Operational model-fitting established that cluding CRISPLD2, DMBT1, GAS1, and SOCS3, have putative jpet.aspetjournals.org the long-acting b2-adrenoceptor agonists (LABA) indacaterol, anti-inflammatory, antibacterial, and/or antiviral activity. Numer- salmeterol, formoterol, and picumeterol were full agonists on ous indacaterol-regulated genes were also induced or repressed BEAS-2B cells transfected with a cAMP-response element in BEAS-2B cells and human primary bronchial epithelial cells by reporter but differed in efficacy (indacaterol $ formoterol .
    [Show full text]
  • Expression of a Mirna Targeting Mutated SOD1 in Astrocytes Induces Motoneuron Plasticity and Improves Neuromuscular Function in ALS Mice
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.08.425706; this version posted January 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Expression of a miRNA targeting mutated SOD1 in astrocytes induces motoneuron plasticity and improves neuromuscular function in ALS mice Rochat C.1, Bernard-Marissal N.1,6, Pradervand S.3, Perrin F.E.4, Raoul C.5, Aebischer P.1, Schneider B.L.1,2* 1 Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland 2 Bertarelli Platform for Gene Therapy, Ecole Polytechnique Fédérale de Lausanne (EPFL), Geneva, Switzerland 3 Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland. 4 INSERM U1198, University of Montpellier, EPHE, Place Eugène Bataillon CC105, F-34095, Montpellier, France 5 The Neuroscience Institute of Montpellier, Inserm UMR1051, Univ Montpellier, Saint Eloi Hospital, Montpellier, France 6 Aix Marseille Univ, INSERM, MMG, Marseille, France *Correspondence should be addressed to B.L.S. ([email protected]) Short title: miRNA gene therapy targeting astrocytes in ALS Study was performed in Lausanne, Switzerland Current address of corresponding author: Bernard Schneider EPFL SV PTECH PTBTG Ch. des Mines 9 CH-1202 Genève Switzerland Email: [email protected] Tel: +41 21 693 95 05 bioRxiv preprint doi: https://doi.org/10.1101/2021.01.08.425706; this version posted January 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Follow-Up Examination of Linkage and Association to Chromosome 1Q43 in Multiple Sclerosis
    Genes and Immunity (2009) 10, 624–630 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE Follow-up examination of linkage and association to chromosome 1q43 in multiple sclerosis JL McCauley1, RL Zuvich1, Y Bradford1, SJ Kenealy1, N Schnetz-Boutaud1, SG Gregory2, SL Hauser3, JR Oksenberg3, DP Mortlock1, MA Pericak-Vance4 and JL Haines1 1Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA; 2Center for Human Genetics and Department of Medicine, Duke University Medical Center, Durham, NC, USA; 3Department of Neurology, University of California San Francisco, San Francisco, CA, USA and 4Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease affecting 44 00 000 individuals in the United States. Population and family-based studies have suggested that there is a strong genetic component. Numerous genomic linkage screens have identified regions of interest for MS loci. Our own second-generation genome-wide linkage study identified a handful of non-major histocompatibility complex regions with suggestive linkage. Several of these regions were further examined using single-nucleotide polymorphisms (SNPs) with average spacing between SNPs of B1.0 Mb in a dataset of 173 multiplex families. The results of that study provided further evidence for the involvement of the chromosome 1q43 region. This region is of particular interest given linkage evidence in studies of other autoimmune and inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus. In this follow-up study, we saturated the region with B700 SNPs (average spacing of 10 kb per SNP) in search of disease-associated variation within this region.
    [Show full text]
  • Confounding by Linkage Disequilibrium
    Journal of Human Genetics (2014) 59, 110–115 & 2014 The Japan Society of Human Genetics All rights reserved 1434-5161/14 OPEN www.nature.com/jhg CORRESPONDENCE Confounding by linkage disequilibrium Journal of Human Genetics (2014) 59, 110–115; doi:10.1038/jhg.2013.130; published online 19 December 2013 Linkage disequilibrium (LD) and confound- association between height and uterine fitted model for the test of association may ing are two widely discussed concepts in fibroids) have been reported; these associa- become overspecified, more precisely over- Genetics and in Epidemiology, yet their tions could be explained by mere LD, more adjusted because of adjustment for a covari- relationship has received only intuitive or precisely they might result from confounding ate (BMI) influenced by a genetic locus no considerations. Taken in the narrow sense, by LD or GPD between loci influencing (locus 1) in LD with the causal locus LD refers to the nonrandom association of height and uterine fibroids. (locus 2). Most importantly, the covariate alleles at two or more linked genetic loci. The needs not to be on the causal pathway, bias degree to which these alleles are associated is toward the null can still be observed if gene CONFOUNDING BY LD the basis behind genetic association studies locus 1 contributes significantly to the var- To illustrate the notion of confounding by whereby the genetic variation across target iance of the obesity trait in the study sample. LD, let us consider the simple scenario of a chromosomal intervals or over the entire Furthermore, because of the population-spe- Mendelian disease with complete or quasi- genome is captured by a set of representative cific pattern of LD, confounding by LD is complete penetrance and a typed marker at genetic markers (tagging markers).
    [Show full text]
  • Genetic Analyses of Human Fetal Retinal Pigment Epithelium Gene Expression Suggest Ocular Disease Mechanisms
    ARTICLE https://doi.org/10.1038/s42003-019-0430-6 OPEN Genetic analyses of human fetal retinal pigment epithelium gene expression suggest ocular disease mechanisms Boxiang Liu 1,6, Melissa A. Calton2,6, Nathan S. Abell2, Gillie Benchorin2, Michael J. Gloudemans 3, 1234567890():,; Ming Chen2, Jane Hu4, Xin Li 5, Brunilda Balliu5, Dean Bok4, Stephen B. Montgomery 2,5 & Douglas Vollrath2 The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis but has limited representation in large-scale functional genomics datasets. Understanding how common human genetic variants affect RPE gene expression could elu- cidate the sources of phenotypic variability in selected monogenic ocular diseases and pin- point causal genes at genome-wide association study (GWAS) loci. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions and discovered hundreds of shared or condition-specific expression or splice quantitative trait loci (e/sQTLs). Co-localizations of fRPE e/sQTLs with age-related macular degeneration (AMD) and myopia GWAS data suggest new candidate genes, and mechan- isms by which a common RDH5 allele contributes to both increased AMD risk and decreased myopia risk. Our study highlights the unique transcriptomic characteristics of fRPE and provides a resource to connect e/sQTLs in a critical ocular cell type to monogenic and complex eye disorders. 1 Department of Biology, Stanford University, Stanford, CA 94305, USA. 2 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. 3 Program in Biomedical Informatics, Stanford University School of Medicine, Stanford 94305 CA, USA. 4 Department of Ophthalmology, Jules Stein Eye Institute, UCLA, Los Angeles 90095 CA, USA.
    [Show full text]
  • Limma: Linear Models for Microarray and RNA-Seq Data User’S Guide
    limma: Linear Models for Microarray and RNA-Seq Data User's Guide Gordon K. Smyth, Matthew Ritchie, Natalie Thorne, James Wettenhall, Wei Shi and Yifang Hu Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia First edition 2 December 2002 Last revised 14 July 2021 This free open-source software implements academic research by the authors and co-workers. If you use it, please support the project by citing the appropriate journal articles listed in Section 2.1. Contents 1 Introduction 5 2 Preliminaries 7 2.1 Citing limma ......................................... 7 2.2 Installation . 9 2.3 How to get help . 9 3 Quick Start 11 3.1 A brief introduction to R . 11 3.2 Sample limma Session . 12 3.3 Data Objects . 13 4 Reading Microarray Data 15 4.1 Scope of this Chapter . 15 4.2 Recommended Files . 15 4.3 The Targets Frame . 15 4.4 Reading Two-Color Intensity Data . 17 4.5 Reading Single-Channel Agilent Intensity Data . 19 4.6 Reading Illumina BeadChip Data . 19 4.7 Image-derived Spot Quality Weights . 20 4.8 Reading Probe Annotation . 21 4.9 Printer Layout . 22 4.10 The Spot Types File . 22 5 Quality Assessment 24 6 Pre-Processing Two-Color Data 26 6.1 Background Correction . 26 6.2 Within-Array Normalization . 28 6.3 Between-Array Normalization . 30 6.4 Using Objects from the marray Package . 33 7 Filtering unexpressed probes 34 1 8 Linear Models Overview 36 8.1 Introduction . 36 8.2 Single-Channel Designs . 37 8.3 Common Reference Designs .
    [Show full text]
  • Egfr Activates a Taz-Driven Oncogenic Program in Glioblastoma
    EGFR ACTIVATES A TAZ-DRIVEN ONCOGENIC PROGRAM IN GLIOBLASTOMA by Minling Gao A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March 2020 ©2020 Minling Gao All rights reserved Abstract Hyperactivated EGFR signaling is associated with about 45% of Glioblastoma (GBM), the most aggressive and lethal primary brain tumor in humans. However, the oncogenic transcriptional events driven by EGFR are still incompletely understood. We studied the role of the transcription factor TAZ to better understand master transcriptional regulators in mediating the EGFR signaling pathway in GBM. The transcriptional coactivator with PDZ- binding motif (TAZ) and its paralog gene, the Yes-associated protein (YAP) are two transcriptional co-activators that play important roles in multiple cancer types and are regulated in a context-dependent manner by various upstream signaling pathways, e.g. the Hippo, WNT and GPCR signaling. In GBM cells, TAZ functions as an oncogene that drives mesenchymal transition and radioresistance. This thesis intends to broaden our understanding of EGFR signaling and TAZ regulation in GBM. In patient-derived GBM cell models, EGF induced TAZ and its known gene targets through EGFR and downstream tyrosine kinases (ERK1/2 and STAT3). In GBM cells with EGFRvIII, an EGF-independent and constitutively active mutation, TAZ showed EGF- independent hyperactivation when compared to EGFRvIII-negative cells. These results revealed a novel EGFR-TAZ signaling axis in GBM cells. The second contribution of this thesis is that we performed next-generation sequencing to establish the first genome-wide map of EGF-induced TAZ target genes.
    [Show full text]