Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-08-14

AUTHORS

Joshua C. Bis, Xueqiu Jian, Brian W. Kunkle, Yuning Chen, Kara L. Hamilton-Nelson, William S. Bush, William J. Salerno, Daniel Lancour, Yiyi Ma, Alan E. Renton, Edoardo Marcora, John J. Farrell, Yi Zhao, Liming Qu, Shahzad Ahmad, Najaf Amin, Philippe Amouyel, Gary W. Beecham, Jennifer E. Below, Dominique Campion, Laura Cantwell, Camille Charbonnier, Jaeyoon Chung, Paul K. Crane, Carlos Cruchaga, L. Adrienne Cupples, Jean-François Dartigues, Stéphanie Debette, Jean-François Deleuze, Lucinda Fulton, Stacey B. Gabriel, Emmanuelle Genin, Richard A. Gibbs, Alison Goate, Benjamin Grenier-Boley, Namrata Gupta, Jonathan L. Haines, Aki S. Havulinna, Seppo Helisalmi, Mikko Hiltunen, Daniel P. Howrigan, M. Arfan Ikram, Jaakko Kaprio, Jan Konrad, Amanda Kuzma, Eric S. Lander, Mark Lathrop, Terho Lehtimäki, Honghuang Lin, Kari Mattila, Richard Mayeux, Donna M. Muzny, Waleed Nasser, Benjamin Neale, Kwangsik Nho, Gaël Nicolas, Devanshi Patel, Margaret A. Pericak-Vance, Markus Perola, Bruce M. Psaty, Olivier Quenez, Farid Rajabli, Richard Redon, Christiane Reitz, Anne M. Remes, Veikko Salomaa, Chloe Sarnowski, Helena Schmidt, Michael Schmidt, Reinhold Schmidt, Hilkka Soininen, Timothy A. Thornton, Giuseppe Tosto, Christophe Tzourio, Sven J. van der Lee, Cornelia M. van Duijn, Otto Valladares, Badri Vardarajan, Li-San Wang, Weixin Wang, Ellen Wijsman, Richard K. Wilson, Daniela Witten, Kim C. Worley, Xiaoling Zhang, Celine Bellenguez, Jean-Charles Lambert, Mitja I. Kurki, Aarno Palotie, Mark Daly, Eric Boerwinkle, Kathryn L. Lunetta, Anita L. Destefano, Josée Dupuis, Eden R. Martin, Gerard D. Schellenberg, Sudha Seshadri, Adam C. Naj, Myriam Fornage, Lindsay A. Farrer

ABSTRACT

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis. More... »

PAGES

1859-1875

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  • Journal

    TITLE

    Molecular Psychiatry

    ISSUE

    8

    VOLUME

    25

    Author Affiliations

  • Department of Medicine (General Internal Medicine), University of Washington, Seattle, WA, USA
  • Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
  • John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
  • Departments of Biostatistics, Boston University School of Public Health, Boston, MA, USA
  • Case Western Reserve University, Cleveland Heights, OH, USA
  • Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  • Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
  • Department of Neuroscience and Ronald M Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
  • Erasmus University Medical Center, Rotterdam, Netherlands
  • Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France
  • University Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France
  • Department of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA
  • Department of Research, Centre Hospitalier du Rouvray, Sotteville-lès-, Rouen, France
  • Department of Genetics and CNR-MAJ, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
  • Department of Psychiatry, Washington University, St. Louis, MO, USA
  • National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA
  • University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, F-33000, Bordeaux, France
  • Department of Neurology and Institute for Neurodegenerative Diseases, Bordeaux University Hospital, Memory Clinic, F-33000, Bordeaux, France
  • Centre National de Recherche en Génomique Humaine, Institut François Jacob, Direction de le Recherche Fondamentale, CEA, Evry, France
  • McDonnell Genome Institute, Washington University, St. Louis, MO, USA
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Inserm UMR-1078, CHRU Brest, Université Brest, Brest, France
  • National Institute for Health and Welfare, Helsinki, Finland
  • Institute of Clinical Medicine - Neurology and Department of Neurology, University of Eastern Finland, Kuopio, Finland
  • Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
  • Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
  • McGill University and Génome Québec Innovation Centre, Montréal, Canada
  • Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
  • Department of Medicine (Computational Biomedicine), Boston University School of Medicine, Boston, MA, USA
  • Columbia University, New York, NY, USA
  • Indiana University School of Medicine, Indianapolis, IN, USA
  • University of Tartu, Estonian Genome Center, Tartu, Estonia
  • Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
  • Inserm, CNRS, Univ. Nantes, CHU Nantes, l’institut du thorax, Nantes, France
  • Unit of Clinical Neuroscience, Neurology, University of Oulu and Medical Research Center, Oulu University Hospital, Oulu, Finland
  • Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Graz, Austria
  • Department of Neurology, Kuopio University Hospital, Kuopio, Finland
  • Department of Statistics, University of Washington, Seattle, WA, USA
  • Department of Biostatistics, University of Washington, Seattle, WA, USA
  • School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
  • Departments of Neurology, Boston University School of Medicine, Boston, MA, USA
  • Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA
  • Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41380-018-0112-7

    DOI

    http://dx.doi.org/10.1038/s41380-018-0112-7

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1106026150

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30108311


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