title: Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.
abstract: Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France. julien.chapuis@pasteur-lille.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Chapuis
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Flaig
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Grenier-Boley
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Eysert
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000, Lille, France.|Univ. Lille, INSERM, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Pottiez
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000, Lille, France.|Univ. Lille, INSERM, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France.
authors.forename: Gaspard
authors.initials: G
authors.lastname: Deloison
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000, Lille, France.|Univ. Lille, INSERM, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vandeputte
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Ayral
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Tiago
authors.initials: T
authors.lastname: Mendes
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Shruti
authors.initials: S
authors.lastname: Desai
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.|Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Departments of Biology and Neuroscience, Brigham Young University, Provo, USA.
authors.forename: John S K
authors.initials: JSK
authors.lastname: Kauwe
authors.affiliation: Univ. Lille, INSERM, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.affiliation: Univ. Lille, INSERM, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Herledan
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Florie
authors.initials: F
authors.lastname: Demiautte
authors.affiliation: Laboratoire d'Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, IPMC, France, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Laboratoire d'Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, IPMC, France, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Checler
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgren's University Hospital, Mölndal, Gothenburg, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgren's University Hospital, Mölndal, Gothenburg, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Memory Research Unit, Dept of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Virginia Man-Yee
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Albert
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Abhay
authors.initials: A
authors.lastname: Moghekar
authors.affiliation: Department of Neurology, Duke Medical Center, Box 2900, Durham, NC, 27710, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: O'Brien
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, University of Washington School of Medicine, Seattle, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Malmanche
authors.affiliation: Stellar-Chance Laboratories, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dourlen
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000, Lille, France.
authors.forename: Ok-Ryul
authors.initials: OR
authors.lastname: Song
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.|Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.affiliation: Univ. Lille, INSERM, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000, Lille, France.
authors.forename: Priscille
authors.initials: P
authors.lastname: Brodin
authors.affiliation: Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C000625252:FERMT2 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering