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

Autor: Joshua C. Bis, Li-San Wang, Waleed Nasser, Giuseppe Tosto, Jean-Charles Lambert, Gary W. Beecham, Lucinda Fulton, Eric Boerwinkle, Reinhold Schmidt, Kara L. Hamilton-Nelson, Josée Dupuis, Cornelia M. van Duijn, Yuning Chen, Stéphanie Debette, Devanshi Patel, Philippe Amouyel, Gaël Nicolas, Farid Rajabli, Mark J. Daly, Richard Redon, Hilkka Soininen, Anita L. DeStefano, Aki S. Havulinna, Weixin Wang, Margaret A. Pericak-Vance, Chloé Sarnowski, Gerard D. Schellenberg, William S. Bush, Eden R. Martin, John J. Farrell, Richard A. Gibbs, Richard Mayeux, Emmanuelle Génin, Yi Zhao, Kwangsik Nho, Céline Bellenguez, Kari Mattila, Jean-François Deleuze, William J Salerno, Alzheimer’s Disease Sequencing, Brian W. Kunkle, Dominique Campion, Mikko Hiltunen, Richard K. Wilson, Sudha Seshadri, Paul K. Crane, Otto Valladares, Jennifer E. Below, Adam C. Naj, Timothy A. Thornton, Stacey Gabriel, Jan Konrad, Markus Perola, Mark Lathrop, Namrata Gupta, Badri N. Vardarajan, Bruce M. Psaty, Seppo Helisalmi, Jonathan L. Haines, Yiyi Ma, Honghuang Lin, Laura B. Cantwell, Carlos Cruchaga, Alan E. Renton, Terho Lehtimäki, Anne M. Remes, Michael A. Schmidt, Benjamin M. Neale, M. Arfan Ikram, Lindsay A. Farrer, Myriam Fornage, Daniel P. Howrigan, Ellen M. Wijsman, Mitja I. Kurki, Helena Schmidt, Aarno Palotie, Daniel Lancour, Camille Charbonnier, Daniela Witten, Liming Qu, Najaf Amin, Eric S. Lander, Alison Goate, Donna M. Muzny, Kathryn L. Lunetta, Jaakko Kaprio, Edoardo Marcora, Amanda B. Kuzma, Sven J. van der Lee, Shahzad Ahmad, Kim C. Worley, Christophe Tzourio, Benjamin Grenier-Boley, Jean-François Dartigues, L. Adrienne Cupples, Veikko Salomaa, Jaeyoon Chung, Christiane Reitz, Xueqiu Jian, Xiaoling Zhang, Olivier Quenez
Přispěvatelé: Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Helsinki and Uusimaa Hospital District, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidemiology
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
DYSBINDIN GENE DTNBP1
Transcription
Genetic
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
SORL1
PROTEIN
Diseases
Genome-wide association study
SUSCEPTIBILITY
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
DISEASE
ABCA7
0302 clinical medicine
Exome sequencing
Aged
80 and over
Genetics
RISK
3. Good health
Psychiatry and Mental health
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology
Female
RNA
Long Noncoding
Alzheimer's disease
Immunoglobulin gene
EXPRESSION
Kruppel-Like Transcription Factors
Biology
Article
CODING MUTATIONS
03 medical and health sciences
Cellular and Molecular Neuroscience
Apolipoproteins E
Alzheimer Disease
Exome Sequencing
medicine
Humans
GENOME-WIDE ASSOCIATION
Molecular Biology
Gene
Genotyping
Aged
Amyloid beta-Peptides
Polymorphism
Genetic
[SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE]
Haplotype
Immunity
3112 Neurosciences
Correction
medicine.disease
030104 developmental biology
Gene Expression Regulation
Haplotypes
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Immunoglobulin G
3111 Biomedicine
030217 neurology & neurosurgery
Zdroj: Molecular psychiatry
Molecular Psychiatry
Molecular Psychiatry, 2018, 25 (8), pp.1859-1875. ⟨10.1038/s41380-018-0112-7⟩
Molecular Psychiatry, Nature Publishing Group, 2018, 25 (8), pp.1859-1875. ⟨10.1038/s41380-018-0112-7⟩
Molecular Psychiatry, 25(8), 1859-1875. Nature Publishing Group
ISSN: 1476-5578
1359-4184
Popis: 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.
Databáze: OpenAIRE
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