Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.

Black or African American / genetics Age Factors Alzheimer Disease / genetics Cognitive Dysfunction / genetics Dementia / genetics Female Genome-Wide Association Study Humans Male Middle Aged Nerve Tissue Proteins / metabolism Species Specificity
Alzheimer’s Diversity Outbred Dlgap2 GWAS aging cognition genetic diversity resilience spines susceptibility translational

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
01 09 2020
Historique:
received: 16 05 2019
revised: 10 02 2020
accepted: 07 08 2020
entrez: 3 9 2020
pubmed: 3 9 2020
medline: 29 5 2021
Statut: ppublish

Résumé

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates.

Identifiants

DOI: 10.1016/j.celrep.2020.108091 PMID: 32877673 PMC: PMC7502175
pubmed: 32877673
pii: S2211-1247(20)31080-9
doi: 10.1016/j.celrep.2020.108091
pmc: PMC7502175
mid: NIHMS1627849
pii:
doi:

Substances chimiques

DLGAP2 protein, human 0
Nerve Tissue Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

108091

Subventions

Organisme : NIA NIH HHS
ID : P30 AG038070
Pays : United States
Organisme : NIDA NIH HHS
ID : P50 DA039841
Pays : United States
Organisme : NIA NIH HHS
ID : U24 AG021886
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054719
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG008702
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054180
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG017917
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG057911
Pays : United States
Organisme : NIA NIH HHS
ID : F31 AG050357
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054080
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061357
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066462
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG059716
Pays : United States
Organisme : NIA NIH HHS
ID : K23 AG062750
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG064614
Pays : United States
Organisme : NIA NIH HHS
ID : K01 AG049164
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057470
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG015819
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG057914
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057471
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG061800
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG062181
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061356
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG032984
Pays : United States
Organisme : NIMH NIH HHS
ID : F31 MH067445
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG036042
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG052410
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG063755
Pays : United States

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests C.C.K. and S.M.N. have filed a related patent application. The other authors declare no competing interests.

Auteurs

Andrew R Ouellette (AR)

The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Science and Engineering, The University of Maine, Orono, ME 04469, USA.

Sarah M Neuner (SM)

The Jackson Laboratory, Bar Harbor, ME 04609, USA; University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Logan Dumitrescu (L)

Vanderbilt Memory and Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37240, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37240, USA.

Laura C Anderson (LC)

The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Daniel M Gatti (DM)

The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Emily R Mahoney (ER)

Vanderbilt Memory and Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37240, USA.

Jason A Bubier (JA)

The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Gary Churchill (G)

The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Luanne Peters (L)

The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Matthew J Huentelman (MJ)

Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.

Jeremy H Herskowitz (JH)

Center for Neurodegeneration and Experimental Therapeutics and Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Hyun-Sik Yang (HS)

Cell Circuits and Epigenomics Program, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.

Alexandra N Smith (AN)

Vanderbilt Memory and Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37240, USA.

Christiane Reitz (C)

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Departments of Neurology and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Brian W Kunkle (BW)

Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

Charles C White (CC)

Cell Circuits and Epigenomics Program, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.

Philip L De Jager (PL)

Cell Circuits and Epigenomics Program, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.

Julie A Schneider (JA)

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.

David A Bennett (DA)

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.

Nicholas T Seyfried (NT)

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.

Elissa J Chesler (EJ)

The Jackson Laboratory, Bar Harbor, ME 04609, USA. Electronic address: elissa.chesler@jax.org.

Niran Hadad (N)

The Jackson Laboratory, Bar Harbor, ME 04609, USA. Electronic address: niran.hadad@jax.org.

Timothy J Hohman (TJ)

Vanderbilt Memory and Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37240, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37240, USA. Electronic address: timothy.j.hohman@vumc.org.

Catherine C Kaczorowski (CC)

The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Science and Engineering, The University of Maine, Orono, ME 04469, USA. Electronic address: catherine.kaczorowski@jax.org.

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Classifications MeSH

questionsmedicales.fr › Personnes › Nord-Américains › Groupes de population aux États-Unis › Populations d'origine continentale › Noir ou Africain Américain › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Facteurs âges › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Cross-Species Analyses Identify Dlgap2 as a...
questionsmedicales.fr › Phénomènes biologiques › Spécificité d'espèce › Cross-Species Analyses Identify Dlgap2 as a...