CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET.

Alzheimer Disease / genetics Humans Cytochrome P-450 CYP1B1 / genetics Positron-Emission Tomography / methods tau Proteins / metabolism Animals Genome-Wide Association Study Male Female Mice Endophenotypes Aged Amyloid beta-Peptides / metabolism Polymorphism, Single Nucleotide Apolipoprotein E4 / genetics Aged, 80 and over Disease Models, Animal

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
20 Sep 2024
Historique:
received: 14 11 2023
accepted: 01 09 2024
medline: 21 9 2024
pubmed: 21 9 2024
entrez: 20 9 2024
Statut: epublish

Résumé

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Identifiants

DOI: 10.1038/s41467-024-52298-2 PMID: 39304655
pubmed: 39304655
doi: 10.1038/s41467-024-52298-2
pii: 10.1038/s41467-024-52298-2
doi:

Substances chimiques

Cytochrome P-450 CYP1B1 EC 1.14.14.1
tau Proteins 0
CYP1B1 protein, human EC 1.14.14.1
Amyloid beta-Peptides 0
Apolipoprotein E4 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

8251

Subventions

Organisme : NIA NIH HHS
ID : R01 AG019771
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072976
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG024904
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG057739
Pays : United States
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : R01-AG061796
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : U19-AG074879
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : R01-NS080820
Organisme : Alzheimer's Association
ID : Alzheimer's Association Zenith Fellows Award

Informations de copyright

© 2024. The Author(s).

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Auteurs

Kwangsik Nho (K)

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of BioHealth Informatics, Indiana University, Indianapolis, USA.

Shannon L Risacher (SL)

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0002-3304-7943

Liana G Apostolova (LG)

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.

Paula J Bice (PJ)

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0001-5357-9966

Jared R Brosch (JR)

Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0002-6578-0584

Rachael Deardorff (R)

Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.

Kelley Faber (K)

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0003-3224-2736

Martin R Farlow (MR)

Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0001-7897-5471

Tatiana Foroud (T)

Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0002-5549-2212

Sujuan Gao (S)

Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of Biostatistics, Indiana University School of Medicine, Indianapolis, USA.

Thea Rosewood (T)

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0001-7025-0222

Jun Pyo Kim (JP)

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0003-4376-3107

Kelly Nudelman (K)

Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0003-4040-1717

Meichen Yu (M)

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0003-4551-0269

Paul Aisen (P)

Department of Neurology, Keck School of Medicine, University of Southern California, San Diego, USA.

Reisa Sperling (R)

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
ORCID: 0000-0003-1535-6133

Basavaraj Hooli (B)

Eli Lilly and Company, Indianapolis, USA.

Sergey Shcherbinin (S)

Eli Lilly and Company, Indianapolis, USA.

Diana Svaldi (D)

Eli Lilly and Company, Indianapolis, USA.

Clifford R Jack (CR)

Department of Radiology, Mayo Clinic, Rochester, USA.
ORCID: 0000-0001-7916-622X

William J Jagust (WJ)

UC Berkeley Helen Wills Neuroscience Institute, University of California - Berkeley, Berkeley, USA.
ORCID: 0000-0002-4458-113X

Susan Landau (S)

UC Berkeley Helen Wills Neuroscience Institute, University of California - Berkeley, Berkeley, USA.

Aparna Vasanthakumar (A)

Genomics Research Center, AbbVie, North Chicago, USA.
ORCID: 0000-0003-3857-8812

Jeffrey F Waring (JF)

Genomics Research Center, AbbVie, North Chicago, USA.

Vincent Doré (V)

CSIRO Health and Biosecurity, Melbourne, Australia.
Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Australia.
ORCID: 0000-0002-8051-0558

Simon M Laws (SM)

Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia.
ORCID: 0000-0002-4355-7082

Colin L Masters (CL)

Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Australia.

Tenielle Porter (T)

Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia.
ORCID: 0000-0002-7887-6622

Christopher C Rowe (CC)

Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Australia.
Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Australia.
ORCID: 0000-0003-3910-2453

Victor L Villemagne (VL)

Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Australia.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, USA.

Logan Dumitrescu (L)

Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, USA.

Timothy J Hohman (TJ)

Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, USA.
ORCID: 0000-0002-3377-7014

Julia B Libby (JB)

Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, USA.

Elizabeth Mormino (E)

Department of Neurology & Neurological Sciences, Stanford University, Stanford, USA.

Rachel F Buckley (RF)

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
ORCID: 0000-0002-5356-5537

Keith Johnson (K)

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.

Hyun-Sik Yang (HS)

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Center for Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
ORCID: 0000-0002-8318-0443

Ronald C Petersen (RC)

Department of Neurology, Mayo Clinic, Rochester, USA.
ORCID: 0000-0002-8178-6601

Vijay K Ramanan (VK)

Department of Neurology, Mayo Clinic, Rochester, USA.
ORCID: 0000-0001-6591-8734

Nilüfer Ertekin-Taner (N)

Department of Neurology, Mayo Clinic, Jacksonville, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, USA.
ORCID: 0000-0003-4436-8889

Prashanthi Vemuri (P)

Department of Radiology, Mayo Clinic, Rochester, USA.
ORCID: 0000-0003-4286-0589

Ann D Cohen (AD)

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, USA.

Kang-Hsien Fan (KH)

Department of Human Genetics, University of Pittsburgh, Pittsburgh, USA.

M Ilyas Kamboh (MI)

Department of Human Genetics, University of Pittsburgh, Pittsburgh, USA.
ORCID: 0000-0002-3453-1438

Oscar L Lopez (OL)

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, USA.
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
ORCID: 0000-0002-8546-8256

David A Bennett (DA)

Department of Neurological Sciences, Rush Medical College, Rush University, Chicago, USA.

Muhammad Ali (M)

Department of Psychiatry, Washington University, St. Louis, USA.
ORCID: 0000-0002-1399-6631

Tammie Benzinger (T)

Department of Radiology, Washington University School of Medicine, St. Louis, USA.

Carlos Cruchaga (C)

Department of Psychiatry, Washington University, St. Louis, USA.
NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, USA.
ORCID: 0000-0002-0276-2899

Diana Hobbs (D)

Department of Radiology, Washington University School of Medicine, St. Louis, USA.
ORCID: 0000-0001-7822-6411

Philip L De Jager (PL)

Center for Translational and Computational Neuroimmunology, Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, USA.
ORCID: 0000-0002-8057-2505

Masashi Fujita (M)

Center for Translational and Computational Neuroimmunology, Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, USA.

Vaishnavi Jadhav (V)

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0009-0002-1227-9996

Bruce T Lamb (BT)

Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, USA.
ORCID: 0000-0001-8507-2561

Andy P Tsai (AP)

Department of Neurology & Neurological Sciences, Stanford University, Stanford, USA.
Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, USA.
Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, USA.
ORCID: 0000-0001-6400-544X

Isabel Castanho (I)

Department for Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
ORCID: 0000-0003-1413-626X

Jonathan Mill (J)

Department for Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
ORCID: 0000-0003-1115-3224

Michael W Weiner (MW)

Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, USA.
Department of Veterans Affairs Medical Center, San Francisco, USA.

Andrew J Saykin (AJ)

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
Department of Neurology, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
ORCID: 0000-0002-1376-8532

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Classifications MeSH

questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Famille-1 de cytochromes P450 › Cytochrome P-450 CYP1B1 › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Techniques de diagnostic radioisotopique › Scintigraphie › Tomoscintigraphie › Tomographie par émission de positons › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Protéines associées aux microtubules › Protéines tau › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Eucaryotes › Animaux › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Endophénotypes › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Peptides bêta-amyloïdes › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines E › Apolipoprotéine E4 › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › CYP1B1-RMDN2 Alzheimer's disease endophenotype...
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