Nature Communications (Sep 2024)
CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET
- Kwangsik Nho,
- Shannon L. Risacher,
- Liana G. Apostolova,
- Paula J. Bice,
- Jared R. Brosch,
- Rachael Deardorff,
- Kelley Faber,
- Martin R. Farlow,
- Tatiana Foroud,
- Sujuan Gao,
- Thea Rosewood,
- Jun Pyo Kim,
- Kelly Nudelman,
- Meichen Yu,
- Paul Aisen,
- Reisa Sperling,
- Basavaraj Hooli,
- Sergey Shcherbinin,
- Diana Svaldi,
- Clifford R. Jack,
- William J. Jagust,
- Susan Landau,
- Aparna Vasanthakumar,
- Jeffrey F. Waring,
- Vincent Doré,
- Simon M. Laws,
- Colin L. Masters,
- Tenielle Porter,
- Christopher C. Rowe,
- Victor L. Villemagne,
- Logan Dumitrescu,
- Timothy J. Hohman,
- Julia B. Libby,
- Elizabeth Mormino,
- Rachel F. Buckley,
- Keith Johnson,
- Hyun-Sik Yang,
- Ronald C. Petersen,
- Vijay K. Ramanan,
- Nilüfer Ertekin-Taner,
- Prashanthi Vemuri,
- Ann D. Cohen,
- Kang-Hsien Fan,
- M. Ilyas Kamboh,
- Oscar L. Lopez,
- David A. Bennett,
- Muhammad Ali,
- Tammie Benzinger,
- Carlos Cruchaga,
- Diana Hobbs,
- Philip L. De Jager,
- Masashi Fujita,
- Vaishnavi Jadhav,
- Bruce T. Lamb,
- Andy P. Tsai,
- Isabel Castanho,
- Jonathan Mill,
- Michael W. Weiner,
- for the Alzheimer’s Disease Neuroimaging Initiative (ADNI),
- the Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI),
- the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN),
- the Australian Imaging, Biomarker & Lifestyle Study (AIBL),
- Andrew J. Saykin
Affiliations
- Kwangsik Nho
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- Shannon L. Risacher
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- Liana G. Apostolova
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- Paula J. Bice
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- Jared R. Brosch
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine
- Rachael Deardorff
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine
- Kelley Faber
- Department of Medical and Molecular Genetics, Indiana University School of Medicine
- Martin R. Farlow
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine
- Tatiana Foroud
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine
- Sujuan Gao
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine
- Thea Rosewood
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- Jun Pyo Kim
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- Kelly Nudelman
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine
- Meichen Yu
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- Paul Aisen
- Department of Neurology, Keck School of Medicine, University of Southern California
- Reisa Sperling
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School
- Basavaraj Hooli
- Eli Lilly and Company
- Sergey Shcherbinin
- Eli Lilly and Company
- Diana Svaldi
- Eli Lilly and Company
- Clifford R. Jack
- Department of Radiology, Mayo Clinic
- William J. Jagust
- UC Berkeley Helen Wills Neuroscience Institute, University of California - Berkeley
- Susan Landau
- UC Berkeley Helen Wills Neuroscience Institute, University of California - Berkeley
- Aparna Vasanthakumar
- Genomics Research Center, AbbVie
- Jeffrey F. Waring
- Genomics Research Center, AbbVie
- Vincent Doré
- CSIRO Health and Biosecurity
- Simon M. Laws
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University
- Colin L. Masters
- Florey Institute of Neuroscience and Mental Health and The University of Melbourne
- Tenielle Porter
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University
- Christopher C. Rowe
- Department of Molecular Imaging & Therapy, Austin Health
- Victor L. Villemagne
- Department of Molecular Imaging & Therapy, Austin Health
- Logan Dumitrescu
- Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center
- Timothy J. Hohman
- Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center
- Julia B. Libby
- Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center
- Elizabeth Mormino
- Department of Neurology & Neurological Sciences, Stanford University
- Rachel F. Buckley
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School
- Keith Johnson
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School
- Hyun-Sik Yang
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School
- Ronald C. Petersen
- Department of Neurology, Mayo Clinic
- Vijay K. Ramanan
- Department of Neurology, Mayo Clinic
- Nilüfer Ertekin-Taner
- Department of Neurology, Mayo Clinic
- Prashanthi Vemuri
- Department of Radiology, Mayo Clinic
- Ann D. Cohen
- Department of Psychiatry, University of Pittsburgh School of Medicine
- Kang-Hsien Fan
- Department of Human Genetics, University of Pittsburgh
- M. Ilyas Kamboh
- Department of Human Genetics, University of Pittsburgh
- Oscar L. Lopez
- Department of Psychiatry, University of Pittsburgh School of Medicine
- David A. Bennett
- Department of Neurological Sciences, Rush Medical College, Rush University
- Muhammad Ali
- Department of Psychiatry, Washington University
- Tammie Benzinger
- Department of Radiology, Washington University School of Medicine
- Carlos Cruchaga
- Department of Psychiatry, Washington University
- Diana Hobbs
- Department of Radiology, Washington University School of Medicine
- Philip L. De Jager
- 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
- Masashi Fujita
- 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
- Vaishnavi Jadhav
- Department of Medical and Molecular Genetics, Indiana University School of Medicine
- Bruce T. Lamb
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine
- Andy P. Tsai
- Department of Neurology & Neurological Sciences, Stanford University
- Isabel Castanho
- Department for Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter
- Jonathan Mill
- Department for Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter
- Michael W. Weiner
- Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco
- for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
- the Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI)
- the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN)
- the Australian Imaging, Biomarker & Lifestyle Study (AIBL)
- Andrew J. Saykin
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- DOI
- https://doi.org/10.1038/s41467-024-52298-2
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 14
Abstract
Abstract 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.
