Acta Neuropathologica Communications (Apr 2023)
Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease
- Muhammad Ali,
- Derek B. Archer,
- Priyanka Gorijala,
- Daniel Western,
- Jigyasha Timsina,
- Maria V. Fernández,
- Ting-Chen Wang,
- Claudia L. Satizabal,
- Qiong Yang,
- Alexa S. Beiser,
- Ruiqi Wang,
- Gengsheng Chen,
- Brian Gordon,
- Tammie L. S. Benzinger,
- Chengjie Xiong,
- John C. Morris,
- Randall J. Bateman,
- Celeste M. Karch,
- Eric McDade,
- Alison Goate,
- Sudha Seshadri,
- Richard P. Mayeux,
- Reisa A. Sperling,
- Rachel F. Buckley,
- Keith A. Johnson,
- Hong-Hee Won,
- Sang-Hyuk Jung,
- Hang-Rai Kim,
- Sang Won Seo,
- Hee Jin Kim,
- Elizabeth Mormino,
- Simon M. Laws,
- Kang-Hsien Fan,
- M. Ilyas Kamboh,
- Prashanthi Vemuri,
- Vijay K. Ramanan,
- Hyun-Sik Yang,
- Allen Wenzel,
- Hema Sekhar Reddy Rajula,
- Aniket Mishra,
- Carole Dufouil,
- Stephanie Debette,
- Oscar L. Lopez,
- Steven T. DeKosky,
- Feifei Tao,
- Michael W. Nagle,
- Knight Alzheimer Disease Research Center (Knight ADRC),
- the Dominantly Inherited Alzheimer Network (DIAN),
- Alzheimer’s Disease Neuroimaging Initiative (ADNI),
- ADNI-DOD, A4 Study Team,
- the Australian Imaging Biomarkers, Lifestyle (AIBL) Study,
- Timothy J. Hohman,
- Yun Ju Sung,
- Logan Dumitrescu,
- Carlos Cruchaga
Affiliations
- Muhammad Ali
- Department of Psychiatry, Washington University
- Derek B. Archer
- Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine
- Priyanka Gorijala
- Department of Psychiatry, Washington University
- Daniel Western
- Department of Psychiatry, Washington University
- Jigyasha Timsina
- Department of Psychiatry, Washington University
- Maria V. Fernández
- Department of Psychiatry, Washington University
- Ting-Chen Wang
- Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine
- Claudia L. Satizabal
- Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health
- Qiong Yang
- Department of Biostatistics, Boston University School of Public Health
- Alexa S. Beiser
- Department of Biostatistics, Boston University School of Public Health
- Ruiqi Wang
- Boston University
- Gengsheng Chen
- Knight Alzheimer’s Disease Research Center, Washington University
- Brian Gordon
- Knight Alzheimer’s Disease Research Center, Washington University
- Tammie L. S. Benzinger
- Knight Alzheimer’s Disease Research Center, Washington University
- Chengjie Xiong
- Knight Alzheimer’s Disease Research Center, Washington University
- John C. Morris
- Knight Alzheimer’s Disease Research Center, Washington University
- Randall J. Bateman
- Knight Alzheimer’s Disease Research Center, Washington University
- Celeste M. Karch
- Department of Psychiatry, Washington University
- Eric McDade
- Department of Neurology, Washington University
- Alison Goate
- Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai
- Sudha Seshadri
- Framingham Heart Study
- Richard P. Mayeux
- The Department of Neurology, Columbia University
- Reisa A. Sperling
- Department of Neurology, Harvard Medical School
- Rachel F. Buckley
- Brigham and Women’s Hospital and Department of Neurology, Massachusetts General Hospital, Harvard Medical School
- Keith A. Johnson
- Massachusetts General Hospital, Harvard Medical School
- Hong-Hee Won
- Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan University
- Sang-Hyuk Jung
- Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan University
- Hang-Rai Kim
- Department of Neurology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine
- Sang Won Seo
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine
- Hee Jin Kim
- Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan University
- Elizabeth Mormino
- Department of Neurology and Neurological Sciences, Stanford University
- Simon M. Laws
- Centre for Precision Health, Edith Cowan University
- Kang-Hsien Fan
- Department of Human Genetics, University of Pittsburgh
- M. Ilyas Kamboh
- Department of Human Genetics, University of Pittsburgh
- Prashanthi Vemuri
- Department of Radiology, Mayo Clinic-Minnesota
- Vijay K. Ramanan
- Department of Neurology, Mayo Clinic-Minnesota
- Hyun-Sik Yang
- Department of Neurology, Brigham and Women’s Hospital
- Allen Wenzel
- Wisconsin Alzheimer’s Institute
- Hema Sekhar Reddy Rajula
- UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre
- Aniket Mishra
- UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre
- Carole Dufouil
- UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre
- Stephanie Debette
- UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre
- Oscar L. Lopez
- Department of Neurology, University of Pittsburgh
- Steven T. DeKosky
- Department of Neurology and McKnight Brain Institute, University of Florida
- Feifei Tao
- Neurogenomics, Genetics-Guided Dementia Discovery, Eisai, Inc
- Michael W. Nagle
- Neurogenomics, Genetics-Guided Dementia Discovery, Eisai, Inc
- Knight Alzheimer Disease Research Center (Knight ADRC)
- the Dominantly Inherited Alzheimer Network (DIAN)
- Alzheimer’s Disease Neuroimaging Initiative (ADNI)
- ADNI-DOD, A4 Study Team
- the Australian Imaging Biomarkers, Lifestyle (AIBL) Study
- Timothy J. Hohman
- Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine
- Yun Ju Sung
- Department of Psychiatry, Washington University
- Logan Dumitrescu
- Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine
- Carlos Cruchaga
- Department of Psychiatry, Washington University
- DOI
- https://doi.org/10.1186/s40478-023-01563-4
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 20
Abstract
Abstract Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10–311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10–09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10–10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10–09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10–08, MAF = 0.006, sex-interaction P = 9.8 × 10–07) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10–08, MAF = 0.004, sex-interaction P = 1.3 × 10–03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.
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