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.
| Original language | English |
|---|---|
| Article number | 68 |
| Journal | Acta Neuropathologica Communications |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
Keywords
- Alzheimer’s disease
- Amyloid PET
- Brain amyloidosis
- GWAS
- Meta-analysis
- Multi-ethnic
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In: Acta Neuropathologica Communications, Vol. 11, No. 1, 68, 12.2023.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease
AU - Knight Alzheimer Disease Research Center (Knight ADRC)
AU - the Dominantly Inherited Alzheimer Network (DIAN)
AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)
AU - ADNI-DOD, A4 Study Team
AU - the Australian Imaging Biomarkers, Lifestyle (AIBL) Study
AU - Ali, Muhammad
AU - Archer, Derek B.
AU - Gorijala, Priyanka
AU - Western, Daniel
AU - Timsina, Jigyasha
AU - Fernández, Maria V.
AU - Wang, Ting Chen
AU - Satizabal, Claudia L.
AU - Yang, Qiong
AU - Beiser, Alexa S.
AU - Wang, Ruiqi
AU - Chen, Gengsheng
AU - Gordon, Brian
AU - Benzinger, Tammie L.S.
AU - Xiong, Chengjie
AU - Morris, John C.
AU - Bateman, Randall J.
AU - Karch, Celeste M.
AU - McDade, Eric
AU - Goate, Alison
AU - Seshadri, Sudha
AU - Mayeux, Richard P.
AU - Sperling, Reisa A.
AU - Buckley, Rachel F.
AU - Johnson, Keith A.
AU - Won, Hong Hee
AU - Jung, Sang Hyuk
AU - Kim, Hang Rai
AU - Seo, Sang Won
AU - Kim, Hee Jin
AU - Mormino, Elizabeth
AU - Laws, Simon M.
AU - Fan, Kang Hsien
AU - Kamboh, M. Ilyas
AU - Vemuri, Prashanthi
AU - Ramanan, Vijay K.
AU - Yang, Hyun Sik
AU - Wenzel, Allen
AU - Rajula, Hema Sekhar Reddy
AU - Mishra, Aniket
AU - Dufouil, Carole
AU - Debette, Stephanie
AU - Lopez, Oscar L.
AU - DeKosky, Steven T.
AU - Tao, Feifei
AU - Nagle, Michael W.
AU - Hohman, Timothy J.
AU - Sung, Yun Ju
AU - Dumitrescu, Logan
AU - Cruchaga, Carlos
N1 - Funding Information: This study was supported by grant U01 AT000162 from the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements, and grant P01 AG025204 from the National Institute on Aging. We would also like to acknowledge the scientific contributions of GEMS investigators from the Pittsburgh site; Lewis H Kuller, William Klunk, Chester Mathis and Howard Aizenstein. Funding Information: DIAN resources : Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19 AG032438) funded by the National Institute on Aging (NIA),the Alzheimer’s Association (SG-20-690363-DIAN), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Spanish Institute of Health Carlos III (ISCIII), Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, and Fonds de Recherche du Québec – Santé. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. Funding Information: Mayo Clinic Study of Aging data was acquired with the support of NIH grants U01 AG006786, R01 AG56366, P50 AG016574, P30 AG062677, R37 AG011378, R01 AG041851, R01 AG034676; GHR Foundation, and the Mayo Foundation for Medical Education and Research. Funding Information: We thank all the participants and their families, as well as the involved cohorts, institutions, and their staff. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30 AG066444 (JCM), P01 AG03991 (JCM), and P01 AG026276 (JCM). This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/) and the Departments of Neurology and Psychiatry at Washington University School of Medicine. DIAN resources : Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19 AG032438) funded by the National Institute on Aging (NIA),the Alzheimer’s Association (SG-20-690363-DIAN), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Spanish Institute of Health Carlos III (ISCIII), Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, and Fonds de Recherche du Québec – Santé. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Mayo Clinic Study of Aging data was acquired with the support of NIH grants U01 AG006786, R01 AG56366, P50 AG016574, P30 AG062677, R37 AG011378, R01 AG041851, R01 AG034676; GHR Foundation, and the Mayo Foundation for Medical Education and Research. This study was supported by grant U01 AT000162 from the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements, and grant P01 AG025204 from the National Institute on Aging. We would also like to acknowledge the scientific contributions of GEMS investigators from the Pittsburgh site; Lewis H Kuller, William Klunk, Chester Mathis and Howard Aizenstein. The A4 Study is a secondary prevention trial in preclinical Alzheimer's disease, aiming to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. The A4 Study is funded by a public-private-philanthropic partnership, including funding from the National Institutes of Health-National Institute on Aging (R01 AG063689, U24 AG057437) Eli Lilly and Company, Alzheimer's Association, Accelerating Medicines Partnership, GHR Foundation, an anonymous foundation and additional private donors, with in-kind support from Avid and Cogstate. The companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study is funded by the Alzheimer's Association and GHR Foundation. The A4 and LEARN Studies are led by Dr. Reisa Sperling at Brigham and Women's Hospital, Harvard Medical School and Dr. Paul Aisen at the Alzheimer's Therapeutic Research Institute (ATRI), University of Southern California. The A4 and LEARN Studies are coordinated by ATRI at the University of Southern California, and the data are made available through the Laboratory for Neuro Imaging at the University of Southern California. The participants screening for the A4 Study provided permission to share their de-identified data in order to advance the quest to find a successful treatment for Alzheimer's disease. We would like to acknowledge the dedication of all the participants, the site personnel, and all of the partnership team members who continue to make the A4 and LEARN Studies possible. The complete A4 Study Team list is available on: a4study.org/a4-study-team. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf The amyloid PET and data were acquired during screening for the A4 Study and LEARN by the A4 Study Team. Full team authorship list available at https://a4study.org/ AIBL acknowledgement Data used in the preparation of this article was obtained from the Australian Imaging Biomarkers and Lifestyle flagship study of ageing (AIBL) funded by the Commonwealth Scientific and Industrial Research Organisation (CSIRO). The AIBL researchers, unless listed, contributed data but did not participate in the analysis or writing of this report. AIBL researchers are listed at www.aibl.csiro.au. Funding Information: AIBL acknowledgement Data used in the preparation of this article was obtained from the Australian Imaging Biomarkers and Lifestyle flagship study of ageing (AIBL) funded by the Commonwealth Scientific and Industrial Research Organisation (CSIRO). The AIBL researchers, unless listed, contributed data but did not participate in the analysis or writing of this report. AIBL researchers are listed at www.aibl.csiro.au . Funding Information: Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: We thank all the participants and their families, as well as the involved cohorts, institutions, and their staff. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30 AG066444 (JCM), P01 AG03991 (JCM), and P01 AG026276 (JCM). This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/ ) and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Funding Information: The A4 Study is a secondary prevention trial in preclinical Alzheimer's disease, aiming to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. The A4 Study is funded by a public-private-philanthropic partnership, including funding from the National Institutes of Health-National Institute on Aging (R01 AG063689, U24 AG057437) Eli Lilly and Company, Alzheimer's Association, Accelerating Medicines Partnership, GHR Foundation, an anonymous foundation and additional private donors, with in-kind support from Avid and Cogstate. The companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study is funded by the Alzheimer's Association and GHR Foundation. The A4 and LEARN Studies are led by Dr. Reisa Sperling at Brigham and Women's Hospital, Harvard Medical School and Dr. Paul Aisen at the Alzheimer's Therapeutic Research Institute (ATRI), University of Southern California. The A4 and LEARN Studies are coordinated by ATRI at the University of Southern California, and the data are made available through the Laboratory for Neuro Imaging at the University of Southern California. The participants screening for the A4 Study provided permission to share their de-identified data in order to advance the quest to find a successful treatment for Alzheimer's disease. We would like to acknowledge the dedication of all the participants, the site personnel, and all of the partnership team members who continue to make the A4 and LEARN Studies possible. The complete A4 Study Team list is available on: a4study.org/a4-study-team. Funding Information: This work was supported by grants from the National Institutes of Health, R01 AG044546 (CC), P01 AG003991 (CC, JCM), RF1 AG053303 (CC), RF1 AG058501 (CC), U01 AG058922 (CC), R01 AG064877 (MIK), P30 AG066468 (MIK), U01 AT000162 (MIK), K23 AG062750 (HY), and the Chan Zuckerberg Initiative (CZI), the Michael J. Fox Foundation (LI, CC), the Department of Defense (LI- W81XWH2010849), and the Alzheimer’s Association Zenith Fellows Award (ZEN-22–848604, awarded to CC). Dr. Mathis and Dr. Klunk receive royalty payments from GE Healthcare (indirect through a license agreement with the University of Pittsburgh). GE Healthcare holds a license agreement with the University of Pittsburgh based on the technology described in this manuscript. Dr. Mathis and Dr Klunk are a co-inventor of PiB and, as such, has a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of this manuscript. All other authors have no conflicts of interest with this work. CC has received research support from: GSK and EISAI. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid Genomics and Circular Genomics and owns Stocks. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - Amyloid PET
KW - Brain amyloidosis
KW - GWAS
KW - Meta-analysis
KW - Multi-ethnic
UR - http://www.scopus.com/inward/record.url?scp=85153912397&partnerID=8YFLogxK
U2 - 10.1186/s40478-023-01563-4
DO - 10.1186/s40478-023-01563-4
M3 - Article
C2 - 37101235
AN - SCOPUS:85153912397
SN - 2051-5960
VL - 11
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
M1 - 68
ER -