학술논문
Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.
Document Type
Academic Journal
Author
Ali M; Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA.; Archer DB; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, TN, USA.; Gorijala P; Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA.; Western D; Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA.; Timsina J; Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA.; Fernández MV; Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA.; Wang TC; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, TN, USA.; Satizabal CL; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health, San Antonio, TX, 78229, USA.; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.; Framingham Heart Study, Framingham, MA, USA.; Yang Q; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.; Beiser AS; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.; Framingham Heart Study, Framingham, MA, USA.; Wang R; Boston University, Boston, MA, USA.; Chen G; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.; Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.; Gordon B; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.; Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.; Benzinger TLS; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.; Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.; Xiong C; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.; Morris JC; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.; Department of Neurology, Washington University, St Louis, MO, USA.; Bateman RJ; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.; Department of Neurology, Washington University, St Louis, MO, USA.; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.; Karch CM; Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.; McDade E; Department of Neurology, Washington University, St Louis, MO, USA.; Goate A; Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Seshadri S; Framingham Heart Study, Framingham, MA, USA.; Boston University School of Medicine, Boston, MA, USA.; Mayeux RP; The Department of Neurology, Columbia University, New York, NY, USA.; Sperling RA; Department of Neurology, Harvard Medical School, Boston, MA, USA.; Brigham and Women's Hospital and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Buckley RF; Brigham and Women's Hospital and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA.; Johnson KA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Won HH; Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.; Jung SH; Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.; Kim HR; Department of Neurology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Republic of Korea.; Seo SW; Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.; Kim HJ; Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.; Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.; Mormino E; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.; Laws SM; Centre for Precision Health, Edith Cowan University, 270 Joondalup Dr, Joondalup, WA, 6027, Australia.; Fan KH; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.; Kamboh MI; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.; Vemuri P; Department of Radiology, Mayo Clinic-Minnesota, Rochester, MN, 55905, USA.; Ramanan VK; Department of Neurology, Mayo Clinic-Minnesota, Rochester, MN, 55905, USA.; Yang HS; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, USA.; Wenzel A; Wisconsin Alzheimer's Institute, Madison, WI, USA.; Rajula HSR; UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Team ELEANOR, 33000, Bordeaux, France.; Mishra A; UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Team ELEANOR, 33000, Bordeaux, France.; Dufouil C; UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Team ELEANOR, 33000, Bordeaux, France.; Debette S; UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Team ELEANOR, 33000, Bordeaux, France.; Department of Neurology, Boston University School of Medicine, Boston, MA, 2115, USA.; Department of Neurology, CHU de Bordeaux, 33000, Bordeaux, France.; Lopez OL; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.; DeKosky ST; Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.; Tao F; Neurogenomics, Genetics-Guided Dementia Discovery, Eisai, Inc, Cambridge, MA, USA.; Nagle MW; Neurogenomics, Genetics-Guided Dementia Discovery, Eisai, Inc, Cambridge, MA, USA.; Hohman TJ; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, TN, USA.; Sung YJ; Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.; NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA.; Dumitrescu L; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, TN, USA.; Cruchaga C; Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.; NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA. cruchagac@wustl.edu.; Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.; Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, USA. cruchagac@wustl.edu.
Source
Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE
Subject
Language
English
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.
(© 2023. The Author(s).)
(© 2023. The Author(s).)