Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

PLoS Genetics, Sep 2014

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.

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Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

et al. (2014) Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias. PLoS Genet 10(9): e1004606. doi:10.1371/journal.pgen.1004606 Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias Gary W. Beecham 0 Kara Hamilton 0 Adam C. Naj 0 Eden R. Martin 0 Matt Huentelman 0 Amanda J. Myers 0 Jason J. Corneveaux 0 John Hardy 0 Jean-Paul Vonsattel 0 Steven G. Younkin 0 David A. Bennett 0 Philip L. De Jager 0 Eric B. Larson 0 Paul K. Crane 0 M. Ilyas Kamboh 0 Julia K. Kofler 0 Deborah C. Mash 0 Linda Duque 0 John R. Gilbert 0 Harry Gwirtsman 0 Joseph D. Buxbaum 0 Patricia Kramer 0 Dennis W. Dickson 0 Lindsay A. Farrer 0 Matthew P. Frosch 0 Bernardino Ghetti 0 Jonathan L. Haines 0 Bradley T. Hyman 0 Walter A. Kukull 0 Richard P. Mayeux 0 Margaret A. Pericak-Vance 0 Julie A. Schneider 0 John Q. Trojanowski 0 Eric M. Reiman 0 the 0 Alzheimer's Disease Genetics Consortium (ADGC)" 0 Gerard D. Schellenberg 0 Thomas J. Montine 0 1 Greg Gibson, Georgia Institute of Technology, United States of America 0 Table S17 Descriptive statistics of cohorts. AAO: age at onset; AAD: age at death; AAE: age at exam; SD: standard deviation. APOE: relative frequency of APOE genotypes where 1 represents E2 or E3. Cohorts: ACT: Adult Changes in Thought Study; ADC: Alzheimer's Disease Center; TGEN: Translational Genomics Research Institute; LOAD: National Institute on Aging Late- Onset Alzheimer's Disease Family Study; MAYO: Mayo Clinic Alzheimer's Disease Research Center; ROSMAP: Religious Orders Study and Memory and Aging Project; UPITT: University of Pittsburgh Alzheimer's Disease Research Center; UM/MASH: University of Miami Brain Endowment Bank; OHSU: Oregon Health & Science University Alzheimer's Disease Center; UM/ VU/MSSM: University of Miami Hussman Institute for Human Genomics/Vanderbilt University Center for Human Genetics Research/Mount Sinai School of Medicine. (PDF) 2 www.plosgenetics.org Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias. - Funding: The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232, the Banner Alzheimers Foundation, The Johnnie B. Byrd Sr. Alzheimers Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimers Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Ba (...truncated)


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Gary W. Beecham, Kara Hamilton, Adam C. Naj, Eden R. Martin, Matt Huentelman, Amanda J. Myers, Jason J. Corneveaux, John Hardy, Jean-Paul Vonsattel, Steven G. Younkin, David A. Bennett, Philip L. De Jager, Eric B. Larson, Paul K. Crane, M. Ilyas Kamboh, Julia K. Kofler, Deborah C. Mash, Linda Duque, John R. Gilbert, Harry Gwirtsman, Joseph D. Buxbaum, Patricia Kramer, Dennis W. Dickson, Lindsay A. Farrer, Matthew P. Frosch, Bernardino Ghetti, Jonathan L. Haines, Bradley T. Hyman, Walter A. Kukull, Richard P. Mayeux, Margaret A. Pericak-Vance, Julie A. Schneider, John Q. Trojanowski, Eric M. Reiman, the Alzheimer's Disease Genetics Consortium (ADGC), Gerard D. Schellenberg, Thomas J. Montine. Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias, PLoS Genetics, 2014, 9, DOI: 10.1371/journal.pgen.1004606