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

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      1 , 1 , 2 , 1 , 3 , 4 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 14 , 1 , 15 , 16 , 17 , 7 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 1 , 8 , 25 , 26 , 27 , 28 , the Alzheimer's Disease Genetics Consortium (ADGC), 26 , 29 , *

      PLoS Genetics

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          Abstract

          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.

          Author Summary

          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 (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.

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          Most cited references 29

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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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            Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

            The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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              Neuropathological stageing of Alzheimer-related changes

               H Braak,  E Braak (1991)
              Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                September 2014
                4 September 2014
                : 10
                : 9
                Affiliations
                [1 ]John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America
                [2 ]Division of Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [3 ]Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America
                [4 ]Department of Psychiatry & Behavioral Sciences, University of Miami, Miami, Florida, United States of America
                [5 ]Department of Molecular Neuroscience, University College London, London, United Kingdom
                [6 ]New York Brain Bank, Columbia University, New York, New York, United States of America
                [7 ]Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America
                [8 ]Department of Neurological Sciences, Rush University, Chicago, Illinois, United States of America
                [9 ]Department of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, United States of America
                [10 ]Group Health Research Institute, Seattle, Washington, United States of America
                [11 ]Department of Medicine, University of Washington, Seattle, Washington, United States of America
                [12 ]Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America
                [13 ]Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
                [14 ]Department of Neurology, University of Miami, Miami, Florida, United States of America
                [15 ]Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, United States of America
                [16 ]Department of Psychiatry, Mount Sinai Hospital, New York, New York, United States of America
                [17 ]Department of Neurology, Oregon Health & Science University, Portland, Oregon, United States of America
                [18 ]Biomedical Genetics, Boston University School of Public Health, Boston, Massachusetts, United States of America
                [19 ]C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America
                [20 ]Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, United States of America
                [21 ]Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
                [22 ]Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
                [23 ]Department of Epidemiology, National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, United States of America
                [24 ]Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America
                [25 ]Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, United States of America
                [26 ]Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [27 ]Arizona Alzheimer's Consortium, Banner Alzheimer's Institute, Phoenix, Arizona, United States of America
                [28 ]Department of Psychiatry, University of Arizona, Phoenix, Arizona, United States of America
                [29 ]Department of Pathology, University of Washington, Seattle, Washington, United States of America
                Georgia Institute of Technology, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GWB DWD MPF BG JAS EMR GDS TJM. Analyzed the data: GWB GDS KH ACN ERM MH JJC LD JRG HG JDB LAF JLH MAPV. Contributed reagents/materials/analysis tools: DWD MPF BG JAS EMR TJM AJM JH JPV SGY DAB PLDJ EBL PKC MIK JKK DCM PK BTH WAK RPM JQT. Wrote the paper: GWB GDS TJM. Critically reviewed manuscript: KH ACN ERM MH JJC LD JRG HG JDB LAF JH JLH MAPV DWD MPF BG JAS EMR AJM JPV SGY DAB PLDJ EBL PKC MIK JKK DCM PK BTH WAK RPM JQT.

                ¶ Membership of the Alzheimer’s Disease Genetics Consortium (ADGC) is provided in Text S1.

                Article
                PGENETICS-D-14-00298
                10.1371/journal.pgen.1004606
                4154667
                25188341

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 15
                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 Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's 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), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MAP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Genome-Wide Association Studies
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Dementia
                Neurology
                Neurodegenerative Diseases

                Genetics

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