344 results on '"Steven G. Younkin"'
Search Results
2. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study
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Eric M. Reiman, Joseph F. Arboleda-Velasquez, Yakeel T. Quiroz, Matthew J. Huentelman, Thomas G. Beach, Richard J. Caselli, Yinghua Chen, Yi Su, Amanda J. Myers, John Hardy, Jean Paul Vonsattel, Steven G. Younkin, David A. Bennett, Philip L. De Jager, Eric B. Larson, Paul K. Crane, C. Dirk Keene, M. Ilyas Kamboh, Julia K. Kofler, Linda Duque, John R. Gilbert, Harry E. Gwirtsman, Joseph D. Buxbaum, Dennis W. Dickson, Matthew P. Frosch, Bernardino F. Ghetti, Kathryn L. Lunetta, Li-San Wang, Bradley T. Hyman, Walter A. Kukull, Tatiana Foroud, Jonathan L. Haines, Richard P. Mayeux, Margaret A. Pericak-Vance, Julie A. Schneider, John Q. Trojanowski, Lindsay A. Farrer, Gerard D. Schellenberg, Gary W. Beecham, Thomas J. Montine, Gyungah R. Jun, and The Alzheimer’s Disease Genetics Consortium
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Science - Abstract
APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.
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- 2020
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3. Alzheimer’s disease and progressive supranuclear palsy share similar transcriptomic changes in distinct brain regions
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Xue Wang, Mariet Allen, Özkan İş, Joseph S. Reddy, Frederick Q. Tutor-New, Monica Castanedes Casey, Minerva M. Carrasquillo, Stephanie R. Oatman, Yuhao Min, Yan W. Asmann, Cory Funk, Thuy Nguyen, Charlotte C.G. Ho, Kimberly G. Malphrus, Nicholas T. Seyfried, Allan I. Levey, Steven G. Younkin, Melissa E. Murray, Dennis W. Dickson, Nathan D. Price, Todd E. Golde, and Nilüfer Ertekin-Taner
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Aging ,Neuroscience ,Medicine - Abstract
Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer’s disease (AD), however, neither disease nor brain region specificity of these transcriptome alterations has been explored. Using RNA-Seq data from 231 temporal cortex and 224 cerebellum samples from patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identified a striking correlation in the directionality and magnitude of gene expression changes between these 2 neurodegenerative proteinopathies. Further, the transcriptomic changes in AD and PSP brains ware highly conserved between the temporal and cerebellar cortices, indicating that highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or downregulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of 2 distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex, and ubiquitous molecular alterations in neurodegenerative diseases.
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- 2022
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4. Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight
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Mark T. W. Ebbert, Tanner D. Jensen, Karen Jansen-West, Jonathon P. Sens, Joseph S. Reddy, Perry G. Ridge, John S. K. Kauwe, Veronique Belzil, Luc Pregent, Minerva M. Carrasquillo, Dirk Keene, Eric Larson, Paul Crane, Yan W. Asmann, Nilufer Ertekin-Taner, Steven G. Younkin, Owen A. Ross, Rosa Rademakers, Leonard Petrucelli, and John D. Fryer
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Camouflaged genes ,Dark genes ,Long-read sequencing ,Pacific Biosciences (PacBio) ,Oxford Nanopore Technologies (ONT) ,10x Genomics ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background The human genome contains “dark” gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions. Results Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer’s Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer’s disease gene, found in disease cases but not in controls. Conclusions While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer’s disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.
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- 2019
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5. Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease
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Jaeyoon Chung, Xiaoling Zhang, Mariet Allen, Xue Wang, Yiyi Ma, Gary Beecham, Thomas J. Montine, Steven G. Younkin, Dennis W. Dickson, Todd E. Golde, Nathan D. Price, Nilüfer Ertekin-Taner, Kathryn L. Lunetta, Jesse Mez, Alzheimer’s Disease Genetics Consortium, Richard Mayeux, Jonathan L. Haines, Margaret A. Pericak-Vance, Gerard Schellenberg, Gyungah R. Jun, and Lindsay A. Farrer
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Alzheimer’s disease ,Neuropathological traits ,Genome-wide association study ,Pleiotropy analysis ,HDAC9 ,ECRG4 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Simultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study. Methods We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. Results Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10−6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10−3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10−3) and visual (P = 5.6 × 10−4) cortices. Conclusions Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
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- 2018
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6. Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience
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Perry G. Ridge, Celeste M. Karch, Simon Hsu, Ivan Arano, Craig C. Teerlink, Mark T. W. Ebbert, Josue D. Gonzalez Murcia, James M. Farnham, Anna R. Damato, Mariet Allen, Xue Wang, Oscar Harari, Victoria M. Fernandez, Rita Guerreiro, Jose Bras, John Hardy, Ronald Munger, Maria Norton, Celeste Sassi, Andrew Singleton, Steven G. Younkin, Dennis W. Dickson, Todd E. Golde, Nathan D. Price, Nilüfer Ertekin-Taner, Carlos Cruchaga, Alison M. Goate, Christopher Corcoran, JoAnn Tschanz, Lisa A. Cannon-Albright, John S. K. Kauwe, and for the Alzheimer’s Disease Neuroimaging Initiative
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Alzheimer’s disease ,Protective variants ,Whole genome sequencing ,Utah Population Database ,Linkage analyses ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background While age and the APOE ε4 allele are major risk factors for Alzheimer’s disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. Methods We used over 200 “AD resilient” individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs. Results Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04). Conclusions Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.
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- 2017
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7. Author Correction: APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
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Jing Zhao, Yuan Fu, Yu Yamazaki, Yingxue Ren, Mary D. Davis, Chia-Chen Liu, Wenyan Lu, Xue Wang, Kai Chen, Yesesri Cherukuri, Lin Jia, Yuka A. Martens, Lucy Job, Francis Shue, Thanh Thanh Nguyen, Steven G. Younkin, Neill R. Graff-Radford, Zbigniew K. Wszolek, David A. Brafman, Yan W. Asmann, Nilüfer Ertekin-Taner, Takahisa Kanekiyo, and Guojun Bu
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Science - Published
- 2021
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8. Correction to: Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience
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Perry G. Ridge, Celeste M. Karch, Simon Hsu, Ivan Arano, Craig C. Teerlink, Mark T. W. Ebbert, Josue D. Gonzalez Murcia, James M. Farnham, Anna R. Damato, Mariet Allen, Xue Wang, Oscar Harari, Victoria M. Fernandez, Rita Guerreiro, Jose Bras, John Hardy, Ronald Munger, Maria Norton, Celeste Sassi, Andrew Singleton, Steven G. Younkin, Dennis W. Dickson, Todd E. Golde, Nathan D. Price, Nilüfer Ertekin-Taner, Carlos Cruchaga, Alison M. Goate, Christopher Corcoran, JoAnn Tschanz, Lisa A. Cannon-Albright, John S. K. Kauwe, and for the Alzheimer’s Disease Neuroimaging Initiative
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Medicine ,Genetics ,QH426-470 - Abstract
Correction The original version of this article [1] unfortunately contained a typographical error. The ‘Alzheimer’s Disease Neuroimaging Initiative’ was erroneously included as ‘Alzheimer’s Disease Neuroimaging Initative’ in the author list of the article.
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- 2018
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9. A Presenilin 1 Mutation Associated with Familial Frontotemporal Dementia Inhibits γ-Secretase Cleavage of APP and Notch
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Zareen Amtul, Patrick A. Lewis, Sian Piper, Richard Crook, Matt Baker, Kirk Findlay, Andrew Singleton, Marion Hogg, Linda Younkin, Steven G. Younkin, John Hardy, Michael Hutton, Bradley F. Boeve, David Tang-Wai, and Todd E. Golde
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
A novel presenilin 1 mutation, insR352, associated with a frontal temporal dementia phenotype has been identified (E. A. Rogaeva et al., 2001, Neurology 57, 621–625). This mutation does not increase Aβ42 levels, but instead acts as dominant negative presenilin, decreasing amyloid β protein (Aβ) production by inhibiting γ-secretase cleavage of the Aβ precursor. The distinct clinical phenotype associated with this mutation suggests that chronic partial inhibition of γ-secretase activity may result in neurodegeneration.
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- 2002
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10. Alterations in Cerebral Blood Flow and Glucose Utilization in Mice Overexpressing the Amyloid Precursor Protein
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Kiyoshi Niwa, Ken Kazama, Steven G. Younkin, George A. Carlson, and Costantino Iadecola
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Alzheimer's disease ,cerebral blood flow ,autoradiography ,cerebrovascular regulation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
We have used quantitative autoradiographic techniques to study the relationship between cerebral blood flow (CBF) and glucose utilization (CGU) in two lines of transgenic mice overexpressing Swedish mutant amyloid precursor protein (APP) and APP-derived Aβ peptides. Mice were studied at an age when there are no amyloid plaques. In the 2123 line, CBF was reduced only in telencephalic regions with no corresponding decrease in CGU. In 2576 transgenics, a line with higher levels of Aβ peptide, both CBF and CGU were reduced throughout the brain. The data indicate that Aβ induces alterations in resting CBF that are either associated with or independent of alterations in CGU and that occur in the absence of amyloid deposition in neuropil of blood vessels. These observations support the hypothesis that cerebrovascular and metabolic abnormalities are early events in the pathogenesis of Alzheimer's disease.
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- 2002
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11. Cholesterol-Dependent γ-Secretase Activity in Buoyant Cholesterol-Rich Membrane Microdomains
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Suzanne Wahrle, Pritam Das, Andrew C. Nyborg, Chris McLendon, Mikio Shoji, Takeshi Kawarabayashi, Linda H. Younkin, Steven G. Younkin, and Todd E. Golde
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Aβ ,Alzheimer's disease ,γ-secretase ,presenilin ,lipid raft ,cholesterol ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Buoyant membrane fractions containing presenilin 1 (PS1), an essential component of the γ-secretase complex, and APP CTFβ, a γ-secretase substrate, can be isolated from cultured cells and brain by several different fractionation procedures that are compatible with in vitro γ-secretase assays. Analysis of these gradients for amyloid β protein (Aβ) and CTFγ production indicated that γ-secretase activity is predominantly localized in these buoyant membrane microdomains. Consistent with this localization, we find that γ-secretase activity is cholesterol dependent. Depletion of membrane cholesterol completely inhibits γ-secretase cleavage, which can be restored by cholesterol replacement. Thus, altering cholesterol levels may influence the development of Alzheimer's disease (AD) by influencing production and deposition of Aβ within cholesterol rich membrane microdomains.
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- 2002
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12. Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein
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Martin Citron, Christopher B. Eckman, Thekla S. Diehl, Chris Corcoran, Beth L. Ostaszewski, Weiming Xia, Georges Levesque, Peter St. George Hyslop, Steven G. Younkin, and Dennis J. Selkoe
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Humans harboring missense mutations in the presenilin 1 (PS1) gene undergo progressive cerebral deposition of the 42-residue amyloid β-protein (Aβ42) at an early age and develop severe Alzheimer's disease. Aβ42is selectively elevated in the conditioned media of cells expressing mutant but not wild-type PS1, indicating that presenilin mutations alter APP processing. Here we analyze the effects of various PS1 mutant constructs on the cellular production of Aβ42. A construct expressing only the PS1 N-terminal endoproteolytic fragment with the mutation Y115H causes no significant increase in Aβ42, whereas a full-length PS1 construct with the same mutation does. This result suggests that the pathogenic effect of mutant presenilins is produced by the full-length molecule even though only a minor proportion of total PS1 occurs as holoprotein in tissues and cell lines. We demonstrate that the effects of two different PS1 mutations are additive when engineered into the same PS1 molecule. Therefore, two mutations alter γ-secretase processing of APP more than one and the PS1 mutations described to date do not cause the maximum possible PS1-mediated rise in Aβ42. When a PS1 mutation was expressed in cells carrying the APPV717Imutation, Aβ42rose dramatically to become the predominant secreted Aβ species, an observation of interest for transgenic modeling of AD. Our results are consistent with the hypothesis that presenilin is a major regulator of the proteolytic processing of APP by γ-secretases.
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- 1998
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13. Co-expression of β-amyloid precursor protein (βAPP) and apolipoprotein E in cell culture: analysis of βAPP processing
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Anja Leona Biere, Beth Ostaszewski, Hongwei Zhao, Susan Gillespie, Steven G. Younkin, and Dennis J. Selkoe
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Alzheimer's disease ,amyloidosis ,β-amyloid peptide ,human ,lipoprotein ,transfection ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Apolipoprotein E (ApoE) is the major genetic risk factor for Alzheimer's disease (AD). The ApoE4 allele is associated with earlier disease onset and greater cerebral deposition of the amyloid beta peptide (Aβ), the major constituent of senile (amyloid) plaques. The molecular mechanism underlying these effects of ApoE4 remains unclear; ApoE alleles could have different influences on Aβ production, extracellular aggregation, or clearance. Because the missense mutations on chromosomes 14 and 21 that cause familial forms of AD appear to lead to increased secretion of Aβ, it is important to determine whether ApoE4 has a similar effect. Here, we have examined the effects of all three ApoE alleles on the processing of βAPP and the secretion of Aβ in intact cells. We established neural (HS683 human glioma) and non-neural (Chinese hamster ovary) cell culture systems that constitutively secrete both ApoE and Aβ at concentrations like those in human cerebrospinal fluid. βAPP metabolites, generated in the presence of each ApoE allele, were analysed and quantified by two methods: immunoprecipitation and phosphorimaging, and ELISA. We detected no consistent allele-specific effects of ApoE on βAPP processing in either cell type. Our data suggest that the higher amyloid burden found in AD subjects expressing ApoE4 is not due to increased amyloidogenic processing of βAPP, in contrast to findings in AD linked to chromosome 14 or 21. These co-expressing cell lines will be useful in the further search for the effects of ApoE on Aβ aggregation or clearance under physiologically relevant conditions.
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- 1995
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14. Correction: Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease.
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Lesley Jones, Peter A. Holmans, Marian L. Hamshere, Denise Harold, Valentina Moskvina, Dobril Ivanov, Andrew Pocklington, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Jaspreet Singh Pahwa, Nicola Jones, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol Brayne, David C. Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S. Brown, Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A. David Smith, Seth Love, Patrick G. Kehoe, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Britta Schürmann, Hendrik van den Bussche, Isabella Heuser, Oliver Peters, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison M. Goate, John S. K. Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panos Deloukas, Ammar Al-Chalabi, Christopher E. Shaw, Andrew B. Singleton, Rita Guerreiro, Thomas W. Mühleisen, Markus M. Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H.-Erich Wichmann, Eckhard Rüther, Minerva M. Carrasquillo, V. Shane Pankratz, Steven G. Younkin, John Hardy, Michael C. O'Donovan, Michael J. Owen, and Julie Williams
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Medicine ,Science - Published
- 2011
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15. Impact of variant-level batch effects on identification of genetic risk factors in large sequencing studies.
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Daniel P Wickland, Yingxue Ren, Jason P Sinnwell, Joseph S Reddy, Cyril Pottier, Vivekananda Sarangi, Minerva M Carrasquillo, Owen A Ross, Steven G Younkin, Nilüfer Ertekin-Taner, Rosa Rademakers, Matthew E Hudson, Liudmila Sergeevna Mainzer, Joanna M Biernacka, and Yan W Asmann
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Medicine ,Science - Abstract
Genetic studies have shifted to sequencing-based rare variants discovery after decades of success in identifying common disease variants by Genome-Wide Association Studies using Single Nucleotide Polymorphism chips. Sequencing-based studies require large sample sizes for statistical power and therefore often inadvertently introduce batch effects because samples are typically collected, processed, and sequenced at multiple centers. Conventionally, batch effects are first detected and visualized using Principal Components Analysis and then controlled by including batch covariates in the disease association models. For sequencing-based genetic studies, because all variants included in the association analyses have passed sequencing-related quality control measures, this conventional approach treats every variant as equal and ignores the substantial differences still remaining in variant qualities and characteristics such as genotype quality scores, alternative allele fractions (fraction of reads supporting alternative allele at a variant position) and sequencing depths. In the Alzheimer's Disease Sequencing Project (ADSP) exome dataset of 9,904 cases and controls, we discovered hidden variant-level differences between sample batches of three sequencing centers and two exome capture kits. Although sequencing centers were included as a covariate in our association models, we observed differences at the variant level in genotype quality and alternative allele fraction between samples processed by different exome capture kits that significantly impacted both the confidence of variant detection and the identification of disease-associated variants. Furthermore, we found that a subset of top disease-risk variants came exclusively from samples processed by one exome capture kit that was more effective at capturing the alternative alleles compared to the other kit. Our findings highlight the importance of additional variant-level quality control for large sequencing-based genetic studies. More importantly, we demonstrate that automatically filtering out variants with batch differences may lead to false negatives if the batch discordances come largely from quality differences and if the batch-specific variants have better quality.
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- 2021
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16. New insights into the genetic etiology of Alzheimer's disease and related dementias
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Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. S., Calero, M., Cantwell, L. B., Chene, G., Chung, J., Cuccaro, M. L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H. -H., Chillotti, C., Ciccone, S., Claassen, J. A. H. R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M. C., Daniele, A., Dardiotis, E., Dartigues, J. -F., de Deyn, P. P., de Paiva Lopes, K., de Witte, L. D., Debette, S., Deckert, J., del Ser, T., Denning, N., Destefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P. D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K. M., Fabrizio, T., Nielsen, S. F., Fardo, D. W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C. B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T. M., Fostinelli, S., Fox, N. C., Franco-Macías, E., Bullido, M. J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J. M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A. M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J. L., Hamilton-Nelson, K. L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A. M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M. T., Hernández, I., Herrmann, M. J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R. H., Hulsman, M., Humphrey, J., Biessels, G. J., Jian, X., Johansson, C., Jun, G. R., Kastumata, Y., Kauwe, J., Kehoe, P. G., Kilander, L., Ståhlbom, A. K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M. H., Kukull, W. A., Kuksa, P. P., Kunkle, B. W., Kuzma, A. B., Lage, C., Laukka, E. J., Launer, L., Lauria, A., Lee, C. -Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A. L., Love, S., Löwemark, M., Luckcuck, L., Lunetta, K. L., Ma, Y., Macías, J., Macleod, C. A., Maier, W., Mangialasche, F., Spallazzi, M., Marquié, M., Marshall, R., Martin, E. R., Montes, A. M., Rodríguez, C. M., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Medina, M., Meggy, A., Mehrabian, S., Mendoza, S., Menéndez-González, M., Mir, P., Moebus, S., Mol, M., Molina-Porcel, L., Montrreal, L., Morelli, L., Moreno, F., Morgan, K., Mosley, T., Nöthen, M. M., Muchnik, C., Mukherjee, S., Nacmias, B., Ngandu, T., Nicolas, G., Nordestgaard, B. G., Olaso, R., Orellana, A., Orsini, M., Ortega, G., Padovani, A., Paolo, C., Papenberg, G., Parnetti, L., Pasquier, F., Pastor, P., Peloso, G., Pérez-Cordón, A., Pérez-Tur, J., Pericard, P., Peters, O., Pijnenburg, Y. A. L., Pineda, J. 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Hyman, Linda, S Hynan, Laura, Ibanez, Gail, P Jarvik, Suman, Jayadev, Lee-Way, Jin, Kim, Johnson, Leigh, Johnson, M Ilyas Kamboh, Anna, M Karydas, Mindy, J Katz, Jeffrey, A Kaye, C Dirk Keene, Aisha, Khaleeq, Ronald, Kim, Janice, Knebl, Neil, W Kowall, Joel, H Kramer, Pavel, P Kuksa, Frank, M LaFerla, James, J Lah, Eric, B Larson, Chien-Yueh, Lee, Edward, B Lee, Alan, Lerner, Yuk Yee Leung, James, B Leverenz, Allan, I Levey, Mingyao, Li, Andrew, P Lieberman, Richard, B Lipton, Mark, Logue, Constantine, G Lyketsos, John, Malamon, Douglas, Mains, Daniel, C Marson, Frank, Martiniuk, Deborah, C Mash, Eliezer, Masliah, Paul, Massman, Arjun, Masurkar, Wayne, C McCormick, Susan, M McCurry, Andrew, N McDavid, Ann, C McKee, Marsel, Mesulam, Jesse, Mez, Bruce, L Miller, Carol, A Miller, Joshua, W Miller, Thomas, J Montine, Edwin, S Monuki, John, C Morris, Amanda, J Myers, Trung, Nguyen, Sid, O'Bryant, John, M Olichney, Marcia, Ory, Raymond, Palmer, Joseph, E Parisi, Henry, L Paulson, Valory, 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Impulsivity & Attention, APH - Personalized Medicine, APH - Methodology, Bellenguez, Céline [0000-0002-1240-7874], Küçükali, Fahri [0000-0002-3835-9639], Amin, Najaf [0000-0002-8944-1771], Holmans, Peter A [0000-0003-0870-9412], van der Lee, Sven J [0000-0003-1606-8643], Costa, Marcos R [0000-0002-4928-2163], Kuulasmaa, Teemu [0000-0002-1795-7314], Yang, Qiong [0000-0002-3658-1375], de Rojas, Itziar [0000-0002-2148-381X], Bis, Joshua C [0000-0002-3409-1110], Yaqub, Amber [0000-0002-3579-8054], Prokic, Ivana [0000-0002-0370-1473], Chapuis, Julien [0000-0002-5802-2857], Ahmad, Shahzad [0000-0002-8658-3790], Giedraitis, Vilmantas [0000-0003-3423-2021], Garcia-Gonzalez, Pablo [0000-0003-0125-5403], Alcolea, Daniel [0000-0002-3819-3245], Alvarez, Ignacio [0000-0002-8537-3935], Tsolaki, Anthoula [0000-0002-5563-7776], Baquero, Miquel [0000-0002-6861-1831], Pastor, Ana Belén [0000-0001-9637-4688], Berr, Claudine [0000-0001-5254-7655], Bessi, Valentina [0000-0002-6176-3584], Boada, Mercè [0000-0003-2617-3009], Bossù, Paola [0000-0002-1432-0078], Bråthen, Geir [0000-0003-3224-7983], Bressler, Jan [0000-0001-6578-4772], Bresner, Catherine [0000-0003-2673-9762], Brodaty, Henry [0000-0001-9487-6617], Brookes, Keeley J [0000-0003-2427-2513], Burholt, Vanessa [0000-0002-6789-127X], Bush, William S [0000-0002-9729-6519], Calero, Miguel [0000-0001-5366-3324], Chung, Jaeyoon [0000-0002-6431-9454], Cervera-Carles, Laura [0000-0003-2286-200X], Costantini, Emanuele [0000-0002-1096-8221], Dalmasso, Maria Carolina [0000-0002-4901-9955], de Paiva Lopes, Katia [0000-0002-0240-0126], de Witte, Lot D [0000-0002-7235-9958], Debette, Stéphanie [0000-0001-8675-7968], Del Ser, Teodoro [0000-0001-9806-7083], Dichgans, Martin [0000-0002-0654-387X], Diehl-Schmid, Janine [0000-0002-7745-1382], Diez-Fairen, Mónica [0000-0003-1882-0309], Djurovic, Srdjan [0000-0002-8140-8061], Dufouil, Carole [0000-0003-2442-4476], Escott-Price, Valentina [0000-0003-1784-5483], Ewers, Michael [0000-0001-5231-1714], Fabrizio, Tagliavini [0000-0003-1039-7315], Fladby, Tormod [0000-0002-9984-9797], Fornage, Myriam [0000-0003-0677-8158], Fox, Nick C [0000-0002-6660-657X], Bullido, María J [0000-0002-6477-1117], Froelich, Lutz [0000-0003-1494-0813], Galimberti, Daniela [0000-0002-9284-5953], García-Alberca, Jose Maria [0000-0003-2951-6644], Goate, Alison M [0000-0002-0576-2472], González-Pérez, Antonio [0000-0001-9771-5982], Green, Emma [0000-0002-8687-5590], Grünblatt, Edna [0000-0001-8505-7265], Gudnason, Vilmundur [0000-0001-5696-0084], Haapasalo, Annakaisa [0000-0003-0959-2957], Harwood, Janet [0000-0002-3225-0069], Heilmann-Heimbach, Stefanie [0000-0003-1057-465X], Herrmann, Martin J [0000-0001-9970-2122], Holstege, Henne [0000-0002-7688-3087], Biessels, Geert Jan [0000-0001-6862-2496], Jian, Xueqiu [0000-0002-0313-6494], Johansson, Charlotte [0000-0002-5351-1950], Jun, Gyungah R [0000-0002-3230-8697], Kastumata, Yuriko [0000-0002-0188-8094], Kehoe, Patrick G [0000-0002-7542-1139], Kornhuber, Johannes [0000-0002-8096-3987], Kosmidis, Mary H [0000-0001-8790-1220], Lage, Carmen [0000-0003-1703-121X], Launer, Lenore [0000-0002-3238-7612], Lee, Chien-Yueh [0000-0002-4304-974X], Lleó, Alberto [0000-0002-2568-5478], Lopez, Oscar [0000-0002-8546-8256], de Munain, Adolfo Lopez [0000-0002-9509-4032], Lunetta, Kathryn L [0000-0002-9268-810X], Ma, Yiyi [0000-0002-3609-8877], MacLeod, Catherine A [0000-0002-9314-7380], Marquié, Marta [0000-0002-0660-0950], Montes, Angel Martín [0000-0002-1694-786X], Mead, Simon [0000-0002-4326-1468], Medina, Miguel [0000-0002-7016-5340], Menéndez-González, Manuel [0000-0002-5218-0774], Mol, Merel [0000-0003-2533-2530], Morgan, Kevin [0000-0002-8217-2396], Nöthen, Markus M [0000-0002-8770-2464], Muchnik, Carolina [0000-0002-1542-3706], Nacmias, Benedetta [0000-0001-9338-9040], Nicolas, Gael [0000-0001-9391-7800], Nordestgaard, Børge G [0000-0002-1954-7220], Pasquier, Florence [0000-0001-9880-9788], Pastor, Pau [0000-0002-7493-8777], Peloso, Gina [0000-0002-5355-8636], Pérez-Cordón, Alba [0000-0002-6028-0791], Pérez-Tur, Jordi [0000-0002-9111-1712], Pericard, Pierre [0000-0001-8167-6448], Pineda, Juan A [0000-0002-3751-0296], Pisanu, Claudia [0000-0002-9151-4319], Posthuma, Danielle [0000-0001-7582-2365], Puerta, Raquel [0000-0002-1191-5893], Quenez, Olivier [0000-0002-8273-8505], Thomassen, Jesper Qvist [0000-0003-3484-9531], Real, Luis M [0000-0003-4932-7429], Reinders, Marcel JT [0000-0002-1148-1562], Reitz, Christiane [0000-0001-8757-7889], Riedel-Heller, Steffi [0000-0003-4321-6090], Rodriguez-Rodriguez, Eloy [0000-0001-7742-677X], Rongve, Arvid [0000-0002-0476-4134], Sáez, María Eugenia [0000-0001-9299-2534], Saltvedt, Ingvild [0000-0002-7897-9808], Juan, Pascual Sánchez [0000-0002-6081-8037], Sarnowski, Chloé [0000-0002-6090-7099], Satizabal, Claudia L [0000-0002-1115-4430], Schott, Jonathan M [0000-0003-2059-024X], Selbæk, Geir [0000-0001-6511-8219], Shadrin, Alexey A [0000-0002-7467-250X], Soininen, Hilkka [0000-0002-2785-9937], Solfrizzi, Vincenzo [0000-0002-8524-0315], Song, Yeunjoo [0000-0002-7452-3731], Sotolongo-Grau, Oscar [0000-0002-9679-0670], Spalletta, Gianfranco [0000-0002-7432-4249], Squassina, Alessio [0000-0001-7415-7607], Stordal, Eystein [0000-0002-2443-7923], Tosto, Giuseppe [0000-0001-7075-8245], Uitterlinden, Andre [0000-0002-7276-3387], Valladares, Otto [0000-0001-8055-2187], Broeckhoven, Christine Van [0000-0003-0183-7665], Vidal, Jean-Sébastien [0000-0001-6770-0720], Vogelgsang, Jonathan [0000-0001-9326-8193], Wagner, Michael [0000-0003-2589-6440], Wallon, David [0000-0002-2634-7198], Wiltfang, Jens [0000-0003-1492-5330], Woods, Bob [0000-0002-6781-651X], Yannakoulia, Mary [0000-0003-2171-7337], Zare, Habil [0000-0001-5902-6238], Zhang, Xiaoling [0000-0001-8237-1857], Farrer, Lindsay A [0000-0001-5533-4225], Psaty, Bruce M [0000-0002-7278-2190], Ghanbari, Mohsen [0000-0002-9476-7143], Raj, Towfique [0000-0002-9355-5704], Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
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tau Proteins/genetics ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neurologi ,MED/03 - GENETICA MEDICA ,45/43 ,Medizin ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,genetics [Alzheimer Disease] ,Genome-Wide Association Study ,Humans ,tau Proteins ,Alzheimer Disease ,Cognitive Dysfunction ,VARIANTS ,pathology [Alzheimer Disease] ,Tau Proteins ,Settore BIO/13 - Biologia Applicata ,Cognitive Dysfunction/psychology ,692/699/375/365/1283 ,IMPUTATION ,article ,1184 Genetics, developmental biology, physiology ,Biología y Biomedicina / Biología ,AMYLOID-BETA ,Settore MED/26 - NEUROLOGIA ,Neurology ,psychology [Cognitive Dysfunction] ,Medical Genetics ,Human ,Neuroscience(all) ,631/208/205/2138 ,All institutes and research themes of the Radboud University Medical Center ,SDG 3 - Good Health and Well-being ,ddc:570 ,Genetics ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,Medicinsk genetik ,MED/26 - NEUROLOGIA ,Alzheimer Disease/genetics ,neurology ,tau Protein ,NECROSIS-FACTOR-ALPHA ,RISK LOCI ,genetics [tau Proteins] ,PREDICTION MODELS ,Human medicine ,GENERATION ,RESPONSES - Abstract
25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
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- 2022
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17. Gene‐based polygenic score analysis identifies novel immune genes with deleterious variants that associate with Alzheimer’s disease
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Joseph S. Reddy, Xue Wang, Mariet Allen, Minerva M. Carrasquillo, Joanna M Biernacka, Jenkins D. Gregory, Brandon J Coombes, Nilufer Ertekin‐Taner, and Steven G. Younkin
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
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18. Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life
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B. Gwen Windham, A. Richey Sharrett, Adrienne Tin, Thomas H. Mosley, Chad Blackshear, Kevin J. Sullivan, Keenan A. Walker, Michael Griswold, Rebecca F. Gottesman, Steven G. Younkin, Michelle M. Mielke, David S. Knopman, and Jeannette Simino
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Male ,medicine.medical_specialty ,Amyloid beta-Peptides ,business.industry ,Middle Aged ,Logistic regression ,Lower risk ,medicine.disease ,Confidence interval ,Internal medicine ,Relative risk ,medicine ,Humans ,Dementia ,Cognitive Dysfunction ,Female ,Neurology (clinical) ,business ,Neurocognitive ,Body mass index ,Retrospective Studies ,Research Article ,Cohort study - Abstract
Background and ObjectivesTo evaluate the association between midlife plasma amyloid-β (Aβ1-42, Aβ1-40, Aβ42:Aβ40) and risk of mild cognitive impairment (MCI) and dementia.MethodsPlasma Aβ42 and Aβ40 were retrospectively measured with a fluorometric bead-based immunoassay in a subsample of the Atherosclerosis Risk in Communities cohort study. We investigated the relationship of plasma Aβ42, Aβ40, and Aβ42:Aβ40 ratio measured in midlife and late life and the change from midlife to late life to risk of MCI, dementia, and combined MCI/dementia outcomes in late life (from 2011–2019). We used multinomial logistic regressions estimating relative risk ratios (RRRs) of these cognitive outcomes vs cognitively normal adjusted for age, sex, education, site-race, APOE, hypertension, diabetes, and body mass index.ResultsA total of 2,284 participants were included (midlife mean age 59.2 ± 5.2, 57% female, 22% Black). Each doubling of midlife Aβ42:Aβ40 was associated with 37% lower risk of MCI/dementia (RRR 0.63, 95% confidence interval [CI] 0.46–0.87), but only up to approximately the median (spline model threshold 0.20). Every 1-SD increase in plasma Aβ42 (10 pg/mL) was associated with 13% lower risk of MCI/dementia (RRR 0.87, 95% CI 0.77–0.98), whereas every 1-SD increase in plasma Aβ40 (67 pg/mL) was associated with 15% higher risk of MCI/dementia (RRR 1.15, 95% CI 1.01–1.29). Associations were comparable but slightly weaker statistically when models were repeated using late-life plasma Aβ predictors. Aβ42 and Aβ40 increased from midlife to late life, but changes were not associated with cognitive outcomes.DiscussionMidlife measurement of plasma Aβ may have utility as a blood-based biomarker indicative of risk for future cognitive impairment.
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- 2021
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19. Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids
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Guojun Bu, Wenyan Lu, Xianlin Han, Jing Zhao, Xue Wang, Mary D. Davis, Meixia Pan, Nilufer Ertekin-Taner, Steven G. Younkin, Chia Chen Liu, Fuyao Li, Zbigniew K. Wszolek, Yuka A. Martens, Yan W. Asmann, Ziying Xu, Yuan Fu, Kai Chen, Neill R. Graff-Radford, Francis Shue, David A. Brafman, Takahisa Kanekiyo, Yingxue Ren, and Dennis W. Dickson
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Apolipoprotein E ,Pathology ,medicine.medical_specialty ,Synucleinopathies ,Induced Pluripotent Stem Cells ,Biology ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Mice ,Apolipoproteins E ,Lipidomics ,mental disorders ,Organoid ,medicine ,Animals ,Humans ,Protein Isoforms ,Original Paper ,Cholesterol ,Dementia with Lewy bodies ,Correction ,Lipid metabolism ,medicine.disease ,Lipid Metabolism ,Organoids ,chemistry ,alpha-Synuclein ,lipids (amino acids, peptides, and proteins) ,Neurology (clinical) ,Cerebral organoid - Abstract
APOE4 is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.
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- 2021
20. Polygenic risk score analysis identifies deleterious protein-coding variants in novel immune pathway genes ATP8B4, FCGR1A, and LILRB1 that associate with Alzheimer’s disease
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Joseph S. Reddy, Xue Wang, Mariet Allen, Minerva M. Carrasquillo, Joanna M. Biernacka, Gregory D. Jenkins, Brandon J. Coombes, Olivia Belbin, Todd E. Golde, Nilüfer Ertekin-Taner, and Steven G. Younkin
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Background: Alterations in innate immunity are pathologically associated with and genetically implicated in Alzheimer’s disease (AD). In the whole exome sequence (WES) dataset generated by the Alzheimer’s Disease Sequencing Project (ADSP), only the previously identified p.R47H variant in the innate immunity gene, TREM2, shows study-wide association with risk of AD. Using a novel approach, we searched the ADSP WES data to identify additional immune pathway genes with deleterious variants that, like TREM2.pR47H, show strong association with AD. Methods: Using polygenic risk scores (PRS) to analyze association with AD, we evaluated deleterious variants (CADD Phred-scaled score > 20) with a minor allele count of 20 or more in 228 genes comprising an immune co-expression network containing TREM2 (CENTREM2). A significant polygenic component composed of deleterious stop-gain and non-synonymous variants was identified, and false discovery rates were determined for the variants in this component. In genes harboring a significant variant, PRS for all variants in the genes were then analyzed. Results: The PRS for the 182 deleterious variants in CENTREM2 showed significant association with AD that was driven by 142 deleterious variants (136 non-synonymous, 6 stop-gain). In the 142 variant polygenic component, four variants had significant AD risk association: TREM2.pR47H, two deleterious stop-gain variants (FCGR1A.pR92X, and LILRB1.pY331X) in novel AD genes and 1 non-synonymous variant (ATP8B4.pG395S). Remarkably, PRS for the 36 additional variants in these four genes also showed significant association with AD. The PRS for all 40 variants in the 4 genes, showed significant, replicable association with AD and 3 additional variants in this polygenic component had significant false discovery rates: ATP8B4.pR1059Q, LILRB1.pP7P, and LILRB1.pY327Y. Conclusions: Here, we identify 3 immune pathway genes (ATP8B4, LILRB1, and FCGR1A) with a variant that associates with AD. Like TREM2.pR47H, each of the variants has a minor allele frequency less than 1% and is a deleterious, protein altering variant with a strong effect that increases or decreases (LILRB1.pY331X) risk of AD. Additional variants in these genes also alter risk of AD. The variants identified here are ideally suited for studies aimed at understanding how the innate immune system may be modulated to alter risk of AD.
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- 2022
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21. Polygenic risk score analysis identifies deleterious protein-coding variants in novel immune pathway genesATP8B4, FCGR1A, andLILRB1that associate with Alzheimer’s disease
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Joseph S. Reddy, Xue Wang, Mariet Allen, Minerva M. Carrasquillo, Joanna M. Biernacka, Gregory D. Jenkins, Brandon J. Coombes, Olivia Belbin, Todd E. Golde, Nilüfer Ertekin-Taner, and Steven G. Younkin
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BackgroundAlterations in innate immunity are pathologically associated with and genetically implicated in Alzheimer’s disease (AD). In the whole exome sequence (WES) dataset generated by the Alzheimer’s Disease Sequencing Project (ADSP), only the previously identified p.R47H variant in the innate immunity gene,TREM2, shows study-wide association with risk of AD. Using a novel approach, we searched the ADSP WES data to identify additional immune pathway genes with deleterious variants that, likeTREM2.pR47H, show strong association with AD.MethodsUsing polygenic risk scores (PRS) to analyze association with AD, we evaluated deleterious variants (CADD Phred-scaled score > 20) with a minor allele count of 20 or more in 228 genes comprising an immune co-expression network containingTREM2(CENTREM2). A significant polygenic component composed of deleterious stop-gain and non-synonymous variants was identified, and false discovery rates were determined for the variants in this component. In genes harboring a significant variant, PRS for all variants in the genes were then analyzed.ResultsThe PRS for the 182 deleterious variants in CENTREM2showed significant association with AD that was driven by 142 deleterious variants (136 non-synonymous, 6 stop-gain). In the 142 variant polygenic component, four variants had significant AD risk association:TREM2.pR47H, two deleterious stop-gain variants (FCGR1A.pR92X, andLILRB1.pY331X) in novel AD genes and 1 non-synonymous variant(ATP8B4.pG395S). Remarkably, PRS for the 36 additional variants in these four genes also showed significant association with AD. The PRS for all 40 variants in the 4 genes, showed significant, replicable association with AD and 3 additional variants in this polygenic component had significant false discovery rates:ATP8B4.pR1059Q,LILRB1.pP7P, andLILRB1.pY327Y.ConclusionsHere, we identify 3 immune pathway genes (ATP8B4, LILRB1, andFCGR1A) with a variant that associates with AD. LikeTREM2.pR47H, each of the variants has a minor allele frequency less than 1% and is a deleterious, protein altering variant with a strong effect that increases or decreases (LILRB1.pY331X) risk of AD. Additional variants in these genes also alter risk of AD. The variants identified here are ideally suited for studies aimed at understanding how the innate immune system may be modulated to alter risk of AD.
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- 2022
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22. Correction to: Apolipoprotein E regulates lipid metabolism and α‑synuclein pathology in human iPSC‑derived cerebral organoids
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Mary D. Davis, Yan W. Asmann, Guojun Bu, Yuan Fu, Nilufer Ertekin-Taner, Zbigniew K. Wszolek, Jing Zhao, Meixia Pan, Kai Chen, Chia Chen Liu, Neill R. Graff-Radford, Yingxue Ren, Fuyao Li, Dennis W. Dickson, Steven G. Younkin, Takahisa Kanekiyo, Xianlin Han, Francis Shue, Yuka A. Martens, Wenyan Lu, Ziying Xu, David A. Brafman, and Xue Wang
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Apolipoprotein E ,Cellular and Molecular Neuroscience ,Chemistry ,Organoid ,Lipid metabolism ,α synuclein ,Neurology (clinical) ,Pathology and Forensic Medicine ,Cell biology - Published
- 2021
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23. Integrative functional genomic analysis of intron retention in human and mouse brain with Alzheimer's disease
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Karen N. McFarland, Paramita Chakrabarty, Nicholas T. Seyfried, Xue Wang, Gilbert S. Omenn, Jeremy D. Burgess, Steven G. Younkin, Todd E. Golde, Cory C. Funk, Hong-Dong Li, Yona Levites, Nathan D. Price, Nilufer Ertekin-Taner, Dennis W. Dickson, Allan I. Levey, James J. Lah, Eric B. Dammer, Mariet Allen, Duc M. Duong, and Minerva M. Carrasquillo
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Proteomics ,Epidemiology ,Quantitative Trait Loci ,Genomics ,Computational biology ,Biology ,intron retention ,Transcriptome ,Pathogenesis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,alternative splicing ,Mice ,0302 clinical medicine ,Developmental Neuroscience ,Alzheimer Disease ,Gene expression ,Animals ,Humans ,Gene ,030304 developmental biology ,Homeodomain Proteins ,0303 health sciences ,Featured Articles ,Health Policy ,Alternative splicing ,Intron ,Brain ,Featured Article ,Alzheimer's disease ,Introns ,Psychiatry and Mental health ,Disease Models, Animal ,Expression quantitative trait loci ,gene expression ,Neurology (clinical) ,Autopsy ,Geriatrics and Gerontology ,030217 neurology & neurosurgery ,integrative analysis - Abstract
Intron retention (IR) has been implicated in the pathogenesis of complex diseases such as cancers; its association with Alzheimer's disease (AD) remains unexplored. We performed genome‐wide analysis of IR through integrating genetic, transcriptomic, and proteomic data of AD subjects and mouse models from the Accelerating Medicines Partnership‐Alzheimer's Disease project. We identified 4535 and 4086 IR events in 2173 human and 1736 mouse genes, respectively. Quantitation of IR enabled the identification of differentially expressed genes that conventional exon‐level approaches did not reveal. There were significant correlations of intron expression within innate immune genes, like HMBOX1, with AD in humans. Peptides with a high probability of translation from intron‐retained mRNAs were identified using mass spectrometry. Further, we established AD‐specific intron expression Quantitative Trait Loci, and identified splicing‐related genes that may regulate IR. Our analysis provides a novel resource for the search for new AD biomarkers and pathological mechanisms.
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- 2021
24. Alzheimer’s disease and progressive supranuclear palsy share similar transcriptomic changes in distinct brain regions
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Steven G. Younkin, Todd E. Golde, Dennis W. Dickson, Joseph S. Reddy, Yuhao Min, Monica Castanedes Casey, Nicholas T. Seyfried, Stephanie R Oatman, Kimberly G. Malphrus, Nathan D. Price, Xue Wang, Thuy Nguyen, Özkan İş, Frederick Q. Tutor-New, Minerva M. Carrasquillo, Cory C. Funk, Charlotte C.G. Ho, Nilufer Ertekin-Taner, Allan I. Levey, Melissa E. Murray, Yan W. Asmann, and Mariet Allen
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Male ,Aging ,Cerebellum ,Bioinformatics ,Neuropathology ,Biology ,Progressive supranuclear palsy ,Transcriptome ,Alzheimer Disease ,medicine ,Humans ,Epigenetics ,Aged ,Temporal cortex ,Concise Communication ,Brain ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,Female ,Supranuclear Palsy, Progressive ,Tauopathy ,Alzheimer's disease ,Neuroscience - Abstract
Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer’s disease (AD), however, neither disease nor brain region specificity of these transcriptome alterations has been explored. Using RNA-Seq data from 231 temporal cortex and 224 cerebellum samples from patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identified a striking correlation in the directionality and magnitude of gene expression changes between these 2 neurodegenerative proteinopathies. Further, the transcriptomic changes in AD and PSP brains ware highly conserved between the temporal and cerebellar cortices, indicating that highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or downregulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of 2 distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex, and ubiquitous molecular alterations in neurodegenerative diseases.
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- 2022
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25. APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
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Hu Wang, Bradley F. Boeve, Michael G. Heckman, Yingxue Ren, Yan W. Asmann, Ana-Caroline Raulin, Yuan Fu, Thomas R. Caulfield, Tadafumi C. Ikezu, Tanis J. Ferman, Cynthia Linares, Lin Jia, Dennis W. Dickson, Carl Frieden, Jing Zhao, Owen A. Ross, Steven G. Younkin, Zbigniew K. Wszolek, Val J. Lowe, Cassandra L. Rosenberg, David S. Knopman, Xia Li, Yonghe Li, John D. Fryer, Xue Wang, Sydney V. Doss, Melissa E. Murray, Wenyan Lu, Clifford R. Jack, Melissa C. Wren, Xianlin Han, Joshua Knight, Zachary A. Trottier, Na Wang, Yuka A. Martens, Joseph E. Parisi, Yixing Chen, Guojun Bu, Aishe Kurti, Neill R. Graff-Radford, Kejal Kantarci, Chia Chen Liu, Glenn E. Smith, Ronald C. Petersen, Prashanthi Vemuri, Na Zhao, and Francis Shue
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Apolipoprotein E ,business.industry ,Self aggregation ,Extramural ,Genetic variants ,General Medicine ,Disease ,medicine.disease ,Bioinformatics ,Apolipoproteins E ,Text mining ,Medicine ,Dementia ,business - Abstract
A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.
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- 2021
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26. Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
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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, Alzheimer's Disease Genetics Consortium (ADGC), Gerard D Schellenberg, and Thomas J Montine
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Genetics ,QH426-470 - 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.
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- 2014
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27. Conserved Architecture of Brain Transcriptome Changes between Alzheimer’s Disease and Progressive Supranuclear Palsy in Pathologically Affected and Unaffected Regions
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Nathan D. Price, Joseph S. Reddy, Steven G. Younkin, Todd E. Golde, Kimberly G. Malphrus, Xue Wang, Minerva M. Carrasquillo, Dennis W. Dickson, Thuy T. Nguyen, Cory C. Funk, Nilufer Ertekin-Taner, Yan W. Asmann, and Mariet Allen
- Subjects
Transcriptome ,Gene expression ,medicine ,Disease ,Biology ,medicine.disease ,Neuroscience ,eye diseases ,Progressive supranuclear palsy - Abstract
We identify a striking correlation in the directionality and magnitude of gene expression changes in brain transcriptomes between Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP). Further, the transcriptome architecture in AD and PSP is highly conserved between the temporal and cerebellar cortices, indicating highly similar transcriptional changes occur in pathologically affected and “unaffected” areas of the brain. These data have broad implications for interpreting transcriptomic data in neurodegenerative disorders.
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- 2021
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28. Identification of novel Alzheimer’s disease genes co-expressed with TREM2
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Minerva M. Carrasquillo, Vivekananda Sarangi, Steven G. Younkin, Todd E. Golde, Joseph S. Reddy, Cyril Pottier, Yingxue Ren, Jason P. Sinnwell, Yan W. Asmann, Owen A. Ross, Xue Wang, Mariet Allen, Curtis S. Younkin, Joanna M. Biernacka, Gregory D. Jenkins, Rosa Rademakers, Nilufer Taner, Brandon J. Coombes, and George M. Eisenberg
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Apolipoprotein E ,Immune system ,TREM2 ,medicine ,Identification (biology) ,Computational biology ,Disease ,Alzheimer's disease ,Allele ,Biology ,medicine.disease ,Gene - Abstract
By analyzing whole-exome data from the Alzheimer’s disease sequencing project (ADSP), we identify a set of 4 genes that show highly significant association with Alzheimer’s disease (AD). These genes were identified within a human TREM2 co-expression network using a novel approach wherein prioritized polygenic score analyses were performed sequentially to identify significant polygenic components. Two of the 4 genes (TREM2, RIN3) have previously been linked to AD and two (ATP8B4, IL17RA) are novel. Like TREM2, the 2 novel AD genes are selectively expressed in human microglial cells. The most significant variants in ATP8B4 and IL17RA are non-synonymous variants with strong effects comparable to the APOE ε4 and ε2 alleles. These protein-altering variants will provide unique opportunities to further explore the biological role of microglial cells in AD and help inform future immune modulatory therapeutic development for AD.
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- 2020
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29. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
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Yan W. Asmann, Yuan Fu, Wenyan Lu, Francis Shue, Yesesri Cherukuri, Nilufer Ertekin-Taner, Yuka A. Martens, Chia Chen Liu, Jing Zhao, Guojun Bu, Lin Jia, Neill R. Graff-Radford, Zbigniew K. Wszolek, Yu Yamazaki, Takahisa Kanekiyo, Mary D. Davis, Lucy Job, Yingxue Ren, Steven G. Younkin, David A. Brafman, Thanh Thanh L. Nguyen, Kai Chen, and Xue Wang
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0301 basic medicine ,Apolipoprotein E ,Science ,General Physics and Astronomy ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,medicine ,Organoid ,Dementia ,lcsh:Science ,Induced pluripotent stem cell ,Multidisciplinary ,business.industry ,Neurodegeneration ,General Chemistry ,medicine.disease ,Phenotype ,030104 developmental biology ,lipids (amino acids, peptides, and proteins) ,lcsh:Q ,business ,human activities ,Neuroscience ,030217 neurology & neurosurgery ,Cerebral organoid - Abstract
APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.
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- 2020
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30. Trophic Regulation of Skeletal Muscle Acetylcholinesterase
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Linda H. Younkin and Steven G. Younkin
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medicine.medical_specialty ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Internal medicine ,medicine ,Skeletal muscle ,Biology ,Acetylcholinesterase ,Trophic level - Published
- 2020
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31. Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy
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Rui Chang, Samantha L. Strickland, Naomi Kouri, Joseph S. Reddy, Kuixi Zhu, Cory C. Funk, Jeremy D. Burgess, Nilufer Ertekin-Taner, Nathan D. Price, Shunsuke Koga, Daniel J. Serie, Curtis S. Younkin, Melissa E. Murray, Julia E. Crook, Thuy T. Nguyen, Minerva M. Carrasquillo, Kimberly G. Malphrus, Steven G. Younkin, Todd E. Golde, Xue Wang, Yan W. Asmann, Sarah Lincoln, Mariet Allen, Melissa Alamprese, and Dennis W. Dickson
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Male ,0301 basic medicine ,Proteome ,Gene regulatory network ,Gene Expression ,Genome-wide association study ,Neuropathology ,Biology ,Pathology and Forensic Medicine ,Progressive supranuclear palsy ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Immune system ,Gene expression ,Transcriptional regulation ,medicine ,Humans ,Gene Regulatory Networks ,Gene ,Aged ,Brain Chemistry ,Neurons ,Original Paper ,Neurofibrillary Tangles ,medicine.disease ,Immunohistochemistry ,eye diseases ,3. Good health ,030104 developmental biology ,Tauopathies ,Astrocytes ,Immune System ,Synapses ,RNA ,Female ,Supranuclear Palsy, Progressive ,Neurology (clinical) ,Neuroscience ,Genome-Wide Association Study - Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP. Electronic supplementary material The online version of this article (10.1007/s00401-018-1900-5) contains supplementary material, which is available to authorized users.
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- 2018
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32. APOE ε4/ε4 diminishes neurotrophic function of human iPSC-derived astrocytes
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Jing Zhao, Mary D. Davis, Neill R. Graff-Radford, Yuka A. Martens, Mitsuru Shinohara, Takahisa Kanekiyo, Guojun Bu, Steven G. Younkin, and Zbigniew K. Wszolek
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0301 basic medicine ,Apolipoprotein E ,Genotype ,Apolipoprotein E4 ,Induced Pluripotent Stem Cells ,Central nervous system ,Apolipoprotein E3 ,Synaptogenesis ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Cognitive decline ,Induced pluripotent stem cell ,Molecular Biology ,Alleles ,Cells, Cultured ,Genetics (clinical) ,Neurons ,Articles ,General Medicine ,Coculture Techniques ,Neural stem cell ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Astrocytes ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Cellular model ,030217 neurology & neurosurgery ,Neurotrophin - Abstract
The ε4 allele of the APOE gene encoding apolipoprotein E (apoE) is a strong genetic risk factor for aging-related cognitive decline as well as late-onset Alzheimer's disease (AD) compared to the common ε3 allele. In the central nervous system, apoE is produced primarily by astrocytes and functions in transporting lipids including cholesterol to support neuronal homeostasis and synaptic integrity. Although mouse models and corresponding primary cells have provided valuable tools for studying apoE isoform-dependent functions, recent studies have shown that human astrocytes have a distinct gene expression profile compare with rodent astrocytes. Human induced pluripotent stem cells (iPSCs) derived from individuals carrying specific gene variants or mutations provide an alternative cellular model more relevant to humans upon differentiation into specific cell types. Thus, we reprogramed human skin fibroblasts from cognitively normal individuals carrying APOE ε3/ε3 or ε4/ε4 genotype to iPSC clones and further differentiated them into neural progenitor cells and then astrocytes. We found that human iPSC-derived astrocytes secreted abundant apoE with apoE4 lipoprotein particles less lipidated compared to apoE3 particles. More importantly, human iPSC-derived astrocytes were capable of promoting neuronal survival and synaptogenesis when co-cultured with iPSC-derived neurons with APOE ε4/ε4 astrocytes less effective in supporting these neurotrophic functions than those with APOE ε3/ε3 genotype. Taken together, our findings demonstrate APOE genotype-dependent effects using human iPSC-derived astrocytes and provide novel evidence that the human iPSC-based model system is a strong tool to explore how apoE isoforms contribute to neurodegenerative diseases.
- Published
- 2017
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33. Comprehensive Screening for Disease Risk Variants in Early-Onset Alzheimer’s Disease Genes in African Americans Identifies Novel PSEN Variants
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Thuy Nguyen, Nilufer Ertekin-Taner, Neill R. Graff-Radford, Steven G. Younkin, Minerva M. Carrasquillo, Maria T. Greig Custo, Xue Wang, Aurelie N'Songo, Ranjan Duara, Yan W. Asmann, and Mariet Allen
- Subjects
Adult ,Male ,0301 basic medicine ,Apolipoprotein E4 ,Population ,Disease ,Bioinformatics ,Article ,Presenilin ,Cohort Studies ,Amyloid beta-Protein Precursor ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Presenilin-2 ,Exome Sequencing ,PSEN2 ,Presenilin-1 ,PSEN1 ,medicine ,Humans ,Genetic Predisposition to Disease ,Early-onset Alzheimer's disease ,Age of Onset ,education ,Exome sequencing ,Aged ,Aged, 80 and over ,Genetics ,education.field_of_study ,business.industry ,General Neuroscience ,Genetic Variation ,General Medicine ,Middle Aged ,medicine.disease ,Black or African American ,Psychiatry and Mental health ,Clinical Psychology ,030104 developmental biology ,Cohort ,Female ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery - Abstract
We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer's disease (EOAD) genes (APP, PSEN1, and PSEN2) in this understudied population. Whole-exome sequencing of 238 African American subjects identified 6 rare missense variants within the EOAD genes, which were observed in AD cases but never among controls. These variants were analyzed in an independent cohort of 300 African American subjects in which PSEN2:NM_000447:exon5:c.T331C:p.Phe111Leu and PSEN1-minilin rs777923890 variants were again not observed, indicating that these novel rare variants, may contribute to AD risk in this population.
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- 2017
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34. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes
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Bradley T. Hyman, Gerard D. Schellenberg, Jean Paul Vonsattel, Yinghua Chen, Matthew J. Huentelman, Thomas G. Beach, Julie A. Schneider, Walter A. Kukull, M. Ilyas Kamboh, Bernardino Ghetti, Richard J. Caselli, Kathryn L. Lunetta, Yi Su, John Q. Trojanowski, Eric B. Larson, Julia Kofler, John Hardy, John Gilbert, Amanda J. Myers, Margaret A. Pericak-Vance, Thomas J. Montine, Richard Mayeux, Paul K. Crane, Joseph D. Buxbaum, Yakeel T. Quiroz, Linda Duque, Steven G. Younkin, David A. Bennett, Matthew P. Frosch, Tatiana Foroud, Lindsay A. Farrer, Joseph F. Arboleda-Velasquez, Harry E. Gwirtsman, Philip L. De Jager, Jonathan L. Haines, C. Dirk Keene, Dennis W. Dickson, Eric M. Reiman, Gyungah Jun, Li-San Wang, and Gary W. Beecham
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Apolipoprotein E ,0303 health sciences ,medicine.medical_specialty ,business.industry ,Odds ratio ,Disease ,medicine.disease ,Lower risk ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,mental disorders ,medicine ,Dementia ,Alzheimer s dementia ,Allele ,business ,030217 neurology & neurosurgery ,Alzheimers dementia ,030304 developmental biology - Abstract
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, such that APOE4 homozygotes have a particularly high risk. While the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with exceptionally low Alzheimer’s dementia odds ratios compared to APOE2/3, 3/3 and 4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of this terrible disease.
- Published
- 2019
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35. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study
- Author
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Eric M, Reiman, Joseph F, Arboleda-Velasquez, Yakeel T, Quiroz, Matthew J, Huentelman, Thomas G, Beach, Richard J, Caselli, Yinghua, Chen, Yi, Su, Amanda J, Myers, John, Hardy, Jean, Paul Vonsattel, Steven G, Younkin, David A, Bennett, Philip L, De Jager, Eric B, Larson, Paul K, Crane, C Dirk, Keene, M Ilyas, Kamboh, Julia K, Kofler, Linda, Duque, John R, Gilbert, Harry E, Gwirtsman, Joseph D, Buxbaum, Dennis W, Dickson, Matthew P, Frosch, Bernardino F, Ghetti, Kathryn L, Lunetta, Li-San, Wang, Bradley T, Hyman, Walter A, Kukull, Tatiana, Foroud, Jonathan L, Haines, Richard P, Mayeux, Margaret A, Pericak-Vance, Julie A, Schneider, John Q, Trojanowski, Lindsay A, Farrer, Gerard D, Schellenberg, Gary W, Beecham, Thomas J, Montine, Gyungah R, Jun, Yi, Zhao, Reiman, Eric M [0000-0002-0705-3696], Arboleda-Velasquez, Joseph F [0000-0002-3192-9117], Dickson, Dennis W [0000-0001-7189-7917], Ghetti, Bernardino F [0000-0002-1842-8019], Lunetta, Kathryn L [0000-0002-9268-810X], Hyman, Bradley T [0000-0002-7959-9401], Haines, Jonathan L [0000-0002-4351-4728], Pericak-Vance, Margaret A [0000-0001-7283-8804], Trojanowski, John Q [0000-0002-9239-8794], Jun, Gyungah R [0000-0002-3230-8697], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Oncology ,Apolipoprotein E ,Male ,Aging ,Apolipoprotein E2 ,Apolipoprotein E4 ,Apolipoprotein E3 ,General Physics and Astronomy ,Disease ,Neurodegenerative ,Alzheimer's Disease ,0302 clinical medicine ,Genotype ,Genetics research ,80 and over ,2.1 Biological and endogenous factors ,Aetiology ,lcsh:Science ,Neuropathology ,Aged, 80 and over ,Multidisciplinary ,Homozygote ,Brain ,Middle Aged ,Alzheimer's disease ,Neurological ,Female ,medicine.medical_specialty ,Science ,Lower risk ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Alzheimer Disease ,Internal medicine ,mental disorders ,medicine ,Acquired Cognitive Impairment ,Genetics ,Dementia ,Humans ,Genetic Predisposition to Disease ,Allele ,Alleles ,Genetic Association Studies ,Aged ,Probability ,business.industry ,Prevention ,Alzheimer’s Disease Genetics Consortium ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,General Chemistry ,Odds ratio ,medicine.disease ,Brain Disorders ,030104 developmental biology ,Good Health and Well Being ,lcsh:Q ,business ,030217 neurology & neurosurgery - Abstract
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, while the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with a low Alzheimer’s dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of the disease., APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.
- Published
- 2019
36. Evaluation of Associations of Alzheimer's Disease Risk Variants that Are Highly Expressed in Microglia with Neuropathological Outcome Measures
- Author
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Michael G. Heckman, Nobutaka Sakae, Emily R. Vargas, Steven G. Younkin, Minerva M. Carrasquillo, Dennis W. Dickson, Koji Kasanuki, Melissa E. Murray, and Nilufer Ertekin-Taner
- Subjects
0301 basic medicine ,Male ,Amyloid ,Genome-wide association study ,Disease ,Neuropathology ,PICALM ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Outcome Assessment, Health Care ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Association Studies ,Aged ,PTK2B ,Microglia ,business.industry ,General Neuroscience ,General Medicine ,medicine.disease ,Immunohistochemistry ,Psychiatry and Mental health ,Clinical Psychology ,Cerebral Amyloid Angiopathy ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Female ,Cerebral amyloid angiopathy ,Autopsy ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
A number of Alzheimer's disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid angiopathy (CAA) and microglial activation, in 93 AD patients. We observed significant associations of CAA pathology with APOEɛ4 and PTK2B rs28834970. Nominally significant associations with measures of microglial activation in white matter were observed for variants in PTK2B, PICALM, and CR1. Our findings suggest that several AD risk variants may also function as disease modifiers through amyloid-β metabolism and white matter microglial activity.
- Published
- 2019
37. Systematic analysis of dark and camouflaged genes: disease-relevant genes hiding in plain sight
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Jonathon P. Sens, Owen A. Ross, Joseph S. Reddy, John D. Fryer, Perry G. Ridge, Steven G. Younkin, Eric C. Larson, Rosa Rademakers, John S. K. Kauwe, Paul K. Crane, Yan W. Asmann, Minerva M. Carrasquillo, Tanner D. Jensen, Leonard Petrucelli, Veronique V. Belzil, Mark T. W. Ebbert, Karen Jansen-West, Dirk C. Keene, Luc Pregent, and Nilufer Ertekin-Taner
- Subjects
Disease gene ,Exon ,Genomics ,Human genome ,Computational biology ,Nanopore sequencing ,Disease ,Biology ,Gene ,Frameshift mutation - Abstract
BackgroundThe human genome contains ‘dark’ gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions that are ‘dark by depth’ (few mappable reads) and others that are ‘camouflaged’ (ambiguous alignment), and we assess how well long-read technologies resolve these regions. We further present an algorithm to resolve most camouflaged regions (including in short-read data) and apply it to the Alzheimer’s Disease Sequencing Project (ADSP; 13142 samples), as a proof of principle.ResultsBased on standard whole-genome lllumina sequencing data, we identified 37873 dark regions in 5857 gene bodies (3635 protein-coding) from pathways important to human health, development, and reproduction. Of the 5857 gene bodies, 494 (8.4%) were 100% dark (142 protein-coding) and 2046 (34.9%) were ≥5% dark (628 protein-coding). Exactly 2757 dark regions were in protein-coding exons (CDS) across 744 genes. Long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduced dark CDS regions to approximately 45.1%, 33.3%, and 18.2% respectively. Applying our algorithm to the ADSP, we rescued 4622 exonic variants from 501 camouflaged genes, including a rare, ten-nucleotide frameshift deletion in CR1, a top Alzheimer’s disease gene, found in only five ADSP cases and zero controls.ConclusionsWhile we could not formally assess the CR1 frameshift mutation in Alzheimer’s disease (insufficient sample-size), we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.
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- 2019
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38. Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight
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Joseph S. Reddy, Paul K. Crane, Steven G. Younkin, Nilufer Ertekin-Taner, Minerva M. Carrasquillo, John D. Fryer, Eric C. Larson, Luc Pregent, Jonathon P. Sens, Veronique V. Belzil, Dirk C. Keene, Karen Jansen-West, Tanner D. Jensen, Perry G. Ridge, Rosa Rademakers, John S. K. Kauwe, Leonard Petrucelli, Mark T. W. Ebbert, Yan W. Asmann, and Owen A. Ross
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Oxford Nanopore Technologies (ONT) ,lcsh:QH426-470 ,Pacific Biosciences (PacBio) ,Genomics ,Computational biology ,Biology ,Frameshift mutation ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Humans ,Genetic Predisposition to Disease ,Long-read sequencing ,Gene ,CR1 ,lcsh:QH301-705.5 ,Illumina dye sequencing ,030304 developmental biology ,Dark genes ,0303 health sciences ,Genome, Human ,Research ,10x Genomics ,Camouflaged genes ,Alzheimer’s Disease Sequencing Project (ADSP) ,Human genetics ,3. Good health ,lcsh:Genetics ,lcsh:Biology (General) ,Mutation ,Human genome ,Nanopore sequencing ,Human medicine ,Engineering sciences. Technology ,030217 neurology & neurosurgery ,APOE - Abstract
Background The human genome contains “dark” gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions. Results Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer’s Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer’s disease gene, found in disease cases but not in controls. Conclusions While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer’s disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies. Electronic supplementary material The online version of this article (10.1186/s13059-019-1707-2) contains supplementary material, which is available to authorized users.
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- 2019
39. Author Correction: APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
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Lucy Job, Yan W. Asmann, Takahisa Kanekiyo, Yuan Fu, David A. Brafman, Nilufer Ertekin-Taner, Zbigniew K. Wszolek, Yesesri Cherukuri, Francis Shue, Yingxue Ren, Kai Chen, Wenyan Lu, Mary D. Davis, Yuka A. Martens, Yu Yamazaki, Chia Chen Liu, Steven G. Younkin, Lin Jia, Jing Zhao, Guojun Bu, Neill R. Graff-Radford, Thanh Thanh L. Nguyen, and Xue Wang
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Genotype ,Science ,Apolipoprotein E4 ,Induced Pluripotent Stem Cells ,Apolipoprotein E3 ,General Physics and Astronomy ,General Biochemistry, Genetics and Molecular Biology ,Synapse ,Alzheimer Disease ,Organoid ,medicine ,Humans ,Author Correction ,Multidisciplinary ,business.industry ,Neurodegeneration ,Disease patient ,General Chemistry ,Alzheimer's disease ,medicine.disease ,Organoids ,Mechanisms of disease ,Gene Expression Regulation ,Synapses ,RNA ,Transcriptome ,business ,Neuroscience - Abstract
APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.
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- 2021
40. Impact of variant-level batch effects on identification of genetic risk factors in large sequencing studies
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Vivekananda Sarangi, Matthew E. Hudson, Jason P. Sinnwell, Rosa Rademakers, Cyril Pottier, Owen A. Ross, Joseph S. Reddy, Yan W. Asmann, Nilufer Ertekin-Taner, Liudmila Sergeevna Mainzer, Minerva M. Carrasquillo, Steven G. Younkin, Joanna M. Biernacka, Daniel P. Wickland, and Yingxue Ren
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Male ,Heredity ,Single Nucleotide Polymorphisms ,Alzheimer's Disease ,Mathematical and Statistical Techniques ,Medical Conditions ,Gene Frequency ,Databases, Genetic ,Mitochondrial Precursor Protein Import Complex Proteins ,Genotype ,Medicine and Health Sciences ,Exome ,Principal Component Analysis ,Multidisciplinary ,Statistics ,High-Throughput Nucleotide Sequencing ,Neurodegenerative Diseases ,Genomics ,Genetic Mapping ,Neurology ,Physical Sciences ,Medicine ,Engineering and Technology ,Female ,Identification (biology) ,Research Article ,Quality Control ,Science ,Variant Genotypes ,Single-nucleotide polymorphism ,Computational biology ,Biology ,Research and Analysis Methods ,Polymorphism, Single Nucleotide ,Statistical power ,Apolipoproteins E ,Alzheimer Disease ,Mental Health and Psychiatry ,Industrial Engineering ,Covariate ,Genetics ,Genome-Wide Association Studies ,Humans ,Genetic Predisposition to Disease ,Statistical Methods ,Allele ,Alleles ,Genetic association ,Membrane Transport Proteins ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Sequence Analysis, DNA ,Genome Analysis ,Genetic Loci ,Multivariate Analysis ,Genetics of Disease ,Dementia ,Mathematics ,Genome-Wide Association Study - Abstract
Background: Genetic studies have shifted to sequencing-based rare variants discovery after decades of success in identifying common disease variants by Genome-Wide Association Studies using Single Nucleotide Polymorphism chips. Sequencing-based studies require large sample sizes for statistical power but often inadvertently introduce batch effects because samples are typically collected, processed, and sequenced at multiple centers. Conventionally, batch effects are first detected and visualized using Principal Components Analysis and then controlled by including batch covariates in the disease association models. For sequencing-based genetic studies, because all variants included in the association analyses have passed quality control measures, this conventional approach treats every variant as equal and ignores the substantial differences still remaining in variant qualities and characteristics such as genotype quality scores, alternative allele fractions (fraction of reads supporting alternative allele at a variant position) and sequencing depths. Results: In the Alzheimer’s Disease Sequencing Project (ADSP) exome dataset of 9,904 cases and controls, we discovered hidden variant-level differences between sample batches of three sequencing centers and two exome capture kits. Although sequencing centers were included as a covariate in our association models, we observed differences at the variant level in genotype quality and alternative allele fraction between samples processed by different exome capture kits that significantly impacted both the confidence of variant detection and the identification of disease-associated variants. Furthermore, we found that the association signals of a subset of top disease risk variants came exclusively from samples processed by one exome capture kit that was more effective at capturing the alternative alleles compared to the other kit. Conclusions: Our findings highlight the importance of additional variant-level quality control for large sequencing-based genetic studies. More importantly, we demonstrate that automatically filtering out variants with batch differences may lead to false negatives if the batch discordance came largely from quality differences and if the variants from one batch had better quality scores.
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- 2021
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41. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression
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Jeremy D. Burgess, Christopher Medway, Chen Wang, Daniel J. Serie, Yan W. Asmann, Thuy Nguyen, Mariet Allen, Samantha L. Strickland, Joanna Siuda, Michaela Kachadoorian, Kevin Morgan, Kimberly G. Malphrus, David A. Bennett, Curtis S. Younkin, Xue Wang, Sarah Lincoln, Philip L. De Jager, Neill R. Graff-Radford, Dennis W. Dickson, Julia E. Crook, Pritha Chanana, Ronald C. Petersen, Nilufer Ertekin-Taner, Shivani Aryal, Steven G. Younkin, Todd E. Golde, Nathan D. Price, Asha Nair, Charles C. White, and Minerva M. Carrasquillo
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Male ,0301 basic medicine ,Epidemiology ,TREML1 ,Regulatory variant ,Quantitative Trait Loci ,Gene Expression ,Locus (genetics) ,Biology ,Quantitative trait locus ,eQTL ,Linkage Disequilibrium ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Developmental Neuroscience ,Alzheimer Disease ,Cerebellum ,Gene cluster ,TREM2 ,Humans ,Genetic Predisposition to Disease ,Receptors, Immunologic ,Aged ,Aged, 80 and over ,Temporal cortex ,Genetics ,Membrane Glycoproteins ,Microarray analysis techniques ,Health Policy ,Genetic Variation ,Alzheimer's disease ,Microarray Analysis ,Temporal Lobe ,Psychiatry and Mental health ,030104 developmental biology ,Multigene Family ,Expression quantitative trait loci ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Hypersensitive site ,030217 neurology & neurosurgery - Abstract
Introduction We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid ( TREM ) gene cluster influence disease through gene expression. Methods Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. Results A variant within a DNase hypersensitive site 5′ of TREM2 , rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10 −3 and 4.6 × 10 −2 , respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets ( n = 1006) confirmed these associations (uncorrected P = 3.4 × 10 −2 and 3.5 × 10 −3 , Bonferroni-corrected P = 6.7 × 10 −2 and 7.1 × 10 −3 , respectively). Discussion Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.
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- 2016
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42. MAPT haplotype diversity in multiple system atrophy
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Steven G. Younkin, Ronald L. Walton, Ronald C. Petersen, William P. Cheshire, Neill R. Graff-Radford, Kotaro Ogaki, Zbigniew K. Wszolek, Dennis W. Dickson, Michael G. Heckman, Phillip A. Low, Ryan J. Uitti, Elizabeth A. Coon, Oswaldo Lorenzo-Betancor, Shinsuke Fujioka, Alexandra I. Soto-Ortolaza, Wolfgang Singer, Owen A. Ross, Paola Sandroni, Catherine Labbé, Shunsuke Koga, Melissa E. Murray, Bradley F. Boeve, and Jay A. van Gerpen
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Male ,Risk ,0301 basic medicine ,medicine.medical_specialty ,Pathology ,Genotype ,tau Proteins ,Single-nucleotide polymorphism ,Disease ,Polymorphism, Single Nucleotide ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,stomatognathic system ,Internal medicine ,parasitic diseases ,mental disorders ,medicine ,Humans ,Genetic Predisposition to Disease ,Aged ,Aged, 80 and over ,business.industry ,Haplotype ,Significant difference ,Parkinson Disease ,Progressive neurodegenerative disorder ,Middle Aged ,Multiple System Atrophy ,medicine.disease ,LRRK2 ,nervous system diseases ,030104 developmental biology ,Haplotypes ,nervous system ,Neurology ,alpha-Synuclein ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery - Abstract
Introduction Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as SNCA, COQ2 and LRRK2 have demonstrated that there is a genetic contribution to the disease. MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the MAPT H2 haplotype with MSA in 61 pathologically confirmed cases. Methods In the present study, we assessed the full MAPT haplotype diversity in MSA patients using six MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls. Results We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%, Controls:22.7%, p = 0.024) and H1E (MSA:3.0%, Controls:9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%, Controls:1.3%, p = 0.030) and H1J (MSA:3.0%, Controls:0.9%, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6% of patients in our pathologically confirmed series (P Conclusions Our findings provide further evidence that MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of MAPT and other genes in MSA.
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- 2016
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43. Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci
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Daniel J. Serie, Zhifu Sun, Nathan D. Price, Tamas Ordog, Sarah Lincoln, Gerard D. Schellenberg, Dennis W. Dickson, Jeremy D. Burgess, Steven G. Younkin, Chen Wang, Todd E. Golde, Saurabh Baheti, Travis Ballard, Xue Wang, Thuy Nguyen, Julia E. Crook, Curtis S. Younkin, Kimberly G. Malphrus, Melissa E. Murray, Naomi Kouri, Nilufer Ertekin-Taner, Yan W. Asmann, Mariet Allen, and Minerva M. Carrasquillo
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Male ,Risk ,0301 basic medicine ,Gene Expression ,tau Proteins ,Single-nucleotide polymorphism ,Neuropathology ,Biology ,Polymorphism, Single Nucleotide ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Humans ,Epigenetics ,Alleles ,Aged ,Aged, 80 and over ,Temporal cortex ,Genetics ,Methylation ,DNA Methylation ,eye diseases ,030104 developmental biology ,CpG site ,Genetic Loci ,Reduced representation bisulfite sequencing ,DNA methylation ,Female ,Supranuclear Palsy, Progressive ,Neurology (clinical) ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3′ region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci.
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- 2016
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44. Evaluating pathogenic dementia variants in posterior cortical atrophy
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Neill R. Graff-Radford, Sarah Lincoln, Gamze Balci Camsari, Imelda Barber, Julia E. Crook, Qurat ul Ain Khan, Li Ma, Kevin Morgan, Steven G. Younkin, Minerva M. Carrasquillo, Dennis W. Dickson, Gina Bisceglio, Melissa E. Murray, Bradley F. Boeve, Nilufer Ertekin-Taner, and Thuy Nguyen
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Adult ,Male ,0301 basic medicine ,Aging ,Genotype ,Genotyping Techniques ,Population ,Vision Disorders ,Neuropathology ,Bioinformatics ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Presenilin-2 ,medicine ,Humans ,Dementia ,Exome ,Receptors, Immunologic ,education ,Exome sequencing ,Aged ,Aged, 80 and over ,education.field_of_study ,Membrane Glycoproteins ,business.industry ,General Neuroscience ,Posterior cortical atrophy ,Syndrome ,Middle Aged ,medicine.disease ,3. Good health ,030104 developmental biology ,Mutation ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Alzheimer's disease ,business ,030217 neurology & neurosurgery ,Developmental Biology ,Frontotemporal dementia - Abstract
Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to “posterior Alzheimer’s disease (AD)” pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n=67) or posterior AD neuropathology (n=57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ~4,300 European-American population controls from the NHLBI Exome Sequencing Project (ESP). We identified two rare variants not previously reported in PCA, TREM2 Arg47His and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report two rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.
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- 2016
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45. O3‐06‐02: POLYGENIC SCORE ANALYSIS OF EXONIC VARIANTS IN AN IMMUNE CO‐REGULATORY NETWORK IDENTIFIES NOVEL PROTEIN‐ALTERING VARIANTS THAT ASSOCIATE WITH ALZHEIMER'S DISEASE
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Owen A. Ross, Shannon K. McDonnell, Jenkins D. Gregory, Nilufer Ertekin-Taner, Xue Wang, Jason P. Sinnwell, Yan W. Asmann, Minerva M. Carrasquillo, Cyril Pottier, Vivekananda Sarangi, Mariet Allen, Joanna M. Biernacka, Curtis S. Younkin, Shastri M. Toral, Steven G. Younkin, Rosa Rademakers, Joseph S. Reddy, and Yingxue Ren
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Immune system ,Developmental Neuroscience ,Epidemiology ,Novel protein ,Health Policy ,Neurology (clinical) ,Computational biology ,Disease ,Geriatrics and Gerontology ,Biology - Published
- 2018
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46. Association study between multiple system atrophy and TREM2 p.R47H
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Zbigniew K. Wszolek, Wolfgang Singer, Ronald L. Walton, Alexandra I. Soto, William P. Cheshire, Phillip A. Low, Guojun Bu, Yuka A. Martens, Ryan J. Uitti, Shunsuke Koga, Kotaro Ogaki, Michael G. Heckman, Emily R. Vargas, Dennis W. Dickson, Catherine Labbé, Jay A. van Gerpen, Steven G. Younkin, Oswaldo Lorenzo-Betancor, Owen A. Ross, and Shinsuke Fujioka
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0301 basic medicine ,medicine.medical_specialty ,Disease ,Gastroenterology ,Article ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Atrophy ,stomatognathic system ,Internal medicine ,parasitic diseases ,mental disorders ,medicine ,Risk factor ,Genotyping ,Genetics (clinical) ,Sanger sequencing ,business.industry ,TREM2 ,Odds ratio ,medicine.disease ,3. Good health ,nervous system diseases ,030104 developmental biology ,nervous system ,symbols ,Neurology (clinical) ,Alzheimer's disease ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveThe triggering receptor expressed on myeloid cells 2 (TREM2) p.R47H substitution (rs75932628) is a risk factor for Alzheimer disease (AD) but has not been well studied in relation to the risk of multiple system atrophy (MSA); the aim of this study was to evaluate the association between the TREM2 p.R47H variant and the risk of MSA.MethodsA total of 168 patients with pathologically confirmed MSA, 89 patients with clinically diagnosed MSA, and 1,695 controls were included. TREM2 p.R47H was genotyped and assessed for association with MSA. Positive results in the Taqman genotyping assay were confirmed by Sanger sequencing. The primary comparison involved patients with pathologically confirmed MSA and controls due to the definitive MSA diagnosis in the pathologically confirmed series.ResultsWe identified TREM2 p.R47H in 3 patients with pathologically confirmed MSA (1.79%), 1 patient with clinically diagnosed MSA (1.12%), and 7 controls (0.41%). Minimal AD pathology was observed for the pathologically confirmed MSA p.R47H carriers. For the primary comparison of patients with pathologically confirmed MSA and controls, risk of disease was significantly higher for p.R47H carriers (odds ratio [OR]: 4.39, p = 0.033). When supplementing the 168 pathologically confirmed patients with the 89 clinically diagnosed and examining the combined MSA series, the association with TREM2 p.R47H remained significant (OR: 3.81, p = 0.034).ConclusionsOur preliminary results suggest that the TREM2 p.R47H substitution may be a risk factor for MSA, implying a link to neuroinflammatory processes, especially microglial activation. Validation of this finding will be important, given our relatively small sample size; meta-analytic approaches will be needed to better define the role of this variant in MSA.
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- 2018
47. O2-10-01: STOP-GAIN AND NON-SYNONYMOUS VARIANTS IN NOVEL GENES OF AN IMMUNE CO-REGULATORY NETWORK SHOW STRONG ASSOCIATION WITH ALZHEIMER'S DISEASE
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Mariet Allen, Joseph S. Reddy, Nilufer Ertekin-Taner, Minerva M. Carrasquillo, Xue Wang, Joanna M. Biernacka, Steven G. Younkin, and Jenkins D. Gregory
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Genetics ,Epidemiology ,Health Policy ,Association (object-oriented programming) ,Disease ,Biology ,Novel gene ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Immune system ,Developmental Neuroscience ,Neurology (clinical) ,Geriatrics and Gerontology ,Non synonymous - Published
- 2019
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48. Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia
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Paul K. Crane, Christopher Medway, Shobha Potluri, Joe Chiles, James F. Simpson, Shubhabrata Mukherjee, Ying Liang, Christian M. Paumi, Dianna S. Howard, Steven G. Younkin, David W. Fardo, Steven Estus, Hualin S. Xi, and Manasi Malik
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Male ,Linkage disequilibrium ,Myeloid ,Genotype ,RNA Stability ,Sialic Acid Binding Ig-like Lectin 3 ,CD33 ,Gene Expression ,Single-nucleotide polymorphism ,Biology ,Antibodies, Monoclonal, Humanized ,Polymorphism, Single Nucleotide ,Lintuzumab ,Cell Line ,Exon ,Alzheimer Disease ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,RNA, Messenger ,Molecular Biology ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Association Studies Articles ,Myeloid leukemia ,Exons ,General Medicine ,medicine.disease ,Introns ,Alternative Splicing ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Immunology ,Cancer research ,Female ,medicine.drug - Abstract
The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.
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- 2015
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49. Convergent genetic and expression data implicate immunity in Alzheimer's disease
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John R. Gilbert, Simon Lovestone, Diana Zelenika, Walter A. Kukull, Peter Passmore, Chiao-Feng Lin, Nathalie Fievet, Brian W. Kunkle, Dominique Campion, Philip L. De Jager, Adam C. Naj, Kara L. Hamilton-Nelson, Lina Keller, Jean-Charles Lambert, Denise Harold, Paul K. Crane, John Powell, Kathryn L. Lunetta, Paolo Caffarra, Lei Yu, Anthony Bayer, Tricia A. Thornton-Wells, Christiane Reitz, Eric B. Larson, Florentino Sanchez Garcia, Lindsay A. Farrer, Charlene Thomas, Ekaterina Rogaeva, Victoria Alavarez, Alfredo Ramirez, Pascale Barberger-Gateau, Dan Rujescu, Paul Hollingworth, Margaret A. Pericak-Vance, Daniela Galimberti, J. Kornhuber, Alexey Vedernikov, Philippe Amouyel, Peter Holmans, Gianfranco Spalletta, Carole Dufouil, Wolfgang Maier, Patrick G. Kehoe, Florence Pasquier, Lesley Jones, Harald Hampel, Stephen Todd, Valur Emilsson, Pau Pastor, Manuel Mayhaus, Claudine Berr, Seth Love, Michelangelo Mancuso, Mikko Hiltunen, Simon Mead, Hilkka Soininen, Vincent Deramecourt, Bernadette McGuinness, Magda Tsolaki, Jean-François Dartigues, Jordi Clarimón, Marie-Thérèse Bihoreau, Laura Fratiglioni, Duane Beekly, Sabrina Pichler, Caroline Graff, Albert V. Smith, Nick C. Fox, Amy Gerrish, Karen Ritchie, Carlos Cruchaga, John Hardy, Benedetta Nacmias, Maria Candida Deniz Naranjo, Christine Van Broeckhoven, Laura B. Cantwell, Minerva M. Carrasquillo, Richard Mayeux, Karolien Bettens, Vincent Chouraki, Clive Holmes, Thomas H. Mosley, David C. Rubinsztein, Gyungah Jun, Anita L. DeStefano, Lenore J. Launer, Alexander Richards, Jerome I. Rotter, Lars Lannfelt, Annette L. Fitzpatrick, Fanggeng Zou, Joseph D. Buxbaum, Cristina Razquin, Mercè Boada, Najaf Amin, Palmi V. Jonsson, Martin Dichgans, Thomas J. Montine, Yoichiro Kamatani, Debby W. Tsuang, Alexis Brice, Hakon Hakonarson, John Collinge, Albert Hofman, Eden R. Martin, Oscar L. Lopez, Olivier Hanon, Melanie L. Dunstan, Kevin Morgan, Nicola Jones, Cornelia M. van Duijn, Valentina Escott-Price, Vilmundur Gudnason, Susanne Moebus, Peter St George-Hyslop, Michael Conlon O'Donovan, Michael Gill, Tim Becker, Markus M. Nöthen, Sandro Sorbi, Céline Bellenguez, Mike A. Nalls, Martin Ingelsson, Otto Valladares, Kristel Sleegers, Sudha Seshadri, Gerard D. Schellenberg, María J. Bullido, Patrizia Mecocci, Eric Boerwinkle, Michael John Owen, Helena Schmidt, Kristelle Brown, Julie Williams, Renée F.A.G. de Bruijn, Jonathan L. Haines, Mark Lathrop, Maria Del Zompo, Denis A. Evans, Rebecca Sims, Badri N. Vardarajan, John S. K. Kauwe, Luc Letteneur, Agustín Ruiz, David Craig, Steven G. Younkin, Bruce M. Psaty, Ignacio Mateo, Tatiana Foroud, David Wallon, P. Bosco, Alberti Lleò, Amanda J. Myers, Alberto Pilotto, Petra Proitsi, Reinhold Schmidt, Matthew J. Huentelman, David A. Bennett, Onofre Combarros, Kelley Faber, Gudny Eiriksdottir, M. Arfan Ikram, Lluís Tárraga, Francesco Panza, Carla A. Ibrahim-Verbaas, Joshua C. Bis, Li-San Wang, Matthias Riemenschneider, Gary W. Beecham, Alison Goate, Seung Hoan Choi, John Gallacher, Robert Clarke, Didier Hannequin, Deborah Blacker, Frank Jessen, Christophe Tzourio, Tamara B. Harris, Benjamin Grenier-Boley, Paola Bossù, Janet A. Johnston, M. Ilyas Kamboh, Giancarlo Russo, Timothy Stone, Carol Brayne, Eliecer Coto, French National Foundation on Alzheimer’s Disease and Related Disorders, Institut Pasteur, National Institutes of Health (US), Centre National de Genotypage (France), Fédération pour la Recherche sur le Cerveau (France), Erasmus University Rotterdam, Medical Research Council (UK), International Genomics of Alzheimer's Disease Consortium (IGAP), Neurology, and Epidemiology
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Pathway analysis ,Epidemiology ,ALIGATOR ,Alzheimer's disease ,Cholesterol metabolism ,Dementia ,Endocytosis ,Immune response ,Neurodegeneration ,Ubiquitination ,Weighted gene co-expression network analysis ,Medizin ,Genome-wide association study ,genetics [Alzheimer Disease] ,Gene expression ,Genetics ,education.field_of_study ,Health Policy ,Brain ,Single Nucleotide ,3. Good health ,Psychiatry and Mental Health ,Algorithms ,Alzheimer Disease ,Genome-Wide Association Study ,Humans ,Polymorphism, Single Nucleotide ,Genetic Predisposition to Disease ,Developmental Neuroscience ,Neurology (clinical) ,Geriatrics and Gerontology ,Cellular and Molecular Neuroscience ,Alzheimer’s disease ,metabolism [Alzheimer Disease] ,Population ,Genomics ,Biology ,Aligator ,Article ,Biological pathway ,SDG 3 - Good Health and Well-being ,medicine ,ddc:610 ,Polymorphism ,education ,medicine.disease ,Protein ubiquitination ,metabolism [Brain] ,Human medicine - Abstract
© 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).
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- 2015
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50. Late-onset Alzheimer’s risk variants in memory decline, incident mild cognitive impairment, and Alzheimer’s disease
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Ronald C. Petersen, Glenn E. Smith, Otto Pedraza, Li Ma, Kimberly G. Malphrus, Mary M. Machulda, Julia E. Crook, Rosebud O. Roberts, Colleen S. Thomas, Thuy Nguyen, Robert J. Ivnik, Neill R. Graff-Radford, V. Shane Pankratz, Gina Bisceglio, Mariet Allen, Nilufer Ertekin-Taner, Minerva M. Carrasquillo, John A. Lucas, and Steven G. Younkin
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Male ,Risk ,Oncology ,Gerontology ,Aging ,medicine.medical_specialty ,Apolipoprotein E4 ,Genome-wide association study ,Late onset ,Disease ,White People ,Article ,Alzheimer Disease ,Memory ,Internal medicine ,mental disorders ,medicine ,Humans ,Cognitive Dysfunction ,Cognitive decline ,Genetic risk ,Cognitive impairment ,Aged ,Genetic association ,Aged, 80 and over ,Framingham Risk Score ,Receptor, EphA1 ,Incidence ,General Neuroscience ,Genetic Variation ,Membrane Proteins ,Middle Aged ,Clusterin ,Monomeric Clathrin Assembly Proteins ,Disease Progression ,ATP-Binding Cassette Transporters ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Psychology ,Genome-Wide Association Study ,Developmental Biology - Abstract
We tested association of nine late-onset Alzheimer’s disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memory and incident MCI/LOAD. MS4A6A-rs610932-C associated with increased incident MCI/LOAD and suggestively with lower baseline memory. ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in subjects with a final diagnosis of MCI/LOAD. PICALM-rs3851179-G had an unexpected protective effect on incident MCI/LOAD. Only APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Discovery of biologically functional variants at these loci may uncover stronger effects on memory and incident disease.
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- 2015
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