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1. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease.

Author: Celeste Sassi, Perry G Ridge, Michael A Nalls, Raphael Gibbs, Jinhui Ding, Michelle K Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S Brown, Christopher Medway, Jenny Lord, James Turton, ARUK Consortium, Kevin Morgan, John F Powell, John S Kauwe, Carlos Cruchaga, Jose Bras, Alison M Goate, Andrew B Singleton, Rita Guerreiro, and John Hardy
Subjects: Medicine, Science
Abstract: The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4
Published: 2016
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2. Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington’s Disease

Author: Christopher Medway, Vanessa C. Wheeler, Diane Lucente, Amelia Tee, Douglas Barker, Seung Kwak, Anka G Ehrhardt, Jean Paul Vonsattel, Kevin Correia, Michael J. Chao, Jacob M. Loupe, Darren G. Monckton, Alastair Maxwell, Jayalakshmi S. Mysore, Lesley Jones, Michael Orth, Richard H. Myers, Thomas Massey, Hugh Rickards, Ira Shoulson, Timothy Stone, Kyung Hee Kim, Marcy E. MacDonald, Marc Ciosi, Branduff McAllister, Erik van Duijn, Lynsey Hall, Tammy Gillis, Duncan McLauchlan, Jong-Min Lee, Ricardo Mouro Pinto, James F. Gusella, Eliana Marisa Ramos, Eun Pyo Hong, Jane S. Paulsen, Peter Holmans, G. Bernhard Landwehrmeyer, Cristina Sampaio, Afroditi Chatzi, Natalie Ellis, Kawther Abu Elneel, and Jeffrey D. Long
Subjects: 0301 basic medicine, medicine.medical_specialty, Psychosis, Population, Disease, Irritability, Article, 03 medical and health sciences, Cognition, 0302 clinical medicine, Huntington's disease, Risk Factors, Genetic variation, Humans, Medicine, Apathy, Cognitive decline, Psychiatry, education, Biological Psychiatry, Depression (differential diagnoses), 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, Depression, business.industry, Polygenic risk, medicine.disease, 3. Good health, Huntington Disease, 030104 developmental biology, Psychotic Disorders, Schizophrenia, Psychiatric, medicine.symptom, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Huntington’s disease
Abstract: Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.
Published: 2020
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3. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression

Author: 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
Subjects: 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.
Published: 2016
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4. Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3

Author: Celeste, Sassi, Michael A, Nalls, Perry G, Ridge, Jesse R, Gibbs, Michelle K, Lupton, Claire, Troakes, Katie, Lunnon, Safa, Al-Sarraj, Kristelle S, Brown, Christopher, Medway, Jenny, Lord, James, Turton, Jose, Bras, Sonja, Blumenau, Mareike, Thielke, Christa, Josties, Dorette, Freyer, Annette, Dietrich, Monia, Hammer, Michael, Baier, Ulrich, Dirnagl, Kevin, Morgan, John F, Powell, John S, Kauwe, Carlos, Cruchaga, Alison M, Goate, Andrew B, Singleton, Rita, Guerreiro, Angela, Hodges, and Clive, Holmes
Subjects: Male, Aging, Mendelian leukodystrophies, Hippocampus, White People, Article, Cohort Studies, Mendelian Leukodystrophies, Mice, Alzheimer Disease, Risk Factors, NOTCH3, Animals, Humans, Receptor, Notch3, Genetic Association Studies, Aged, Aged, 80 and over, Cerebral Cortex, Leukodystrophy, Metachromatic, Middle Aged, Alzheimer's disease, CSF1R, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Mutation, Female, Alzheimer’s disease
Abstract: Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant-based and single-gene-based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ core-dense plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.
Published: 2018
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5. Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia

Author: 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
Subjects: 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.
Published: 2015
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6. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author: John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD
Subjects: 0301 basic medicine, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genome-wide association study, genetics [Alzheimer Disease], metabolism [Microglia], Linkage Disequilibrium, 0302 clinical medicine, genetics [Protein Interaction Maps], genetics [Membrane Glycoproteins], Gene Frequency, Immunologic, genetics [Adaptor Proteins, Signal Transducing], Receptors, genetics [Exome], Odds Ratio, Innate, genetics [Receptors, Immunologic], Exome, Protein Interaction Maps, genetics [Genetic Predisposition to Disease], Receptors, Immunologic, ABI3 protein, human, Genetics, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Membrane Glycoproteins, Microglia, Phospholipase C gamma, Sequence Homology, Amino Acid, Polymorphism, Single Nucleotide, Adaptor Proteins, Single Nucleotide, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid, Settore MED/26 - NEUROLOGIA, genetics [Phospholipase C gamma], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Common disease-common variant, Biology, Article, 03 medical and health sciences, ddc:570, medicine, Journal Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Polymorphism, Allele frequency, TREM2 protein, human, TREM2, Case-control study, Signal Transducing, Immunity, medicine.disease, R1, Minor allele frequency, genetics [Immunity, Innate], 030104 developmental biology, Human medicine, 030217 neurology & neurosurgery
Abstract: International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
Published: 2017
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7. F119EXPLORING THE UTILITY OF BIOLOGICALLY INFORMED POLYGENIC RISK SCORES IN SCHIZOPHRENIA

Author: Peter Holmans, Antonio F. Pardiñas, Michael John Owen, Lynsey S. Hall, Michael Conlon O'Donovan, James T.R. Walters, and Christopher Medway
Subjects: Pharmacology, Psychiatry and Mental health, Neurology, business.industry, Schizophrenia (object-oriented programming), Medicine, Pharmacology (medical), Polygenic risk score, Neurology (clinical), business, Biological Psychiatry, Clinical psychology
Published: 2019
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8. PHARMACOGENOMIC ARCHITECTURE OF CLOZAPINE PLASMA CONCENTRATIONS

Author: Andrew Pocklington, Michael Conlon O'Donovan, Adrian King, Michael John Owen, James T.R. Walters, John A. Jansen, Christopher Medway, Mariana Nalmpanti, Sophie Sophie, Antonio F. Pardiñas, and Marinka Helthuis
Subjects: Pharmacology, business.industry, Psychiatry and Mental health, Neurology, Pharmacogenomics, Plasma concentration, medicine, Pharmacology (medical), Neurology (clinical), business, Biological Psychiatry, Clozapine, medicine.drug
Published: 2019
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9. 47TRANSCRIPTOME-WIDE ASSOCIATION ANALYSIS OF SCHIZOPHRENIA IMPLICATES PROCESSES INVOLVED IN SYNAPTIC DEVELOPMENT AND PLASTICITY, AND IMPAIRED LONG-TERM POTENTIATION

Author: Michael John Owen, Elliott Rees, Lynsey S. Hall, Valentina Escott-Price, Michael Conlon O'Donovan, James T.R. Walters, Christopher Medway, Antonio F. Pardiñas, Peter Holmans, and Andrew Pocklington
Subjects: Pharmacology, Psychiatry and Mental health, Neurology, Schizophrenia (object-oriented programming), Pharmacology (medical), Long-term potentiation, Neurology (clinical), Biology, Plasticity, Neuroscience, Biological Psychiatry, Genetic association
Published: 2019
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10. CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset

Author: Alastair Maxwell, Richard H. Myers, Michael Orth, Kyung Hee Kim, Kawther Abu Elneel, Lynsey S. Hall, Diane Lucente, Tammy Gillis, Anka G. Ehrhardt, Vanessa C. Wheeler, Christopher Medway, Douglas Barker, Michael J. Chao, Jacob M. Loupe, Darren G. Monckton, Jeffrey D. Long, Thomas Massey, Marc Ciosi, Jayalakshmi S. Mysore, Branduff McAllister, Jongmin Lee, Seung Kwak, E. Ray Dorsey, Kevin Correia, James F. Gusella, Ira Shoulson, Jean Paul G. Vonsattel, Jane S. Paulsen, Peter Holmans, G. Bernhard Landwehrmeyer, Lesley Jones, Eliana Marisa Ramos, Cristina Sampaio, Marcy E. MacDonald, Ricardo Mouro Pinto, Timothy Stone, Afroditi Chatzi, and Eun Pyo Hong
Subjects: Male, Huntingtin, Genome-wide association study, Disease, Pathogenesis, 0302 clinical medicine, Age of Onset, Aged, 80 and over, CAG repeat, Genetics, Huntingtin Protein, genetic modifier, 0303 health sciences, disease modification, Middle Aged, Huntington Disease, Phenotype, polyglutamine disease, Female, age at onset, trinucleotide repeat, Huntington’s disease, Adult, congenital, hereditary, and neonatal diseases and abnormalities, DNA repair, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, somatic DNA expansion, Huntington's disease, mental disorders, medicine, Humans, Gene, Alleles, Aged, 030304 developmental biology, Base Sequence, medicine.disease, nervous system diseases, Haplotypes, Genetic Loci, DNA maintenance, Peptides, Trinucleotide Repeat Expansion, Trinucleotide repeat expansion, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Summary Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin’s polyglutamine segment, dictates the rate at which Huntington’s disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question the fundamental premise that polyglutamine length determines the rate of pathogenesis in the “polyglutamine disorders.”, Graphical Abstract, Highlights • Uninterrupted CAG repeat, not polyglutamine, size drives the timing of HD onset • HD age at onset is influenced by at least six genes involved in DNA maintenance • Genetic modifier loci often show both onset-delaying and onset-hastening haplotypes • The rate-determining mechanism is likely to be somatic expansion of the CAG repeat, The onset of Huntington’s disease is shown to be dependent on the size of the uninterrupted CAG repeat sequence, not polyglutamine.
Published: 2019
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11. Review: The genetics of Alzheimer's disease; putting flesh on the bones

Author: Christopher Medway and Kevin Morgan
Subjects: Genetics, Histology, Flesh, Genome-wide association study, Disease, Biology, medicine.disease, Pathology and Forensic Medicine, Neurology, Physiology (medical), medicine, Disease process, Neurology (clinical), Alzheimer's disease, Genetic association
Abstract: For two decades the search for genes involved in Alzheimer's disease brought little reward; it was not until the advent of genome-wide association studies (GWAS) that genetic associations started to be revealed. Since 2009 increasingly large GWAS have revealed 20 loci, which in itself is a substantial increase in our understanding, but perhaps the more important feature is that these studies have highlighted novel pathways that are potentially involved in the disease process. This commentary assembles our latest knowledge while acknowledging that the casual functional variants, and undoubtedly, other genes are still yet to be discovered. This is the challenge that remains and the promise of next-generation sequencing is anticipated as there are a number of large initiatives which themselves should start to yield information before long.
Published: 2014
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12. The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project

Author: Kristelle Brown, Helen Butler, C M van Duijn, Naomi Hammond, A. D. Smith, Mario Cortina-Borja, Rachel Barber, de Bruijn Rfag., Christopher Medway, Mohammad Arfan Ikram, Gordon K. Wilcock, Eliecer Coto, Ignacio Mateo, Pascual Sánchez-Juan, Onofre Combarros, Patrick G. Kehoe, R. Heun, D J Lehmann, Peter J. Koudstaal, Heike Kölsch, Panagiotis Deloukas, Olivia Belbin, Kevin Morgan, Donald Warden, Michael G Lehmann, Victoria Alvarez, Carla A. Ibrahim-Verbaas, Neurology, Epidemiology, and Radiology & Nuclear Medicine
Subjects: Male, Risk, medicine.medical_specialty, Linkage disequilibrium, Estrogen receptor, Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Aromatase, Gene Frequency, Alzheimer Disease, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Genetics (clinical), Aged, Aged, 80 and over, Sex Characteristics, Case-control study, Epistasis, Genetic, Odds ratio, medicine.disease, Interleukin-10, Endocrinology, Case-Control Studies, biology.protein, Epistasis, Female, Alzheimer's disease
Abstract: Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG = 1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor = 1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.
Published: 2014
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13. Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array

Author: Jennifer Harris, James Lowe, David M. A. Mann, Bernadette McGuinness, Kevin Morgan, Reinhard Heun, Janet A. Johnston, Jose Bras, A. David Smith, Imelda Barber, Nigel M. Hooper, Anna Richardson, Tulsi Patel, Emma R.L.C. Vardy, Peter Passmore, Matthew Jones, Heike Kölsch, David Craig, Clive Holmes, Stuart Pickering-Brown, Donald Warden, Patrick G. Kehoe, Naomi Clement, Anne Braae, Christopher Medway, Andrew B. Singleton, Stephen Todd, Dena G. Hernandez, Julie S. Snowden, Sally Chappell, Keeley J. Brookes, John Hardy, Tamar Guetta-Baranes, David Neary, Rita Guerreiro, and Gordon K. Wilcock
Subjects: 0301 basic medicine, Aging, Parkinson's disease, Alzheimer's Disease, Parkinson's Disease, Sporadic, Early-onset, NeuroX, Screening, Ubiquitin-Protein Ligases, DNA Mutational Analysis, tau Proteins, Disease, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Early-onset Alzheimer's disease, Genetic Testing, Genetic Association Studies, Oligonucleotide Array Sequence Analysis, Genetic testing, Genetics, medicine.diagnostic_test, screening, General Neuroscience, Neurodegeneration, Genetic Variation, Parkinson Disease, medicine.disease, NeuroX, 030104 developmental biology, sporadic, Parkinson’s disease, Mutation testing, early-onset, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Alzheimer’s disease, 030217 neurology & neurosurgery, Developmental Biology
Abstract: We have screened sporadic early-onset Alzheimer’s disease (sEOAD, n=408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found two sEOAD individuals harbouring a known causative variant in PARK2 known to cause early-onset Parkinson’s disease (EOPD); p.T240M (n=1) and p.Q34fs delAG (n=1). Additionally, we identified three sEOAD individuals harbouring a predicted pathogenic variant in MAPT (p.A469T) which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.
Published: 2017
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14. P3‐092: Mapping Regulatory Variants in the Alzheimer's Disease Candidate Gene ABCA7

Author: Jeremy D. Burgess, Minerva M. Carrasquillo, Naomi Clement, Nilufer Ertekin-Taner, Steven G. Younkin, Neill R. Graff-Radford, Sally Chappell, Christopher Medway, Tamar Guetta-Baranes, Ronald C. Petersen, Kevin Morgan, Tammie Tam, Mariet Allen, and Dennis W. Dickson
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Candidate gene, Developmental Neuroscience, Epidemiology, Health Policy, biology.protein, Neurology (clinical), Disease, Computational biology, Geriatrics and Gerontology, Biology, ABCA7
Published: 2016
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15. O2‐10‐04: A Regulatory Variant at the TREM Gene Cluster Associates with Decreased Alzheimer’s Disease Risk and Increased TREML1 and TREM2 Brain Gene Expression

Author: Minerva M. Carrasquillo, Mariet Allen, Jeremy D. Burgess, Samantha L. Strickland, Shivani Aryal, Joanna Siuda, Michaela Kachadoorian, Christopher Medway, Curtis S. Younkin, Asha Nair, Pritha Chanana, Xue Wang, Daniel Serie, Thuy Nguyen, Sarah Lincoln, Kimberly G. Malphrus, Kevin Morgan, Todd E. Golde, Nathan D. Price, Charles White, Philip Jager, David A. Bennett, Yan W. Asmann, Julia E. Crook, Dennis W. Dickson, Steven G. Younkin, and Nilufer Ertekin-Taner
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2016
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16. P2‐065: Identifying Polymorphisms in The Alzheimer’s Related APP Gene Using The Oxford Nanopore Minion Sequencer

Author: Sally Chappell, Keeley J. Brookes, Naomi Clement, Christopher Medway, Kevin Morgan, Anne Braae, Tulsi Patel, Imelda Barber, Gabriela Zapata-Erazo, and Tamar Guetta-Baranes
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Minion, Amyloid precursor protein, biology.protein, Neurology (clinical), Nanopore sequencing, Geriatrics and Gerontology, Biology
Published: 2016
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17. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease

Author: Imelda S. Barber, Jennyfer M. García-Cárdenas, Chidchanok Sakdapanichkul, Christopher Deacon, Gabriela Zapata Erazo, Rita Guerreiro, Jose Bras, Dena Hernandez, Andrew Singleton, Tamar Guetta-Baranes, Anne Braae, Naomi Clement, Tulsi Patel, Keeley Brookes, Christopher Medway, Sally Chappell, David M. Mann, Kevin Morgan, Peter Passmore, David Craig, Janet Johnston, Bernadette McGuinness, Stephen Todd, Reinhard Heun, Heike Kölsch, Patrick G. Kehoe, Emma R.L.C. Vardy, Nigel M. Hooper, Stuart Pickering-Brown, Julie Snowden, Anna Richardson, Matt Jones, David Neary, Jenny Harris, James Lowe, A. David Smith, Gordon Wilcock, Donald Warden, and Clive Holmes
Subjects: Male, 0301 basic medicine, Aging, Biology, Article, Cohort Studies, Amyloid beta-Protein Precursor, 03 medical and health sciences, Exon, 0302 clinical medicine, Gene Frequency, Alzheimer Disease, medicine, Amyloid precursor protein, Humans, Early-onset Alzheimer's disease, Genetic Testing, Base Pairing, Allele frequency, Genetic Association Studies, Aged, Temporal cortex, Genetics, rs367709245, General Neuroscience, screening, Intron, Exons, Sequence Analysis, DNA, Middle Aged, medicine.disease, Introns, 030104 developmental biology, Mutation, RNA splicing, sporadic, biology.protein, Female, early-onset, Neurology (clinical), Geriatrics and Gerontology, APP, Alzheimer’s disease, Gene Deletion, 030217 neurology & neurosurgery, Developmental Biology, Minigene
Abstract: Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene. Four samples were shown to be heterozygous for 1 of 3 known causative mutations: p.A713T, p.V717I, and p.V717G; this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6-bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harboring the deletion found no evidence of transcripts with exon 17 removed.
Published: 2016
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18. Investigating Statistical Epistasis in Complex Disorders

Author: Hui Shi, Kevin Morgan, James Bullock, Kristelle Brown, Steven G. Younkin, Christopher Medway, James Turton, Neill R. Graff-Radford, Minerva M. Carrasquillo, Dennis W. Dickson, Noor Kalsheker, Olivia Belbin, and Ronald C. Petersen
Subjects: Genotype, Biology, Logistic regression, Polymorphism, Single Nucleotide, Epistatic interaction, Alzheimer Disease, Missing heritability problem, Statistics, Confidence Intervals, Humans, Aged, Genetic association, Statistical hypothesis testing, Models, Statistical, Interleukin-6, General Neuroscience, Epistasis, Genetic, General Medicine, Outcome (probability), Interleukin-10, Psychiatry and Mental health, Clinical Psychology, Sample size determination, Sample Size, Epistasis, Geriatrics and Gerontology, Software, Genome-Wide Association Study
Abstract: The missing heritability exhibited by late-onset Alzheimer's disease is unexplained and has been partly attributed to epistatic interaction. Methods available to explore this are often based on logistic regression and allow for determination of deviation from an expected outcome as a result of statistical epistasis. Three such methodologies including Synergy Factor and the PLINK modules, -epistasis and -fast-epistasis, were applied to study an epistatic interaction between interleukin-6 and interleukin-10. The models analyzed consisted of two synergistic interactions (SF ≈ 4.2 and 1.6) and two antagonistic interactions (SF ≈ 0.9 and 0.6). As with any statistical test, power to detect association is paramount; and most studies will be underpowered for the task. However, the availability of large sample sizes through genome-wide association studies make it feasible to examine approaches for determining epistatic interactions. This study documents the sample sizes needed to achieve a statistically significant outcome from each of the methods examined and discusses the limitations/advantages of the chosen approaches.
Published: 2011
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19. Late-onset Alzheimer disease risk variants mark brain regulatory loci

Author: Christopher Medway, Yan W. Asmann, Chen Wang, Neill R. Graff-Radford, Daniel J. Serie, Thuy Nguyen, Minerva M. Carrasquillo, Julia E. Crook, Lester Manly, Joanna Siuda, Mariet Allen, Curtis S. Younkin, Ronald C. Petersen, Kimberly G. Malphrus, High Seng Chai, Michaela Kachadoorian, Steven G. Younkin, Aditya V. Karhade, Nilufer Ertekin-Taner, Xue Wang, Sarah Lincoln, Li Ma, Fanggeng Zou, Jeremy D. Burgess, and Dennis W. Dickson
Subjects: Genetics, Regulation of gene expression, 0303 health sciences, Candidate gene, Genome-wide association study, Single-nucleotide polymorphism, Genomics, Biology, medicine.disease, Article, 03 medical and health sciences, 0302 clinical medicine, Gene expression, medicine, Neurology (clinical), Alzheimer's disease, Gene, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology
Abstract: Objective: To investigate the top late-onset Alzheimer disease (LOAD) risk loci detected or confirmed by the International Genomics of Alzheimer's Project for association with brain gene expression levels to identify variants that influence Alzheimer disease (AD) risk through gene expression regulation. Methods: Expression levels from the cerebellum (CER) and temporal cortex (TCX) were obtained using Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation assay (WG-DASL) for ∼400 autopsied patients (∼200 with AD and ∼200 with non-AD pathologies). We tested 12 significant LOAD genome-wide association study (GWAS) index single nucleotide polymorphisms (SNPs) for cis association with levels of 34 genes within ±100 kb. We also evaluated brain levels of 14 LOAD GWAS candidate genes for association with 1,899 cis-SNPs. Significant associations were validated in a subset of TCX samples using next-generation RNA sequencing (RNAseq). Results: We identified strong associations of brain CR1, HLA-DRB1, and PILRB levels with LOAD GWAS index SNPs. We also detected other strong cis-SNPs for LOAD candidate genes MEF2C, ZCWPW1, and SLC24A4. MEF2C and SLC24A4, but not ZCWPW1 cis-SNPs, also associate with LOAD risk, independent of the index SNPs. The TCX expression associations could be validated with RNAseq for CR1, HLA-DRB1, ZCWPW1, and SLC24A4. Conclusions: Our results suggest that some LOAD GWAS variants mark brain regulatory loci, nominate genes under regulation by LOAD risk variants, and annotate these variants for their brain regulatory effects.
Published: 2015

20. An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALMisoform

Author: Christopher Medway, Ishita Parikh, Steven G. Younkin, David W. Fardo, and Steven Estus
Subjects: Male, Genotype, Clinical Neurology, Single-nucleotide polymorphism, Genome-wide association study, Allelic Imbalance, Biology, Polymorphism, Single Nucleotide, PICALM, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Humans, Protein Isoforms, SNP, Genetic Predisposition to Disease, Allele, Molecular Biology, Genotyping, Alleles, 030304 developmental biology, Aged, 80 and over, Genetics, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, High-Throughput Nucleotide Sequencing, Molecular biology, Introns, Single nucleotide polymorphism, Allelic expression imbalance, Monomeric Clathrin Assembly Proteins, Next-generation sequencing, Female, Neurology (clinical), Alzheimer’s disease, 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract: Background Although genome wide studies have associated single nucleotide polymorphisms (SNP)s near PICALM with Alzheimer’s disease (AD), the mechanism underlying this association is unclear. PICALM is involved in clathrin-mediated endocytosis and modulates Aß clearance in vitro. Comparing allelic expression provides the means to detect cis-acting regulatory polymorphisms. Thus, we evaluated whether PICALM showed allele expression imbalance (AEI) and whether this imbalance was associated with the AD-associated polymorphism, rs3851179. Results We measured PICALM allelic expression in 42 human brain samples by using next-generation sequencing. Overall, PICALM demonstrated equal allelic expression with no detectable influence by rs3851179. A single sample demonstrated robust global PICALM allelic expression imbalance (AEI), i.e., each of the measured isoforms showed AEI. Moreover, the PICALM isoform lacking exons 18 and 19 (D18-19 PICALM) showed significant AEI in a subset of individuals. Sequencing these individuals and subsequent genotyping revealed that rs588076, located in PICALM intron 17, was robustly associated with this imbalance in D18-19 PICALM allelic expression (p = 9.54 x 10-5). This polymorphism has been associated previously with systolic blood pressure response to calcium channel blocking agents. To evaluate whether this polymorphism was associated with AD, we genotyped 3269 individuals and found that rs588076 was modestly associated with AD. However, when both the primary AD SNP rs3851179 was added to the logistic regression model, only rs3851179 was significantly associated with AD. Conclusions PICALM expression shows no evidence of AEI associated with rs3851179. Robust global AEI was detected in one sample, suggesting the existence of a rare SNP that strongly modulates PICALM expression. AEI was detected for the D18-19 PICALM isoform, and rs588076 was associated with this AEI pattern. Conditional on rs3851179, rs588076 was not associated with AD risk, suggesting that D18-19 PICALM is not critical in AD. In summary, this analysis of PICALM allelic expression provides novel insights into the genetics of PICALM expression and AD risk.
Published: 2014
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21. P1‐055: MULTIPLE ABCA7 MISSENSE VARIANTS MINED FROM THE EXOME VARIANT SERVER SHOW INDEPENDENT ASSOCIATION WITH INCREASED OR DECREASED RISK OF LATE‐ONSET ALZHEIMER'S DISEASE (LOAD)

Author: Kevin Morgan, Shane Pankratz, Christopher Medway, Joanna Siuda, Owen A. Ross, Dennis W. Dickson, Neill R. Graff-Radford, Minerva M. Carrasquillo, Steven G. Younkin, Fanggeng Zou, Gina Bisceglio, Jan O. Aasly, Maria Barcikowska, Zbigniew K. Wszolek, Ronald C. Petersen, Sigrid Botne Sando, SO Abdul-Hay, Li Ma, Tynickwa Mims, and Nilufer Ertekin-Taner
Subjects: Genetics, biology, Epidemiology, business.industry, Health Policy, Late onset, Disease, Bioinformatics, ABCA7, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, biology.protein, Medicine, Missense mutation, Neurology (clinical), Geriatrics and Gerontology, business, Association (psychology), Exome
Published: 2014
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22. P1‐052: DEEP SEQUENCING ALZHEIMER'S DISEASE ASSOCIATED GENES, CLU, PICALM, CR1, ABCA7, BIN1, MS4A, CD2AP, EPHA1, AND CD33 IDENTIFIES POTENTIAL FUNCTIONAL SNPS

Author: Christopher Medway, Kevin Morgan, Imelda Barber, Anne Braae, Kristelle Brown, Jenny Lord, and James Turton
Subjects: Genetics, biology, Epidemiology, business.industry, Health Policy, CD33, Functional snps, Disease, Deep sequencing, ABCA7, PICALM, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, biology.protein, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Gene
Published: 2014
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23. P2‐029: AN INTRONIC 6 BASE PAIR DELETION IN APP THAT POTENTIALLY AFFECTS EXON 17 SPLICING

Author: Kevin Morgan, Christopher Medway, Imelda Barber, Anne Braae, James Turton, Kristelle Brown, and Jenny Lord
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Exon, Developmental Neuroscience, Epidemiology, Base pair, Health Policy, RNA splicing, Neurology (clinical), Geriatrics and Gerontology, Biology
Published: 2014
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24. Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes

Author: Orestis Georgiou, Christopher Medway, Ian R. Mellor, Minal J. Patel, Kevin Morgan, Elena Matsa, Chris Denning, James E. Dixon, Paul J. Kemp, and Andrew Staniforth
Subjects: Pluripotent Stem Cells, ERG1 Potassium Channel, Small interfering RNA, congenital, hereditary, and neonatal diseases and abnormalities, hERG, Mutation, Missense, Gene Expression, Transfection, Sudden death, RNA interference, Gene Knockdown Techniques, Humans, Medicine, Myocytes, Cardiac, Induced pluripotent stem cell, Genetics, Gene knockdown, biology, business.industry, iPS cells, Long-QT syndrome, Arrhythmia, Electrophysiology, Gene therapy, Genetic Therapy, Ether-A-Go-Go Potassium Channels, Electrophysiological Phenomena, Cell biology, Long QT Syndrome, Phenotype, biology.protein, RNA Interference, Stem cell, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. Methods and results We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). Conclusions These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart. © 2013 The Author.
Published: 2013

25. CD2-Associated Protein (CD2AP)

Author: Christopher Medway and Kevin Morgan
Subjects: Immune system, CD2-Associated Protein, Cytoplasm, Disease, Biology, Bioinformatics, Actin cytoskeleton, Endocytosis, Genetic association, Immunological synapse
Abstract: Genome-wide association studies have implicated the cytoplasmic scaffold CD2-associated protein (CD2AP) in Alzheimer’s disease. Although this association requires independent replication, mechanistically it is involved in recognised disease pathways; immune system function and endocytosis. Currently there is little research into the role of CD2AP in healthy or disease brain tissue, which will be essential to translate the genetic data in the future.
Published: 2013
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26. Sialic Acid Binding Immunoglobulin-Like Lectin-3 (CD33)

Author: Kevin Morgan and Christopher Medway
Subjects: chemistry.chemical_compound, Immune system, chemistry, CD33, biology.protein, Extracellular, Sialic acid binding, Disease, Biology, Antibody, Inhibitory postsynaptic potential, Cell biology, Sialic acid
Abstract: CD33 (siglec-3) is a member of the family of immunoglobulin containing siglecs. Expressed in myeloid cells, CD33 contains an inhibitory motif which responds to the extracellular “sialoglycome” to dampen immune responses. Genetic variants within anti-inflammatory signalling proteins may contribute to the hyper-inflammatory state associated with Alzheimer’s disease brain. However, the genetic evidence implicating CD33 in Alzheimer’s disease requires independent replication before translational research can be embarked on.
Published: 2013
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27. Erythropoietin-Producing Human Hepatocellular Carcinoma (EphA1)

Author: Kevin Morgan, Christopher Medway, and Anne Braae
Subjects: Focal adhesion, biology, Extracellular, biology.protein, Erythropoietin-producing hepatocellular (Eph) receptor, Ephrin, Dendritic spine morphogenesis, Receptor, Neuroscience, Neural development, Receptor tyrosine kinase
Abstract: Eph-like receptors belong to the receptor tyrosine kinase family and are divided into two classes, A and B, based on their extracellular domains and the ephrin ligands that they bind. Eph signalling is complex as the two classes of receptors can interact to form functional “clusters” and the receptors themselves are capable of signalling. EphA1 is expressed in multiple tissues and is involved in cell adhesion and organisation of a range of developmental and physiological processes. In the CNS, EphA1 is involved in neural development, synapse plasticity and dendritic spine morphogenesis, suggesting that these receptors may be important as modifiers of neurodegenerative disease. A polymorphism (rs11767557) 3,154 bp upstream of EPHA1 has been significantly associated with Alzheimer’s disease in Caucasian cohorts; however, the functional variant remains unknown. Ephrin receptor signalling operates on known AD pathology pathways. Some ephrin receptors require processing by γ–secretase, which has previously been linked to AD. Furthermore, the role of ephrin receptors in neurodevelopment and spine morphology in AD areas of the brain suggests that differences in neural circuitry may be at fault.
Published: 2013
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28. Next generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions

Author: Jenny Lord, James Turton, Christopher Medway, Hui Shi, Kristelle Brown, James Lowe, David Mann, Stuart Pickering-Brown, Noor Kalsheker, Peter Passmore, and Kevin Morgan
Subjects: Original Article
Abstract: CLU, PICALM and CR1 were identified as genetic risk factors for late onset Alzheimer’s disease (AD) in two large genome wide association studies (GWAS) published in 2009, but the variants that convey this alteration in disease risk, and how the genes relate to AD pathology is yet to be discovered. A next generation sequencing (NGS) project was conducted targeting CLU, CR1 and PICALM, in 96 AD samples (8 pools of 12), in an attempt to discover rare variants within these AD associated genes. Inclusion of repetitive regions in the design of the SureSelect capture lead to significant issues in alignment of the data, leading to poor specificity and a lower than expected depth of coverage. A strong positive correlation (0.964, p
Published: 2012

29. The vitamin D receptor gene is associated with Alzheimer's disease

Author: Donald Warden, D J Lehmann, Gordon K. Wilcock, Helga Refsum, A. D. Smith, and Christopher Medway
Subjects: Risk, medicine.medical_specialty, Inflammation, Dopamine beta-Hydroxylase, Disease, Biology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Calcitriol receptor, Neuroprotection, Cohort Studies, Apolipoproteins E, Alzheimer Disease, Internal medicine, Odds Ratio, medicine, Vitamin D and neurology, Humans, Cognitive decline, Alleles, Polymorphism, Genetic, General Neuroscience, DNA, Human brain, Interleukin-10, Interleukin 10, medicine.anatomical_structure, Endocrinology, Immunology, Receptors, Calcitriol, medicine.symptom
Abstract: Vitamin D may have a role in brain function. Low levels have been frequently associated with cognitive decline and may contribute to diseases of the nervous system. The vitamin D receptor (VDR) is widely expressed in human brain. Vitamin D appears to be neuroprotective and may regulate inflammation in the brain. We examined two VDR polymorphisms, Apa1 and Taq1. We used DNA from 255 Alzheimer's disease (AD) cases and 260 cognitively screened elderly controls from the longitudinal cohort of the Oxford Project to Investigate Memory and Ageing (OPTIMA). The presence of each of the linked alleles, Apa1 T and Taq1 G, was associated with the risk of AD, particularly in people
Published: 2011

30. P1‐262: Genetic Variants Influencing Human Longevity from Late‐Onset Alzheimer's Disease (LOAD) Genome‐Wide Association Studies (GWAS)

Author: Hui Shi, Christopher Medway, Kristelle Brown, Noor Kalsheker, Alison Goate, Petroula Proitsi, John Powell, Simon Lovestone, Minerva Carrasquillo, Steven Younkin, and null Kevin Morgan (for the ART consortium)
Subjects: Genetics, History, Epidemiology, Health Policy, Genetic variants, Genome-wide association study, Late onset, Disease, St louis, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Human longevity, Neurology (clinical), Geriatrics and Gerontology, Demography, Genetic association
Abstract: P1-262 GENETIC VARIANTS INFLUENCING HUMAN LONGEVITY FROM LATE-ONSETALZHEIMER’S DISEASE (LOAD) GENOME-WIDE ASSOCIATION STUDIES (GWAS) Hui Shi, Christopher Medway, Kristelle Brown, Noor Kalsheker, Alison Goate, Petroula Proitsi, John Powell, Simon Lovestone, Minerva Carrasquillo, Steven Younkin Kevin Morgan (for the ART consortium), University of Nottingham, Nottingham, United Kingdom; University of Nottingham, Nottingham, United Kingdom; Washington University, St Louis, Missouri, United States; Kings College London, London, United Kingdom; Mayo Clinic College of Medicine, Jacksonville, Florida, United States.
Published: 2011
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31. P1‐249: Differential Epistatic Interactions with Alternative APOE Alleles in Late‐Onset Alzheimer's Disease

Author: Kevin Morgan, Minerva M. Carrasquillo, Shi Hui, Kristelle Brown, Olivia Belbin, Noor Kalsheker, Steven G. Younkin, James Turton, Christopher Medway, and James Bullock
Subjects: Genetics, Apolipoprotein E, Epidemiology, Health Policy, Late onset, Disease, Biology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epistasis, Neurology (clinical), Geriatrics and Gerontology, Allele, Differential (mathematics)
Published: 2011
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32. A multi-centre study of ACE and the risk of late-onset Alzheimer’s disease

Author: Kevin Morgan, David Craig, Julie Williams, Hui Shi, Patrick G. Kehoe, A. David Smith, Minerva M. Carrasquillo, Steven G. Younkin, Michael John Owen, Reinhard Heun, Richard Abraham, Seth Love, Clive Holmes, Heike Kölsch, Noor Kalsheker, Kristelle Brown, Bernadette McGuinness, Donald Warden, David M. A. Mann, Christopher Medway, Peter Passmore, and Olivia Belbin
Subjects: Male, Genotype, Population, Peptidyl-Dipeptidase A, Polymorphism, Single Nucleotide, Article, White People, Apolipoproteins E, Gene Frequency, Meta-Analysis as Topic, Alzheimer Disease, Risk Factors, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, education, Allele frequency, Aged, Genetics, Aged, 80 and over, education.field_of_study, biology, General Neuroscience, Haplotype, Case-control study, Angiotensin-converting enzyme, General Medicine, Odds ratio, medicine.disease, Europe, Psychiatry and Mental health, Clinical Psychology, Logistic Models, Case-Control Studies, North America, biology.protein, Female, Geriatrics and Gerontology, Alzheimer's disease
Abstract: A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.
Published: 2011

33. Analysis of Genome-Wide Association Study (GWAS) data looking for replicating signals in Alzheimer's disease (AD)

Author: Hui, Shi, Christopher, Medway, James, Bullock, Kristelle, Brown, Noor, Kalsheker, and Kevin, Morgan
Subjects: Original Article
Abstract: We have performed cross-platform comparisons of output from 4 GWAS in late-onset Alzheimer's disease (LOAD) - Reiman et al., 2007; Li et al., 2008; Beecham et al., 2008 and Carrasquillo et al., 2009 to search for new association signals. The aim was to reveal genes that replicated across studies and hence merit further investigation. All SNPs with p-values ranging between 5×10(-5) - 5×10(-8) from each study were assessed across the other studies (either directly or by using a perfect proxy when comparing data from different chip platforms). This revealed only a single SNP (rs929156 in the tripartite motif-containing protein 15, TRIM15, gene) that was replicating across all studies at a level approaching genome-wide significance (P = 8.77×10(-8)) and where meta-analysis of odds ratios showed a significant effect on risk (OR 1.1, 95% Cl 1.0-1.2, P = 0.03). The vast majority of data analysed failed to replicate across these GWAS. The number of replicating association signals we observed is no higher than would be expected due to chance. However, increasing the power by using additional data from larger studies may enable this approach to identify potential LOAD candidate genes for confirmatory association studies.
Published: 2009

34. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease

Author: SO Abdul-Hay, Jan O. Aasly, Shane Pankratz, Christopher Medway, Steven G. Younkin, Zbigniew K. Wszolek, Nilufer Ertekin-Taner, Maria Barcikowska, Dennis W. Dickson, Minerva M. Carrasquillo, Owen A. Ross, Fanggeng Zou, Sigrid Botne Sando, Joanna Siuda, Ronald C. Petersen, Neill R. Graff-Radford, Kevin Morgan, Guojun Bu, Tynickwa Mims, Li Ma, and Gina Bisceglio
Subjects: Apolipoprotein E, Male, Genotype, Clinical Neurology, Short Report, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Apolipoproteins E, Alzheimer Disease, Humans, Genetic Predisposition to Disease, Allele, Age of Onset, Molecular Biology, 030304 developmental biology, Genetic association, Aged, Genetics, 0303 health sciences, Haplotype, Middle Aged, Minor allele frequency, Case-Control Studies, Female, Neurology (clinical), 030217 neurology & neurosurgery, Common disease-common variant, Genome-Wide Association Study
Abstract: Recent genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these "actionable" variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D' = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5 × 10⁻⁰⁵; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D' = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.
Published: 2014

35. Missense variant in TREML2 protects against Alzheimer's disease

Author: Imelda Barber, Ward Ortmann, Gerard D. Schellenberg, Jean-Charles Lambert, Denise Harold, Sheng Chih Jin, Julie Williams, Tushar Bhangale, Christopher Medway, Jonathan L. Haines, Rebecca Sims, R. R. Graham, John Hardy, Kristelle Brown, Richard Mayeux, Margaret A. Pericak-Vance, Oscar Harari, Kevin Morgan, Sarah Bertelsen, Rita Guerreiro, Céline Bellenguez, Michelle K. Lupton, Jenny Lord, Marcel P. van der Brug, Anne M. Fagan, Timothy W. Behrens, John Powell, J. Raphael Gibbs, John C. Morris, Patrick C.G. Haddick, Jose Bras, David M. Holtzman, Jim Turton, John S. K. Kauwe, Bruno A. Benitez, Carlos Cruchaga, Lindsay A. Farrer, AB Singleton, Philippe Amouyel, Celeste Sassi, Anne Braae, and Alison Goate
Subjects: Conditional analysis, Risk, Aging, Neuroscience(all), Clinical Neurology, Mutation, Missense, Genome-wide association study, Single-nucleotide polymorphism, Genome-wide association studies, Gene, Polymorphism, Single Nucleotide, Association, Meta-Analysis as Topic, Alzheimer Disease, TREM2, Medicine, Missense mutation, Genetic Report Abstract, Humans, Receptors, Immunologic, Genetic association, Genetics, business.industry, General Neuroscience, Genetic Variation, Alzheimer's disease, medicine.disease, Ageing, Endophenotype, Chromosomes, Human, Pair 6, Neurology (clinical), Geriatrics and Gerontology, business, Biomarkers, Common disease-common variant, Developmental Biology, Genome-Wide Association Study
Abstract: TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
Published: 2014

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35 results on '"Christopher Medway"'

1. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease.

2. Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington’s Disease

3. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression

4. Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3

5. Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia

6. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

7. F119EXPLORING THE UTILITY OF BIOLOGICALLY INFORMED POLYGENIC RISK SCORES IN SCHIZOPHRENIA

8. PHARMACOGENOMIC ARCHITECTURE OF CLOZAPINE PLASMA CONCENTRATIONS

9. 47TRANSCRIPTOME-WIDE ASSOCIATION ANALYSIS OF SCHIZOPHRENIA IMPLICATES PROCESSES INVOLVED IN SYNAPTIC DEVELOPMENT AND PLASTICITY, AND IMPAIRED LONG-TERM POTENTIATION

10. CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset

11. Review: The genetics of Alzheimer's disease; putting flesh on the bones

12. The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project

13. Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array

14. P3‐092: Mapping Regulatory Variants in the Alzheimer's Disease Candidate Gene ABCA7

15. O2‐10‐04: A Regulatory Variant at the TREM Gene Cluster Associates with Decreased Alzheimer’s Disease Risk and Increased TREML1 and TREM2 Brain Gene Expression

16. P2‐065: Identifying Polymorphisms in The Alzheimer’s Related APP Gene Using The Oxford Nanopore Minion Sequencer

17. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease

18. Investigating Statistical Epistasis in Complex Disorders

19. Late-onset Alzheimer disease risk variants mark brain regulatory loci

20. An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALMisoform

21. P1‐055: MULTIPLE ABCA7 MISSENSE VARIANTS MINED FROM THE EXOME VARIANT SERVER SHOW INDEPENDENT ASSOCIATION WITH INCREASED OR DECREASED RISK OF LATE‐ONSET ALZHEIMER'S DISEASE (LOAD)

22. P1‐052: DEEP SEQUENCING ALZHEIMER'S DISEASE ASSOCIATED GENES, CLU, PICALM, CR1, ABCA7, BIN1, MS4A, CD2AP, EPHA1, AND CD33 IDENTIFIES POTENTIAL FUNCTIONAL SNPS

23. P2‐029: AN INTRONIC 6 BASE PAIR DELETION IN APP THAT POTENTIALLY AFFECTS EXON 17 SPLICING

24. Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes

25. CD2-Associated Protein (CD2AP)

26. Sialic Acid Binding Immunoglobulin-Like Lectin-3 (CD33)

27. Erythropoietin-Producing Human Hepatocellular Carcinoma (EphA1)

28. Next generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions

29. The vitamin D receptor gene is associated with Alzheimer's disease

30. P1‐262: Genetic Variants Influencing Human Longevity from Late‐Onset Alzheimer's Disease (LOAD) Genome‐Wide Association Studies (GWAS)

31. P1‐249: Differential Epistatic Interactions with Alternative APOE Alleles in Late‐Onset Alzheimer's Disease

32. A multi-centre study of ACE and the risk of late-onset Alzheimer’s disease

33. Analysis of Genome-Wide Association Study (GWAS) data looking for replicating signals in Alzheimer's disease (AD)

34. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease

35. Missense variant in TREML2 protects against Alzheimer's disease

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35 results on '"Christopher Medway"'

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