X-chromosome-wide association study for Alzheimer's disease.
Journal: Molecular psychiatry
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Affiliated Institutions: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, LabEx DISTALZ - U-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Lille, France. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. Nuffield Department of Population Health Oxford University, Oxford, UK. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA. Department of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn, University of Bonn, Bonn, Germany. Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany. Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain. Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA. Department of Neurology, Boston University, Boston, MA, USA. Program in Translational Neuro-Psychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA. Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA. Department of Neurology, Emory University, Atlanta, GA, USA. Department of Radiology, Indiana University, Indianapolis, IN, USA. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. Department of Neurology, Mayo Clinic, Rochester, MN, USA. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA. Center for Cognitive Neurology and Departments of Neurology, New York University, School of Medicine, New York, NY, USA. Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA. Department of Neurology, University of California Davis, Sacramento, CA, USA. Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA. Sanders-Brown Center on Aging and University of Kentucky Alzheimer's Disease Research Center, Department of Neuroscience, University of Kentucky, Lexington, KY, USA. Michigan Alzheimer's Disease Center, Department of Neurology, University of Michigan, Ann Arbor, MI, USA. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. University of Pittsburgh Alzheimer's Disease Research Center, Pittsburgh, PA, USA. Department of Neurology, University of Southern California, Los Angeles, CA, USA. Department of Medicine, University of Washington, Seattle, WA, USA. Department of Neurology, University of Washington, Seattle, WA, USA. Department of Epidemiology, University of Washington, Seattle, WA, USA. Geriatric Research, Education and Clinical Center (GRECC), University of Wisconsin, Madison, WI, USA. Gerontology and Geriatric Medicine Center on Diabetes, Obesity, and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC, USA. Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University, New Haven, CT, USA. Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, USA. Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA. Department of Medicine (Neurology), Tanz Centre for Research in Neurodegenerative Disease, Temerty Faculty of Medicine, University of Toronto, and University Health Network, Toronto, ON, USA. Klinik für Psychiatrie und Psychotherapie, Saarbrücken, Germany. Department of Neurology, Washington University, St. Louis, MO, USA. Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Wales, UK. Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. Martin-Luther-University Halle-Wittenberg, University Clinic and Outpatient Clinic for Psychiatry, Psychotherapy and Psychosomatics, Halle (Saale), Germany. Department of Psychiatry and Psychotherapy, LVR-Klinikum Essen, University of Duisburg-Essen, Germany, Medical Faculty, Duisburg, Germany. Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany. Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, , Leipzig, Germany. Department of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic of Barcelona, Fundació Recerca Clinic Barcelona- Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), and University of Barcelona, Barcelona, Spain. German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany. Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine and Health, Klinikum rechts der Isar, Munich, Germany. Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen, Germany. Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. Institute for Urban Public Health, University Hospital of University Duisburg-Essen, Essen, Germany. st Department of Neurology, Medical school, Aristotle University of Thessaloniki, Thessaloniki, Makedonia, Greece. Taub Institute for Research in Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Depatment of Neurology, Columbia University, New York, NY, USA. CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain. Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona, Spain. Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain. Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain. Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Lleida, Spain. Depatamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain. Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland. Faculty of Medicine, University of Lisbon, Lisbon, Portugal. Clinic of Neurology, UH "Alexandrovska", Medical University-Sofia, Sofia, Bulgaria. Memory Clinic, Department of Neurology, Charles University, Second Faculty of Medicine and Motol University Hospital, Praha, Czech Republic. Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark. Department of Neurology, Erasmus MC, Rotterdam, The Netherlands. Maastricht University, Department of Psychiatry & Neuropsychologie, Alzheimer Center Limburg, Maastricht, The Netherlands. Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital-Solna, , Stockholm, Sweden. Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden. Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden. Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, , Evry, France. Univ Rouen Normandie, Normandie Univ, Inserm U and CHU Rouen, Department of Genetics and CNRMAJ, F-, Rouen, France. Inserm, Bordeaux Population Health Research Center, UMR , Univ. Bordeaux, ISPED, CIC -EC, Univ. Bordeaux, Bordeaux, France. Univ. Lille, Inserm , CHU Clinical and Research Memory Research Centre (CMRR) of Distalz, Lille, France. Université de Paris, EA , APHP, Hôpital Broca, Paris, France. University Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France. Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland. Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, , Italy. Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy. Department of Clinical Sciences and Community Health, University of Milan, , Milan, Italy. Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy. Interdisciplinary Department of Medicine, Geriatric Medicine and Memory Unit, University of Bari "A. Moro", Bari, Italy. Centre for Memory Disturbances, Lab of Clinical Neurochemistry, Section of Neurology, University of Perugia, Perugia, Italy. Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy. Neurology Unit, "San Gerardo" Hospital, Monza and University of Milano-Bicocca, Milan, Italy. Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence, Italy. Department of Medicine and Surgery, Unit of Neurology, University-Hospital of Parma, Parma, Italy. Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy. Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy. Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy. Laboratory of Experimental Neuropsychobiology, IRCCS Santa Lucia Foundation, Rome, Italy. Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. Department of Population and Quantitative Health Sciences and Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA. NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, LabEx DISTALZ - U-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Lille, France. celine.bellenguez@pasteur-lille.fr.
Abstract summary
Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.Authors & Co-authors: Le Borgne Julie J Gomez Lissette L Heikkinen Sami S Amin Najaf N Ahmad Shahzad S Choi Seung Hoan SH Bis Joshua J Grenier-Boley Benjamin B Rodriguez Omar Garcia OG Kleineidam Luca L Young Juan J Tripathi Kumar Parijat KP Wang Lily L Varma Achintya A Campos-Martin Rafael R van der Lee Sven S Damotte Vincent V de Rojas Itziar I Palmal Sagnik S Lipton Richard R Reiman Eric E McKee Ann A De Jager Philip P Bush William W Small Scott S Levey Allan A Saykin Andrew A Foroud Tatiana T Albert Marilyn M Hyman Bradley B Petersen Ronald R Younkin Steven S Sano Mary M Wisniewski Thomas T Vassar Robert R Schneider Julie J Henderson Victor V Roberson Erik E DeCarli Charles C LaFerla Frank F Brewer James J Swerdlow Russell R Van Eldik Linda L Hamilton-Nelson Kara K Paulson Henry H Naj Adam A Lopez Oscar O Chui Helena H Crane Paul P Grabowski Thomas T Kukull Walter W Asthana Sanjay S Craft Suzanne S Strittmatter Stephen S Cruchaga Carlos C Leverenz James J Goate Alison A Kamboh M Ilyas MI George-Hyslop Peter St PS Valladares Otto O Kuzma Amanda A Cantwell Laura L Riemenschneider Matthias M Morris John J Slifer Susan S Dalmasso Carolina C Castillo Atahualpa A Küçükali Fahri F Peters Oliver O Schneider Anja A Dichgans Martin M Rujescu Dan D Scherbaum Norbert N Deckert Jürgen J Riedel-Heller Steffi S Hausner Lucrezia L Molina-Porcel Laura L Düzel Emrah E Grimmer Timo T Wiltfang Jens J Heilmann-Heimbach Stefanie S Moebus Susanne S Tegos Thomas T Scarmeas Nikolaos N Dols-Icardo Oriol O Moreno Fermin F Pérez-Tur Jordi J Bullido María J MJ Pastor Pau P Sánchez-Valle Raquel R Álvarez Victoria V Boada Mercè M García-González Pablo P Puerta Raquel R Mir Pablo P Real Luis M LM Piñol-Ripoll Gerard G García-Alberca Jose María JM Royo Jose Luís JL Rodriguez-Rodriguez Eloy E Soininen Hilkka H de Mendonça Alexandre A Mehrabian Shima S Traykov Latchezar L Hort Jakub J Vyhnalek Martin M Thomassen Jesper Qvist JQ Pijnenburg Yolande A L YAL Holstege Henne H van Swieten John J Ramakers Inez I Verhey Frans F Scheltens Philip P Graff Caroline C Papenberg Goran G Giedraitis Vilmantas V Boland Anne A Deleuze Jean-François JF Nicolas Gael G Dufouil Carole C Pasquier Florence F Hanon Olivier O Debette Stéphanie S Grünblatt Edna E Popp Julius J Ghidoni Roberta R Galimberti Daniela D Arosio Beatrice B Mecocci Patrizia P Solfrizzi Vincenzo V Parnetti Lucilla L Squassina Alessio A Tremolizzo Lucio L Borroni Barbara B Nacmias Benedetta B Spallazzi Marco M Seripa Davide D Rainero Innocenzo I Daniele Antonio A Bossù Paola P Masullo Carlo C Rossi Giacomina G Jessen Frank F Fernandez Victoria V Kehoe Patrick Gavin PG Frikke-Schmidt Ruth R Tsolaki Magda M Sánchez-Juan Pascual P Sleegers Kristel K Ingelsson Martin M Haines Jonathan J Farrer Lindsay L Mayeux Richard R Wang Li-San LS Sims Rebecca R DeStefano Anita A Schellenberg Gerard D GD Seshadri Sudha S Amouyel Philippe P Williams Julie J van der Flier Wiesje W Ramirez Alfredo A Pericak-Vance Margaret M Andreassen Ole A OA Van Duijn Cornelia C Hiltunen Mikko M Ruiz Agustín A Dupuis Josée J Martin Eden E Lambert Jean-Charles JC Kunkle Brian B Bellenguez Céline C
Study Outcome
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Citations : Lambert JC, Ramirez A, Grenier-Boley B, Bellenguez C. Step by step: towards a better understanding of the genetic architecture of Alzheimer’s disease. Mol Psychiatry. 2023;28:2716–27.Authors : 173
Identifiers
Doi : 10.1038/s41380-024-02838-5SSN : 1476-5578