. 2024 Jul 11;111(7):1316-1329.

doi: 10.1016/j.ajhg.2024.05.017. Epub 2024 Jun 17.

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Claudia Manzoni¹, Demis A Kia², Raffaele Ferrari², Ganna Leonenko³, Beatrice Costa², Valentina Saba⁴, Edwin Jabbari², Manuela Mx Tan⁵, Diego Albani⁶, Victoria Alvarez⁷, Ignacio Alvarez⁸, Ole A Andreassen⁹, Antonella Angiolillo¹⁰, Andrea Arighi¹¹, Matt Baker¹², Luisa Benussi¹³, Valentina Bessi¹⁴, Giuliano Binetti¹⁵, Daniel J Blackburn¹⁶, Merce Boada¹⁷, Bradley F Boeve¹⁸, Sergi Borrego-Ecija¹⁹, Barbara Borroni²⁰, Geir Bråthen²¹, William S Brooks²², Amalia C Bruni²³, Paola Caroppo²⁴, Sara Bandres-Ciga²⁵, Jordi Clarimon²⁶, Rosanna Colao²³, Carlos Cruchaga²⁷, Adrian Danek²⁸, Sterre Cm de Boer²⁹, Itziar de Rojas¹⁷, Alfonso di Costanzo¹⁰, Dennis W Dickson¹², Janine Diehl-Schmid³⁰, Carol Dobson-Stone³¹, Oriol Dols-Icardo³², Aldo Donizetti³³, Elise Dopper³⁴, Elisabetta Durante³⁵, Camilla Ferrari¹⁴, Gianluigi Forloni⁶, Francesca Frangipane²³, Laura Fratiglioni³⁶, Milica G Kramberger³⁷, Daniela Galimberti³⁸, Maurizio Gallucci³⁹, Pablo García-González¹⁷, Roberta Ghidoni¹³, Giorgio Giaccone²⁴, Caroline Graff⁴⁰, Neill R Graff-Radford⁴¹, Jordan Grafman⁴², Glenda M Halliday³¹, Dena G Hernandez⁴³, Lena E Hjermind⁴⁴, John R Hodges⁴⁵, Guy Holloway⁴⁶, Edward D Huey⁴⁷, Ignacio Illán-Gala³², Keith A Josephs¹⁸, David S Knopman¹⁸, Mark Kristiansen⁴⁸, John B Kwok³¹, Isabelle Leber⁴⁹, Hampton L Leonard⁵⁰, Ilenia Libri²⁰, Alberto Lleo³², Ian R Mackenzie⁵¹, Gaganjit K Madhan⁴⁸, Raffaele Maletta²³, Marta Marquié¹⁷, Ales Maver⁵², Manuel Menendez-Gonzalez⁵³, Graziella Milan⁵⁴, Bruce L Miller⁵⁵, Christopher M Morris⁵⁶, Huw R Morris², Benedetta Nacmias⁵⁷, Judith Newton⁴⁶, Jørgen E Nielsen⁴⁴, Christer Nilsson⁵⁸, Valeria Novelli⁵⁹, Alessandro Padovani²⁰, Suvankar Pal⁴⁶, Florence Pasquier⁶⁰, Pau Pastor⁶¹, Robert Perneczky⁶², Borut Peterlin⁵², Ronald C Petersen¹⁸, Olivier Piguet⁶³, Yolande Al Pijnenburg⁶⁴, Annibale A Puca⁶⁵, Rosa Rademakers⁶⁶, Innocenzo Rainero⁶⁷, Lianne M Reus⁶⁸, Anna Mt Richardson⁶⁹, Matthias Riemenschneider⁷⁰, Ekaterina Rogaeva⁷¹, Boris Rogelj⁷², Sara Rollinson⁷³, Howard Rosen⁷⁴, Giacomina Rossi²⁴, James B Rowe⁷⁵, Elisa Rubino⁶⁷, Agustin Ruiz¹⁷, Erika Salvi⁷⁶, Raquel Sanchez-Valle¹⁹, Sigrid Botne Sando²¹, Alexander F Santillo⁷⁷, Jennifer A Saxon⁶⁹, Johannes Cm Schlachetzki⁷⁸, Sonja W Scholz⁷⁹, Harro Seelaar³⁴, William W Seeley⁷⁴, Maria Serpente¹¹, Sandro Sorbi⁵⁷, Sabrina Sordon⁷⁰, Peter St George-Hyslop⁸⁰, Jennifer C Thompson⁸¹, Christine Van Broeckhoven⁸², Vivianna M Van Deerlin⁸³, Sven J Van der Lee⁸⁴, John Van Swieten³⁴, Fabrizio Tagliavini²⁴, Julie van der Zee⁸², Arianna Veronesi³⁵, Emilia Vitale⁸⁵, Maria Landqvist Waldo⁸⁶, Jennifer S Yokoyama⁸⁷, Mike A Nalls⁸⁸, Parastoo Momeni⁸⁹, Andrew B Singleton⁹⁰, John Hardy⁹¹, Valentina Escott-Price⁹²

Affiliations

¹ UCL School of Pharmacy, London, UK. Electronic address: c.manzoni@ucl.ac.uk.
² Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
³ Division of Psychological Medicine and Clinical Neurosciences, UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
⁴ Medical and Genomic Statistics Unit, Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁶ Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
⁷ Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.
⁸ Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain; Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona, Spain.
⁹ NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹⁰ Centre for Research and Training in Medicine of Aging, Department of Medicine and Health Science "V. Tiberio," University of Molise, Campobasso, Italy.
¹¹ Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
¹² Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA.
¹³ Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁴ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
¹⁵ MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁶ University of Sheffield, Sheffield, UK.
¹⁷ Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
¹⁸ Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA.
¹⁹ Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology. Hospital Clínic de Barcelona, Fundació Clínic Barcelona-IDIBAPS, Barcelona, Spain.
²⁰ Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
²¹ Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway; Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
²² Neuroscience Research Australia, and Randwick Clinical Campus, UNSW Medicine and Health, University of New South Wales, Sydney, Australia.
²³ Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy.
²⁴ Unit of Neurology (V) and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
²⁵ Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
²⁶ Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
²⁷ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA.
²⁸ Neurologische Klinik, LMU Klinikum, Munich, Germany.
²⁹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
³⁰ Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; kbo-Inn-Salzach-Klinikum, Wasserburg, Germany.
³¹ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
³² Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
³³ Department of Biology, University of Naples Federico II, Naples, Italy.
³⁴ Department of Neurology & Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁵ Immunohematology and Transfusional Medicine Service, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy.
³⁶ Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden; Theme Inflammation and Aging, Karolinska Universtiy Hospital, Stockholm, Sweden.
³⁷ Department of Neurology, University Medical Center, Medical faculty, Ljubljana University of Ljubljana, Ljubljana, Slovenia; Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Huddinge, Sweden.
³⁸ Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
³⁹ Cognitive Impairment Center, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy.
⁴⁰ Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden; Unit for hereditary dementia, Karolinska Universtiy Hospital-Solna, Stockholm, Sweden.
⁴¹ Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA.
⁴² Shirley Ryan AbilityLab, Chicago, IL, USA.
⁴³ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴⁴ Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Copenhagen University Hospital, Copenhagen, Denmark.
⁴⁵ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
⁴⁶ Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK.
⁴⁷ Bio Med Psychiatry & Human Behavior, Brown University, Providence, RI, USA.
⁴⁸ UCL Genomics, London, UK; UCL Great Ormond Street Institute of Child Health, London, UK; Zayed Centre for Research into Rare Disease in Children, London, UK.
⁴⁹ Sorbonne Université, INSERM U1127, CNRS 7225, Institut du Cerveau - ICM, Paris, France; AP-HP Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Neurology, Institute of Memory and Alzheimer's Disease, Paris, France.
⁵⁰ Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International LLC, Washington, DC, USA; DZNE Tübingen, Tübingen, Germany.
⁵¹ Department of Pathology, University of British Columbia, Vancouver, Canada; Department of Pathology, Vancouver Coastal Health, Vancouver, Canada.
⁵² Clinical institute of Genomic Medicine, University Medical Center Ljubljana, Ljubljana, Slovenija.
⁵³ Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Universidad de Oviedo, Medicine Department, Oviedo, Spain.
⁵⁴ Geriatric Center "Frullone" ASL NA1, Naples, Italy.
⁵⁵ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA; Trinity College Dublin, Dublin, Ireland.
⁵⁶ Newcastle Brain Tissue Resource, Newcastle University, Edwardson Building, Nuns Moor Road, Newcastle upon Tyne, UK.
⁵⁷ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁵⁸ Department of Clinical Sciences, Neurology, Lund University, Lund/Malmö, Sweden.
⁵⁹ Centro Cardiologico Monzino IRCCS, Milan, Italy.
⁶⁰ University of Lille, Lille, France; CHU Lille, Lille, France; Inserm, Labex DISTALZ, LiCEND, Lille, France.
⁶¹ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
⁶² Department of Psychiatry and Psychotherapy, LMU Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, UK; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
⁶³ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; School of Psychology, University of Sydney, Sydney, NSW, Australia.
⁶⁴ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
⁶⁵ Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana," University of Salerno, Fisciano, Italy; Cardiovascular Research Unit, IRCCS MultiMedica, Milan, Italy.
⁶⁶ Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA; VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁶⁷ Department of Neuroscience, "Rita Levi Montalcini," University of Torino, Torino, Italy; Center for Alzheimer's Disease and Related Dementias, Department of Neuroscience and Mental Health, A.O.UCittà della Salute e della Scienza di Torino, Torino, Italy.
⁶⁸ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
⁶⁹ Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Trust, Manchester Academic Health Sciences Unit, University of Manchester, Manchester, UK.
⁷⁰ Department of Psychiatry, Saarland University, Homburg, Germany.
⁷¹ Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁷² Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
⁷³ Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
⁷⁴ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁷⁵ University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, UK.
⁷⁶ Unit of Neuroalgologia (III), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Data science center, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁷⁷ Department of Clinical Sciences, Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund/Malmö, Sweden.
⁷⁸ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
⁷⁹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁸⁰ Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Neurology, Columbia University, New York, NY, USA.
⁸¹ Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Trust, Manchester Academic Health Sciences Unit, University of Manchester, Manchester, UK; Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
⁸² Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁸³ Perelman School of Medicine at the University of Pennsylvania, Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Philadelphia, PA, USA.
⁸⁴ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
⁸⁵ Institute of Biochemistry and Cell Biology, National Research Council (CNR), Naples, Italy; School of Integrative Science and Technology Department of Biology Kean University, Union, NJ, USA.
⁸⁶ Clinical Sciences Helsingborg, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁸⁷ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA; Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA; Trinity College Dublin, Dublin, Ireland.
⁸⁸ Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International LLC, Washington, DC, USA.
⁸⁹ Rona Holdings, Cupertino, CA, USA.
⁹⁰ Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁹¹ UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK; NIHR University College London Hospitals Biomedical Research Centre, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
⁹² Division of Psychological Medicine and Clinical Neurosciences, UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK. Electronic address: escottpricev@cardiff.ac.uk.

PMID: 38889728
PMCID: PMC11267522
DOI: 10.1016/j.ajhg.2024.05.017

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Claudia Manzoni et al. Am J Hum Genet. 2024.

. 2024 Jul 11;111(7):1316-1329.

doi: 10.1016/j.ajhg.2024.05.017. Epub 2024 Jun 17.

Authors

Affiliations

¹ UCL School of Pharmacy, London, UK. Electronic address: c.manzoni@ucl.ac.uk.
² Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
³ Division of Psychological Medicine and Clinical Neurosciences, UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
⁴ Medical and Genomic Statistics Unit, Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁵ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁶ Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
⁷ Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.
⁸ Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain; Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona, Spain.
⁹ NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹⁰ Centre for Research and Training in Medicine of Aging, Department of Medicine and Health Science "V. Tiberio," University of Molise, Campobasso, Italy.
¹¹ Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
¹² Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA.
¹³ Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁴ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
¹⁵ MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁶ University of Sheffield, Sheffield, UK.
¹⁷ Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
¹⁸ Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA.
¹⁹ Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology. Hospital Clínic de Barcelona, Fundació Clínic Barcelona-IDIBAPS, Barcelona, Spain.
²⁰ Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
²¹ Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway; Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
²² Neuroscience Research Australia, and Randwick Clinical Campus, UNSW Medicine and Health, University of New South Wales, Sydney, Australia.
²³ Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy.
²⁴ Unit of Neurology (V) and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
²⁵ Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
²⁶ Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
²⁷ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA.
²⁸ Neurologische Klinik, LMU Klinikum, Munich, Germany.
²⁹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
³⁰ Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; kbo-Inn-Salzach-Klinikum, Wasserburg, Germany.
³¹ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
³² Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
³³ Department of Biology, University of Naples Federico II, Naples, Italy.
³⁴ Department of Neurology & Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁵ Immunohematology and Transfusional Medicine Service, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy.
³⁶ Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden; Theme Inflammation and Aging, Karolinska Universtiy Hospital, Stockholm, Sweden.
³⁷ Department of Neurology, University Medical Center, Medical faculty, Ljubljana University of Ljubljana, Ljubljana, Slovenia; Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Huddinge, Sweden.
³⁸ Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
³⁹ Cognitive Impairment Center, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy.
⁴⁰ Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden; Unit for hereditary dementia, Karolinska Universtiy Hospital-Solna, Stockholm, Sweden.
⁴¹ Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA.
⁴² Shirley Ryan AbilityLab, Chicago, IL, USA.
⁴³ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴⁴ Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Copenhagen University Hospital, Copenhagen, Denmark.
⁴⁵ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
⁴⁶ Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK.
⁴⁷ Bio Med Psychiatry & Human Behavior, Brown University, Providence, RI, USA.
⁴⁸ UCL Genomics, London, UK; UCL Great Ormond Street Institute of Child Health, London, UK; Zayed Centre for Research into Rare Disease in Children, London, UK.
⁴⁹ Sorbonne Université, INSERM U1127, CNRS 7225, Institut du Cerveau - ICM, Paris, France; AP-HP Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Neurology, Institute of Memory and Alzheimer's Disease, Paris, France.
⁵⁰ Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International LLC, Washington, DC, USA; DZNE Tübingen, Tübingen, Germany.
⁵¹ Department of Pathology, University of British Columbia, Vancouver, Canada; Department of Pathology, Vancouver Coastal Health, Vancouver, Canada.
⁵² Clinical institute of Genomic Medicine, University Medical Center Ljubljana, Ljubljana, Slovenija.
⁵³ Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Universidad de Oviedo, Medicine Department, Oviedo, Spain.
⁵⁴ Geriatric Center "Frullone" ASL NA1, Naples, Italy.
⁵⁵ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA; Trinity College Dublin, Dublin, Ireland.
⁵⁶ Newcastle Brain Tissue Resource, Newcastle University, Edwardson Building, Nuns Moor Road, Newcastle upon Tyne, UK.
⁵⁷ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁵⁸ Department of Clinical Sciences, Neurology, Lund University, Lund/Malmö, Sweden.
⁵⁹ Centro Cardiologico Monzino IRCCS, Milan, Italy.
⁶⁰ University of Lille, Lille, France; CHU Lille, Lille, France; Inserm, Labex DISTALZ, LiCEND, Lille, France.
⁶¹ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
⁶² Department of Psychiatry and Psychotherapy, LMU Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, UK; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
⁶³ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; School of Psychology, University of Sydney, Sydney, NSW, Australia.
⁶⁴ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
⁶⁵ Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana," University of Salerno, Fisciano, Italy; Cardiovascular Research Unit, IRCCS MultiMedica, Milan, Italy.
⁶⁶ Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA; VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁶⁷ Department of Neuroscience, "Rita Levi Montalcini," University of Torino, Torino, Italy; Center for Alzheimer's Disease and Related Dementias, Department of Neuroscience and Mental Health, A.O.UCittà della Salute e della Scienza di Torino, Torino, Italy.
⁶⁸ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
⁶⁹ Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Trust, Manchester Academic Health Sciences Unit, University of Manchester, Manchester, UK.
⁷⁰ Department of Psychiatry, Saarland University, Homburg, Germany.
⁷¹ Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁷² Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
⁷³ Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
⁷⁴ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁷⁵ University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, UK.
⁷⁶ Unit of Neuroalgologia (III), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Data science center, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁷⁷ Department of Clinical Sciences, Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund/Malmö, Sweden.
⁷⁸ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
⁷⁹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁸⁰ Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Neurology, Columbia University, New York, NY, USA.
⁸¹ Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Trust, Manchester Academic Health Sciences Unit, University of Manchester, Manchester, UK; Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
⁸² Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁸³ Perelman School of Medicine at the University of Pennsylvania, Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Philadelphia, PA, USA.
⁸⁴ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands; Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
⁸⁵ Institute of Biochemistry and Cell Biology, National Research Council (CNR), Naples, Italy; School of Integrative Science and Technology Department of Biology Kean University, Union, NJ, USA.
⁸⁶ Clinical Sciences Helsingborg, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁸⁷ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA; Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA; Trinity College Dublin, Dublin, Ireland.
⁸⁸ Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International LLC, Washington, DC, USA.
⁸⁹ Rona Holdings, Cupertino, CA, USA.
⁹⁰ Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁹¹ UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK; NIHR University College London Hospitals Biomedical Research Centre, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
⁹² Division of Psychological Medicine and Clinical Neurosciences, UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK. Electronic address: escottpricev@cardiff.ac.uk.

PMID: 38889728
PMCID: PMC11267522
DOI: 10.1016/j.ajhg.2024.05.017

Abstract

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10^-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10^-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10^-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

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Conflict of interest statement

Declaration of interests O.A.A. has received speakers’ honoraria from Janssen, Lundbeck, and Sunovion and is a consultant to Cortechs.ai. C.C. received research support from GSK and EISAI. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. C.C. is a member of the advisory board of Vivid Genomics and Circular Genomics. M.A.N. and H.L.L. hold part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. currently serves on the scientific advisory board for Character Bio Inc. and Neuron23 Inc. I.R.M. receives license royalties for patent related to PGRN therapy and is a member of the scientific advisory committee for Prevail Therapeutics. H.R.M. is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics, and Amylyx; lecture fees/honoraria from BMJ, Kyowa Kirin, and Movement Disorders Society; and research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, and the Michael J. Fox Foundation. H.R.M. is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). R.P. has received honoraria for advisory boards and speaker engagements from Roche, EISAI, Eli Lilly, Biogen, Janssen-Cilag, Astra Zeneca, Schwabe, Grifols, Novo Nordisk, and Tabuk. R.S.-V. served in advisory board meetings for Wave Life Sciences, Ionis, and Novo Nordisk; has received personal fees for participating in educational activities from Janssen, Roche Diagnostics, and Neuraxpharm; and has received funding to her institution for research projects from Biogen and Sage Pharmaceuticals. S.W.S. received research support from Cerevel Therapeutics and is a member of the scientific advisory board of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. J.S.Y. serves on the scientific advisory board for the Epstein Family Alzheimer’s Research Collaboration. J.H. does consulting and gives talks for Eli-Lilly, Roche, and Eisai and is on the Ceracuity advisory board.

Figures

**Figure 1**
QC pipeline for the three cohorts contributing to discovery and replication The discovery and replication sets were further subdivided into Central/Nordic and Mediterranean Europeans (PCA-based genetically estimated ancestry) to assess potential population-specific disease risk loci.

**Figure 2**
Discovery phase: Manhattan plot Red arrows identify genome-wide-significant signals (chromosomes 17 and 19); yellow arrows identify suggestive towers (10⁻⁸ < p > 10⁻⁵) including at least 20 markers (chromosomes 3 and 9). The plot is cut at −log₁₀(p) = 1. The gene symbols represent the locus and do not necessarily imply functional/biological relevance.

**Figure 3**
Manhattan plot for discovery-phase Central/Nordic European cohort Red arrow indicates the genome-wide significant signal (chromosome 17). The plot is cut at −log₁₀(p) = 1. The gene symbols represent the locus and do not necessarily imply functional/biological relevance.

**Figure 4**
Risk allele frequencies of top marker (rs6857) at the chromosome 19 locus in the Central/Nordic and Mediterranean European discovery cohorts Uncorrected p values calculated via χ² are reported; association p values (ap) are reported for the case-control comparisons.

See this image and copyright information in PMC

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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

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