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

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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2024-06-17 , DOI: 10.1016/j.ajhg.2024.05.017
Claudia Manzoni ₁ , Demis A Kia ₂ , Raffaele Ferrari ₂ , Ganna Leonenko ₃ , Beatrice Costa ₂ , Valentina Saba ₄ , Edwin Jabbari ₂ , Manuela Mx Tan ₅ , Diego Albani ₆ , Victoria Alvarez ₇ , Ignacio Alvarez ₈ , Ole A Andreassen ₉ , Antonella Angiolillo ₁₀ , Andrea Arighi ₁₁ , Matt Baker ₁₂ , Luisa Benussi ₁₃ , Valentina Bessi ₁₄ , Giuliano Binetti ₁₅ , Daniel J Blackburn ₁₆ , Merce Boada ₁₇ , Bradley F Boeve ₁₈ , Sergi Borrego-Ecija ₁₉ , Barbara Borroni ₂₀ , Geir Bråthen ₂₁ , William S Brooks ₂₂ , Amalia C Bruni ₂₃ , Paola Caroppo ₂₄ , Sara Bandres-Ciga ₂₅ , Jordi Clarimon ₂₆ , Rosanna Colao ₂₃ , Carlos Cruchaga ₂₇ , Adrian Danek ₂₈ , Sterre Cm de Boer ₂₉ , Itziar de Rojas ₁₇ , Alfonso di Costanzo ₁₀ , Dennis W Dickson ₁₂ , Janine Diehl-Schmid ₃₀ , Carol Dobson-Stone ₃₁ , Oriol Dols-Icardo ₃₂ , Aldo Donizetti ₃₃ , Elise Dopper ₃₄ , Elisabetta Durante ₃₅ , Camilla Ferrari ₁₄ , Gianluigi Forloni ₆ , Francesca Frangipane ₂₃ , Laura Fratiglioni ₃₆ , Milica G Kramberger ₃₇ , Daniela Galimberti ₃₈ , Maurizio Gallucci ₃₉ , Pablo García-González ₁₇ , Roberta Ghidoni ₁₃ , Giorgio Giaccone ₂₄ , Caroline Graff ₄₀ , Neill R Graff-Radford ₄₁ , Jordan Grafman ₄₂ , Glenda M Halliday ₃₁ , Dena G Hernandez ₄₃ , Lena E Hjermind ₄₄ , John R Hodges ₄₅ , Guy Holloway ₄₆ , Edward D Huey ₄₇ , Ignacio Illán-Gala ₃₂ , Keith A Josephs ₁₈ , David S Knopman ₁₈ , Mark Kristiansen ₄₈ , John B Kwok ₃₁ , Isabelle Leber ₄₉ , Hampton L Leonard ₅₀ , Ilenia Libri ₂₀ , Alberto Lleo ₃₂ , Ian R Mackenzie ₅₁ , Gaganjit K Madhan ₄₈ , Raffaele Maletta ₂₃ , Marta Marquié ₁₇ , Ales Maver ₅₂ , Manuel Menendez-Gonzalez ₅₃ , Graziella Milan ₅₄ , Bruce L Miller ₅₅ , Christopher M Morris ₅₆ , Huw R Morris ₂ , Benedetta Nacmias ₅₇ , Judith Newton ₄₆ , Jørgen E Nielsen ₄₄ , Christer Nilsson ₅₈ , Valeria Novelli ₅₉ , Alessandro Padovani ₂₀ , Suvankar Pal ₄₆ , Florence Pasquier ₆₀ , Pau Pastor ₆₁ , Robert Perneczky ₆₂ , Borut Peterlin ₅₂ , Ronald C Petersen ₁₈ , Olivier Piguet ₆₃ , Yolande Al Pijnenburg ₆₄ , Annibale A Puca ₆₅ , Rosa Rademakers ₆₆ , Innocenzo Rainero ₆₇ , Lianne M Reus ₆₈ , Anna Mt Richardson ₆₉ , Matthias Riemenschneider ₇₀ , Ekaterina Rogaeva ₇₁ , Boris Rogelj ₇₂ , Sara Rollinson ₇₃ , Howard Rosen ₇₄ , Giacomina Rossi ₂₄ , James B Rowe ₇₅ , Elisa Rubino ₆₇ , Agustin Ruiz ₁₇ , Erika Salvi ₇₆ , Raquel Sanchez-Valle ₁₉ , Sigrid Botne Sando ₂₁ , Alexander F Santillo ₇₇ , Jennifer A Saxon ₆₉ , Johannes Cm Schlachetzki ₇₈ , Sonja W Scholz ₇₉ , Harro Seelaar ₃₄ , William W Seeley ₇₄ , Maria Serpente ₁₁ , Sandro Sorbi ₅₇ , Sabrina Sordon ₇₀ , Peter St George-Hyslop ₈₀ , Jennifer C Thompson ₈₁ , Christine Van Broeckhoven ₈₂ , Vivianna M Van Deerlin ₈₃ , Sven J Van der Lee ₈₄ , John Van Swieten ₃₄ , Fabrizio Tagliavini ₂₄ , Julie van der Zee ₈₂ , Arianna Veronesi ₃₅ , Emilia Vitale ₈₅ , Maria Landqvist Waldo ₈₆ , Jennifer S Yokoyama ₈₇ , Mike A Nalls ₈₈ , Parastoo Momeni ₈₉ , Andrew B Singleton ₉₀ , John Hardy ₉₁ , Valentina Escott-Price ₃

Affiliation

UCL School of Pharmacy, London, UK.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
Division of Psychological Medicine and Clinical Neurosciences, UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
Medical and Genomic Statistics Unit, Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology, Oslo University Hospital, Oslo, Norway.
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.
Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain; Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona, Spain.
NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Centre for Research and Training in Medicine of Aging, Department of Medicine and Health Science "V. Tiberio," University of Molise, Campobasso, Italy.
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA.
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
University of Sheffield, Sheffield, UK.
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.
Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA.
Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology. Hospital Clínic de Barcelona, Fundació Clínic Barcelona-IDIBAPS, Barcelona, Spain.
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
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.
Neuroscience Research Australia, and Randwick Clinical Campus, UNSW Medicine and Health, University of New South Wales, Sydney, Australia.
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy.
Unit of Neurology (V) and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
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.
Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
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.
Neurologische Klinik, LMU Klinikum, Munich, Germany.
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.
Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; kbo-Inn-Salzach-Klinikum, Wasserburg, Germany.
Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
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.
Department of Biology, University of Naples Federico II, Naples, Italy.
Department of Neurology & Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
Immunohematology and Transfusional Medicine Service, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy.
Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden; Theme Inflammation and Aging, Karolinska Universtiy Hospital, Stockholm, Sweden.
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.
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
Cognitive Impairment Center, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy.
Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden; Unit for hereditary dementia, Karolinska Universtiy Hospital-Solna, Stockholm, Sweden.
Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA.
Shirley Ryan AbilityLab, Chicago, IL, USA.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Copenhagen University Hospital, Copenhagen, Denmark.
Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK.
Bio Med Psychiatry & Human Behavior, Brown University, Providence, RI, USA.
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.
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.
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.
Department of Pathology, University of British Columbia, Vancouver, Canada; Department of Pathology, Vancouver Coastal Health, Vancouver, Canada.
Clinical institute of Genomic Medicine, University Medical Center Ljubljana, Ljubljana, Slovenija.
Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Universidad de Oviedo, Medicine Department, Oviedo, Spain.
Geriatric Center "Frullone" ASL NA1, Naples, Italy.
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.
Newcastle Brain Tissue Resource, Newcastle University, Edwardson Building, Nuns Moor Road, Newcastle upon Tyne, UK.
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
Department of Clinical Sciences, Neurology, Lund University, Lund/Malmö, Sweden.
Centro Cardiologico Monzino IRCCS, Milan, Italy.
University of Lille, Lille, France; CHU Lille, Lille, France; Inserm, Labex DISTALZ, LiCEND, Lille, France.
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.
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.
Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; School of Psychology, University of Sydney, Sydney, NSW, Australia.
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.
Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana," University of Salerno, Fisciano, Italy; Cardiovascular Research Unit, IRCCS MultiMedica, Milan, Italy.
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.
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.
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.
Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Trust, Manchester Academic Health Sciences Unit, University of Manchester, Manchester, UK.
Department of Psychiatry, Saarland University, Homburg, Germany.
Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Toronto, ON, Canada.
Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, UK.
Unit of Neuroalgologia (III), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Data science center, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Department of Clinical Sciences, Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund/Malmö, Sweden.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
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.
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.
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.
Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Perelman School of Medicine at the University of Pennsylvania, Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Philadelphia, PA, 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; Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
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.
Clinical Sciences Helsingborg, Department of Clinical Sciences, Lund University, Lund, Sweden.
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.
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.
Rona Holdings, Cupertino, CA, USA.
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.
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.

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 (rs199443; = 2.5 × 10, OR = 1.27) and (rs6857; = 1.31 × 10, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; = 2.41 × 10, OR = 1.16) in the intergenic region between and , contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in- genes at the and - loci. The association with the (H1c clade) and - loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) ( and - loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) ( locus). Our data also suggest population specificity of the risk signals, with and 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 haplotype(s) and the functional involvement and contribution of the haplotype and - loci to pathogenesis of sporadic forms of FTD in brain cortex.

中文翻译：

全基因组分析揭示了 MAPT、MOBP 和 APOE 位点在散发性额颞叶痴呆中的潜在作用

额颞叶痴呆（FTD）是继阿尔茨海默病（AD）之后早发性痴呆的第二常见原因。该领域的工作主要集中在家族形式疾病（fFTD）上，而对散发性 FTD（sFTD）的遗传病因学的研究则不太常见。在当前的工作中，我们分析了 4,685 例 sFTD 病例和 15,308 例对照，寻找 sFTD 的常见遗传决定因素。我们在 (rs199443; = 2.5 × 10, OR = 1.27) 和 (rs6857; = 1.31 × 10, OR = 1.27) 位点处发现了一组变异，并且在 3 号染色体上发现了一个候选位点 (rs1009966; = 2.41 × 10, OR = 1.16) 在和之间的基因间区域，通过影响和 - 基因座上功能相关的 in- 基因在大脑皮层中的表达和/或剪接，导致 sFTD 风险增加。与 (H1c 分支) 和 - 基因座的关联可能表明 FTD 和进行性核上性麻痹 (PSP)（和 - 基因座）以及 FTD、AD、帕金森病 (PD) 和皮质基底节变性 (CBD) 之间存在共同的遗传多效性（轨迹）。我们的数据还表明风险信号的人群特异性，以及基因座关联分别主要由中欧/北欧和地中海欧洲人驱动。这项研究为未来的工作奠定了基础，旨在进一步表征潜在 FTD 判别单倍型的人群特异性特征，以及单倍型和基因座对大脑皮层散发形式 FTD 发病机制的功能参与和贡献。

更新日期：2024-06-17

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