title: MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium.
abstract: The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona School of Medicine, Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain.
authors.forename: Fermín
authors.initials: F
authors.lastname: Moreno
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.affiliation: Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain.
authors.forename: Onofre
authors.initials: O
authors.lastname: Combarros
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Calero
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain.|Neurosciences Area, Institute Biodonostia and Department of Neurosciences, University of Basque Country, UPV-EHU San Sebastián, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.|Institute of Sanitary Research"Hospital la Paz" (IdIPaz), Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Bullido
authors.affiliation: BIOMICs Research Group, Centro de Investigación "Lascaray" Ikergunea, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: Marian M
authors.initials: MM
authors.lastname: de Pancorbo
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Carro
authors.affiliation: Alzheimer's disease and other cognitive disorders Unit, Neurology Department, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Antonell
authors.affiliation: Molecular Genetics Laboratory, Genetics Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortega-Cubero
authors.affiliation: Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernandez
authors.affiliation: Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Tárraga
authors.affiliation: Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Boada
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Dols-Icardo
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain.|Universitat Oberta de Catalunya (UOC), Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Kulisevsky
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Vázquez-Higuera
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain.
authors.forename: Jon
authors.initials: J
authors.lastname: Infante
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Department of Neuropathology and Tissue Bank, Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Alzheimer Center Reina Sofia Foundation, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.affiliation: Alzheimer Disease Research Unit, CIEN Foundation, Alzheimer Center Reina Sofia Foundation, Carlos III Institute of Health, Madrid, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Fernández-Blázquez
authors.affiliation: Alzheimer Disease Research Unit, CIEN Foundation, Alzheimer Center Reina Sofia Foundation, Carlos III Institute of Health, Madrid, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Valentí
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Indakoetxea
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain.
authors.forename: Myriam
authors.initials: M
authors.lastname: Barandiarán
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurosciences Area, Institute Biodonostia and Department of Neurosciences, University of Basque Country, UPV-EHU San Sebastián, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gorostidi
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Sanitary Research"Hospital la Paz" (IdIPaz), Madrid, Spain.|NeurologyService, Hospital Universitario La Paz (UAM), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Frank-García
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.|Institute of Sanitary Research"Hospital la Paz" (IdIPaz), Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Sastre
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Lorenzo
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.|Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Pastor
authors.affiliation: BIOMICs Research Group, Centro de Investigación "Lascaray" Ikergunea, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: Xabier
authors.initials: X
authors.lastname: Elcoroaristizabal
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Lennarz
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Wolfang
authors.initials: W
authors.lastname: Maier
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Rámirez
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Spain, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano-Ríos
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Suzee E
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.|Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain.
authors.forename: Pascual
authors.initials: P
authors.lastname: Sánchez-Juan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013030:Spain; D016875:tau Proteins / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; C054369:MAPT protein, human; D016875:tau Proteins
keywords: A152T; Alzheimer’s disease; H1H2; MAPT; frontotemporal dementia; genetic association