title: ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.
abstract: To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.
authors.affiliation: 1] Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain [2] Hospital Universitari Vall d'Hebron-Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Boada
authors.affiliation: Dementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Antúnez
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Ramírez-Lorca
authors.affiliation: 1] Department of Neurology Boston University School of Medicine, Boston, MA, USA [2] Department of Biostatistics, Boston University School of Medicine, Boston, MA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: DeStefano
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: A
authors.initials: A
authors.lastname: González-Pérez
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Gayán
authors.affiliation: Memory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: López-Arrieta
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Hernández
authors.affiliation: Dementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Marín
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Galán
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Mauleón
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Rosende-Roca
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Moreno-Rey
authors.affiliation: Icelandic Heart Association, Kopavogur University of Iceland, Kopavogur, Iceland.
authors.forename: V
authors.initials: V
authors.lastname: Gudnasson
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: Morón
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Velasco
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Carrasco
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Alegret
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Espinosa
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Vinyes
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Lafuente
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Vargas
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Fitzpatrick
authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Washington, DC, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: M E
authors.initials: ME
authors.lastname: Sáez
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Vázquez
authors.affiliation: Alzheimer's Disease Research Center, Departments of Neurology, Psychiatry and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Becker
authors.affiliation: Alzheimer's Disease Research Center, Departments of Neurology, Psychiatry and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: O L
authors.initials: OL
authors.lastname: López
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Spain, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Serrano-Ríos
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Tárraga
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Real
authors.affiliation: 1] Department of Neurology Boston University School of Medicine, Boston, MA, USA [2] Department of Biostatistics, Boston University School of Medicine, Boston, MA, USA [3] National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: 1] Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain [2] Department of Structural Genomics, Neocodex, Sevilla, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ruiz
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D015331:Cohort Studies; D003198:Computer Simulation; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000226:Mitochondrial ADP, ATP Translocases; C000594261:ATP5PD protein, human