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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.

Original publication

DOI

10.1038/mp.2013.86

Type

Journal article

Journal

Molecular psychiatry

Publication Date

06/2014

Volume

19

Pages

682 - 687

Addresses

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.

Keywords

Alzheimer’s Disease Neuroimaging Initiative, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Mitochondrial ADP, ATP Translocases, Cohort Studies, Polymorphism, Single Nucleotide, Computer Simulation, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Genetic Loci, Genotyping Techniques