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Mol Psychiatry. 2014 Jun;19(6):682-7. doi: 10.1038/mp.2013.86. Epub 2013 Jul 16.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

Author information

1
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.
2
Dementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain.
3
Department of Structural Genomics, Neocodex, Sevilla, Spain.
4
1] Department of Neurology Boston University School of Medicine, Boston, MA, USA [2] Department of Biostatistics, Boston University School of Medicine, Boston, MA, USA.
5
Memory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain.
6
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
7
Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
8
Department of Medicine, University of Washington, Seattle, WA, USA.
9
Icelandic Heart Association, Kopavogur University of Iceland, Kopavogur, Iceland.
10
Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Washington, DC, USA.
11
Alzheimer's Disease Research Center, Departments of Neurology, Psychiatry and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
12
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Spain, Hospital Clínico San Carlos, Madrid, Spain.
13
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.
14
1] Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain [2] Department of Structural Genomics, Neocodex, Sevilla, Spain.

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.

PMID:
23857120
PMCID:
PMC4031637
DOI:
10.1038/mp.2013.86
[Indexed for MEDLINE]
Free PMC Article

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