@article{2fcdefdedcf341898ee8dc4856698bab,
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 Fundaci{\'o} 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 Fundaci{\'o} 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.",
keywords = "Alzheimer's disease, GWAS, SNP, genomics, molecular epidemiology",
author = "M. Boada and C. Ant{\'u}nez and R. Ram{\'i}rez-Lorca and Destefano, {A. L.} and A. Gonz{\'a}lez-P{\'e}rez and J. Gay{\'a}n and J. L{\'o}pez-Arrieta and Ikram, {M. A.} and I. Hern{\'a}ndez and J. Mar{\'i}n and Gal{\'a}n, {J. J.} and Bis, {J. C.} and A. Maule{\'o}n and M. Rosende-Roca and C. Moreno-Rey and V. Gudnasson and Mor{\'o}n, {F. J.} and J. Velasco and Carrasco, {J. M.} and M. Alegret and A. Espinosa and G. Vinyes and A. Lafuente and L. Vargas and Fitzpatrick, {A. L.} and Launer, {L. J.} and S{\'a}ez, {M. E.} and E. V{\'a}zquez and Becker, {J. T.} and L{\'o}pez, {O. L.} and M. Serrano-R{\'i}os and L. T{\'a}rraga and {Van Duijn}, {C. M.} and Real, {L. M.} and S. Seshadri and A. Ruiz",
note = "Funding Information: We thank the patients and controls who participated in this project. This work has been partially funded by the Fundaci{\'o}n Alzheimur (Murcia), the Ministerio de Educaci{\'o}n y Ciencia (PCT-010000-2007-18), (DEX-580000-2008-4; Gobierno de Espa{\~n}a), Corporaci{\'o}n Tecnol{\'o}gica de Andaluc{\'i}a (08/211) and Agencia IDEA (841318) (Consejer{\'i}a de Innovaci{\'o}n, Junta de Andaluc{\'i}a). The Diabetes Research Laboratory, Biomedical Research Foundation. University Hospital Cl{\'i}nico San Carlos has been supported by CIBER de Diabetes y Enfermedades Metab{\'o}licas Asociadas (CIBERDEM); CIBERDEM is an ISCIII Project. We are indebted to Trinitat Port-Carb{\'o} and her family who are supporting Fundaci{\'o} ACE research programs. We also are indebted to TGEN investigators who provided a free access to genotype data to other researchers via Coriell Biorepositories. The genotypic and associated phenotypic data used in the study, {\textquoteleft}Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer{\textquoteright}s Disease (GenADA){\textquoteright} were provided by the GlaxoSmithKline, R&D Limited. The data sets used for analyses described in this manuscript were obtained from dbGaP through dbGaP accession number phs000219.v1.p1. Funding support for the {\textquoteleft}Genetic Consortium for Late Onset Alzheimer{\textquoteright}s Disease{\textquoteright} was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer{\textquoteright}s Disease includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late Onset Alzheimer{\textquoteright}s Disease. The data sets used for analyses described in this manuscript were obtained from dbGaP through dbGaP accession number phs000168.v1.p1. Data collection and sharing for this project was funded by the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: Abbott; Alzheimer{\textquoteright}s Association; Alzheimer{\textquoteright}s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Disease Cooperative Study at the University of California, San Diego, CA, USA. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles, CA, USA. This research was also supported by NIH Grants P30 AG010129, K01 AG030514 and the Dana Foundation. Fundaci{\'o} ACE collaborates with CIBERNED. The following have contributed to the papers as collaborators: Alejandro Romo, Irene Blanca, Susana Ruiz, Mar Buend{\'i}a, Fuensanta Noguera-Perea, Emma Rodr{\'i}guez-Noriega, Evaristo Fernandez-Aranda, Agustina Legaz-Garc{\'i}a, Laura Vivancos-Moreau, Am{\'e}rica Morera, Marina Guitart, Susana Lara, Martirio Antequera-Torres, Salvadora Manzanares, Sandra Casta{\~n}o, Blanca Garc{\'i}a, Bego{\~n}a Mart{\'i}nez-Herrada, Sergi Valero.",
year = "2014",
month = jun,
doi = "10.1038/mp.2013.86",
language = "English (US)",
volume = "19",
pages = "682--687",
journal = "Molecular psychiatry",
issn = "1359-4184",
publisher = "Springer Nature",
number = "6",
}