Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer's Disease Pathology
Zou, Fanggeng (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Belbin, Olivia (Institut d'Investigació Biomèdica Sant Pau)
Carrasquillo, Minerva M. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Culley, Oliver J. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Hunter, Talisha A. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Ma, Li (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Bisceglio, Gina D. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Allen, Mariet (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Dickson, Dennis W. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica). Department of Neuroscience)
Graff-Radford, Neill R. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Petersen, Ronald C. (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Morgan, Kevin (University of Nottingham)
Younkin, Steven G. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica))
Harold, Denise (Cardiff University (Regne Unit))
Sims, Rebecca C. (Cardiff University)
Gerrish, Amy (Cardiff University)
Chapman, Jade A. (Cardiff University)
Moskvina, V. (Cardiff University)
Abraham, Richard (Cardiff University)
Hollingworth, Paul (Cardiff University)
Hamshere, M. (Cardiff University)
Singh Pahwa, J. (Cardiff University)
Dowzell, K. (Cardiff University)
Williams, A. (Cardiff University)
Jones, Nicola (Cardiff University)
Thomas, Charlene (Cardiff University)
Stretton, A. (Cardiff University)
Morgan, A. (Cardiff University)
Williams, K. (Cardiff University)
Lovestone, S. (King's College London)
Powell, J. (King's College London)
Proitsi, P. (King's College London)
Lupton, M.K. (King's College London)
Brayne, C. (University of Cambridge)
Rubinsztein, D.C. (University of Cambridge)
Gill, M. (St. James Hospital and Trinity College)
Lawlor, B. (St. James Hospital and Trinity College)
Lynch, A. (St. James Hospital and Trinity College)
Brown, K. (University of Nottingham)
Passmore, P. (Queen's University Belfast)
Craig, D. (Queen's University Belfast)
McGuinness, B. (Queen's University Belfast)
Johnston, J.A. (Queen's University Belfast)
Todd, S. (Queen's University Belfast)
Holmes, Clive (University of Southampton)
Mann, D. (University of Manchester)
David Smith, A. (University of Oxford)
Love, S. (University of Bristol Institute of Clinical Neurosciences)
Kehoe, P.G. (University of Bristol Institute of Clinical Neurosciences)
Hardy, J. (Institute of Neurology)
Guerreiro, R. (University College London)
Singleton, A. (National Institute on Aging (Bethesda, Estats Units d'Amèrica))
Mead, S. (UCL Institute of Neurology (Regne Unit))
Fox, N. (University College London)
Rossor, M. (University College London)
Collinge, J. (UCL Institute of Neurology (Regne Unit))
Maier, W. (University of Bonn)
Jessen, Frank (University of Bonn)
Heun, R. (University of Bonn)
Schürmann, B. (University of Bonn)
Ramirez, A. (University of Bonn)
Herold, C. (Deutsches Zentrum für Neurodegenerative Erkrankungen)
Lacour, A. (Deutsches Zentrum für Neurodegenerative Erkrankungen)
Drichel, D. (Deutsches Zentrum für Neurodegenerative Erkrankungen)
van den Bussche, H. (University Medical Center Hamburg-Eppendorf)
Heuser, I. (Charité Berlin. Department of Psychiatry)
Kornhuber, J. (University of Erlangen)
Wiltfang, J. (University Duisburg-Essen)
Dichgans, M. (Klinikum der Universität München)
Frölich, L. (University of Heidelberg)
Hampel, H. (Goethe University)
Hüll, M. (University of Freiburg)
Rujescu, D. (Ludwig-Maximilian University)
Goate, A. (Washington University School of Medicine)
Kauwe, J.S.K. (Brigham Young University)
Cruchaga, Carlos (Washington University School of Medicine)
Nowotny, P. (Washington University School of Medicine)
Morris, J.C. (Washington University School of Medicine)
Mayo, K. (Washington University School of Medicine)
Livingston, G. (University College London)
Bass, N.J. (University College London)
Gurling, H. (University College London)
McQuillin, A. (University College London)
Gwilliam, R. (Wellcome Trust Sanger Institute (Regne Unit))
Deloukas, P. (Wellcome Trust Sanger Institute (Regne Unit))
Nöthen, M.M. (University of Bonn)
Holmans, P. (Cardiff University)
O'Donovan, M. (Cardiff University)
Owen, M.J. (Cardiff University)
Williams, J. (Cardiff University)
Universitat Autònoma de Barcelona

Data:	2013
Resum:	GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0. 75-0. 85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0. 61-1. 20) with no significant association (all p>0. 32). Four variants were hetergeneous across the populations (all p<0. 02) due to a potentially inflated effect size (OR = 0. 61-0. 66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0. 82-0. 88; all p<0. 04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9. 5×10-9. 3×10). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = -0. 34, p = 0. 0006) and senile plaque counts (r = -0. 32, p = 0. 001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = -0. 28, p = 0. 005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level. © 2013 Zou et al.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PloS one, Vol. 8 Núm. 5 (28 2013) , p. e64802, ISSN 1932-6203

DOI: 10.1371/journal.pone.0064802
PMID: 23724096

11 p, 498.3 KB

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