title: A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly.
abstract: Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.
authors.affiliation: 1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France.
authors.forename: V
authors.initials: V
authors.lastname: Chouraki
authors.affiliation: 1] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands [2] Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands [3] Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
authors.forename: R F A G
authors.initials: RF
authors.lastname: De Bruijn
authors.affiliation: 1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France.
authors.forename: J
authors.initials: J
authors.lastname: Chapuis
authors.affiliation: Cardiovascular Health Resarch Unit and Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: 1] The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA [2] The Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA [3] The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Reitz
authors.affiliation: 1] Université Lille-Nord de France, Lille, France [2] Inserm U837, Jean-Pierre Aubert Research Centre, Lille, France [3] Centre Hospitalier Régional Universitaire de Lille, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Schraen
authors.affiliation: 1] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands [2] Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: C A
authors.initials: CA
authors.lastname: Ibrahim-Verbaas
authors.affiliation: 1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France.
authors.forename: B
authors.initials: B
authors.lastname: Grenier-Boley
authors.affiliation: 1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Delay
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rogers
authors.affiliation: 1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Demiautte
authors.affiliation: 1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Mounier
authors.affiliation: Cardiovascular Health Resarch Unit and Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Fitzpatrick
authors.affiliation: INSERM U888, Hôpital La Colombière, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Berr
authors.affiliation: INSERM U593, Victor Segalen University, Bordeaux, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Dartigues
authors.affiliation: 1] Netherlands Consortium for Healthy Aging, Leiden, The Netherlands [2] Department of Internal medicine, Leiden, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: 1] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.affiliation: 1] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands [2] DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Breteler
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: 1] Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France [2] Centre National de Genotypage, Institut Genomique, Commissariat à l'énergie Atomique, Evry, France.
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: The Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Schupf
authors.affiliation: INSERM U708, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Alpérovitch
authors.affiliation: 1] The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA [2] The Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: 1] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: 1] Université Lille-Nord de France, Lille, France [2] Inserm U837, Jean-Pierre Aubert Research Centre, Lille, France [3] Centre Hospitalier Régional Universitaire de Lille, Lille, France.
authors.forename: L
authors.initials: L
authors.lastname: Buée
authors.affiliation: 1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France [4] Centre Hospitalier Régional Universitaire de Lille, Lille, France.
authors.forename: P
authors.initials: P
authors.lastname: Amouyel
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: Lopez
authors.affiliation: 1] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands [2] Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands [3] Netherlands Consortium for Healthy Aging, Leiden, The Netherlands [4] Department of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: 1] INSERM U593, Victor Segalen University, Bordeaux, France [2] INSERM U708, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Tzourio
authors.affiliation: 1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Lambert
mesh_terms: D000375:Aging / Q000097:blood* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000097:blood*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C524838:CTXN3 protein, human; D008565:Membrane Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)