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A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Molecular Psychiatry volume 19, pages 1326–1335 (2014)Cite this article

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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.

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Acknowledgements

The work was made possible by the generous participation of the control participants and their families. This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease). JC was funded by the MEDIALZ Project (Grant 11001003) financed by ERDF (European Regional Development Fund) and Conseil Régional Nord Pas de Calais. The three-city study was performed as a part of collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai. The Rotterdam study is sponsored by the Erasmus Medical Center and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (I), The Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Further support was obtained from the Netherlands Consortium for Healthy Ageing. Dr Ikram was supported by a ZonMW Veni grant: 916.13.054. The cardiovascular health study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; 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.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; 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’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514.

Author information

Author notes

  1. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Authors and Affiliations

  1. INSERM U744, Lille, France

    V Chouraki, J Chapuis, B Grenier-Boley, C Delay, F Demiautte, A Mounier, P Amouyel & J-C Lambert

  2. Institut pasteur de Lille, Lille, France

    V Chouraki, J Chapuis, B Grenier-Boley, C Delay, F Demiautte, A Mounier, P Amouyel & J-C Lambert

  3. Université Lille-Nord de France, Lille, France,

    V Chouraki, J Chapuis, S Schraen, B Grenier-Boley, C Delay, F Demiautte, A Mounier, L Buée, P Amouyel & J-C Lambert

  4. Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    R F A G De Bruijn, C A Ibrahim-Verbaas, A Hofman, M Breteler, C M van Duijn & M A Ikram

  5. Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    R F A G De Bruijn, C A Ibrahim-Verbaas & M A Ikram

  6. Netherlands Consortium for Healthy Aging, Leiden, The Netherlands

    R F A G De Bruijn, A G Uitterlinden, A Hofman, C M van Duijn & M A Ikram

  7. Cardiovascular Health Resarch Unit and Department of Medicine, University of Washington, Seattle, WA, USA

    J C Bis & A L Fitzpatrick

  8. The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA,

    C Reitz, R Rogers & R Mayeux

  9. The Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA,

    C Reitz & N Schupf

  10. The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    C Reitz

  11. Inserm U837, Jean-Pierre Aubert Research Centre, Lille, France

    S Schraen & L Buée

  12. Centre Hospitalier Régional Universitaire de Lille, Lille, France,

    S Schraen, L Buée & P Amouyel

  13. INSERM U888, Hôpital La Colombière, Montpellier, France

    C Berr

  14. INSERM U593, Victor Segalen University, Bordeaux, France

    J-F Dartigues & C Tzourio

  15. Department of Internal medicine, Leiden, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    A G Uitterlinden

  16. DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany

    M Breteler

  17. Departments of Neurology, Alzheimer’s Disease Research Center, Psychiatry and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J T Becker & O L Lopez

  18. Fondation Jean Dausset—Centre d'Etude du Polymorphisme Humain, Paris, France

    M Lathrop

  19. Centre National de Genotypage, Institut Genomique, Commissariat à l'énergie Atomique, Evry, France

    M Lathrop

  20. INSERM U708, Paris, France

    A Alpérovitch & C Tzourio

  21. The Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    R Mayeux

  22. Department of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    M A Ikram

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  1. V Chouraki
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  2. R F A G De Bruijn
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The Alzheimer's Disease Neuroimaging Initiative

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Correspondence to J-C Lambert.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Chouraki, V., De Bruijn, R., Chapuis, J. et al. A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly. Mol Psychiatry 19, 1326–1335 (2014). https://doi.org/10.1038/mp.2013.185

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  • DOI: https://doi.org/10.1038/mp.2013.185

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