The CALHM1 P86L Polymorphism is a Genetic Modifier of Age at Onset in Alzheimer's Disease: a Meta-Analysis Study

Article type: Research Article

Authors: Lambert, Jean-Charles^{a; b; c; *} | Sleegers, Kristel^{d; e} | González-Pérez, Antonio^f | Ingelsson, Martin^g | Beecham, Gary W.^h | Hiltunen, Mikkoⁱ | Combarros, Onofre^j | Bullido, Maria J.^k | Brouwers, Nathalie^{d; e} | Bettens, Karolien^{d; e} | Berr, Claudine^l | Pasquier, Florence^{c; m} | Richard, Florence^{a; b; c; m} | DeKosky, Steven T.ⁿ | Hannequin, Didier^o | Haines, Jonathan L.^p | Tognoni, Gloria^q | Fiévet, Nathalie^{a; b} | Dartigues, Jean-François^r | Tzourio, Christophe^{s; t} | Engelborghs, Sebastiaan^{e; u} | Arosio, Beatrice^v | Coto, Elicer^w | De Deyn, Peter^{e; u} | Del Zompo, Maria^x | Mateo, Ignacio^j | Boada, Merce^{y; z} | Antunez, Carmen^{aa; bb} | Lopez-Arrieta, Jesus^cc | Epelbaum, Jacques^dd | Schjeide, Brit-Maren Michaud^ee | Frank-Garcia, Ana^ff | Giedraitis, Vilmentas^g | Helisalmi, Seppo^j | Porcellini, Elisa^gg | Pilotto, Alberto^hh | Forti, Paolaⁱⁱ | Ferri, Raffaele^jj | Delepine, Marc^kk | Zelenika, Diana^kk | Lathrop, Mark^{kk; ll} | Scarpini, Elio^mm | Siciliano, Gabriele^q | Solfrizzi, Vincenzoⁿⁿ | Sorbi, Sandro^oo | Spalletta, Gianfranco^pp | Ravaglia, Giovanniⁱⁱ | Valdivieso, Fernando^k | Vepsäläinen, Saila^g | Alvarez, Victoria^w | Bosco, Paolo^jj | Mancuso, Michelangelo^q | Panza, Francescoⁿⁿ | Nacmias, Benedetta^oo | Bossù, Paola^pp | Hanon, Olivier^dd | Piccardi, Paola^x | Annoni, Giorgio^qq | Mann, David^rr | Marambaud, Philippe^{ss; tt} | Seripa, Davide^hh | Galimberti, Daniela^mm | Tanzi, Rudolph E^uu | Bertram, Lars^ee | Lendon, Corinne^vv | Lannfelt, Lars^g | Licastro, Federico^gg | Campion, Dominique^o | Pericak-Vance, Margaret A.^h | Soininen, Hilkkaⁱ | Van Broeckhoven, Christine^{e; d} | Alpérovitch, Annick^{s; t} | Ruiz, Agustin^f | Kamboh, M. Ilyas^ww | Amouyel, Philippe^{a; b; c; m}

Affiliations: [a] INSERM U744, Lille, France | [b] Institut Pasteur de Lille, Lille, France | [c] Université de Lille Nord de France, Lille, France | [d] Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium | [e] Institute Born-Bunge and University of Antwerp, Antwerp, Belgium | [f] Department of Structural Genomics. Neocodex, Sevilla, Spain | [g] Uppsala University, Stockholm, Sweden | [h] John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA | [i] Department of Neurology, Kuopio University and University Hospital, Kuopio, Finland | [j] Neurology Service and CIBERNED, "Marqués de Valdecilla" University Hospital (University of Cantabria), Santander, Spain | [k] Centro de Biologia Molecular Severo Ochoa (UAM-CSIC) and CIBERNED, Universidad Autonoma, Cantoblanco, Madrid, Spain | [l] INSERM U888, Hôpital La Colombière, Montpellier, France | [m] CHRU de Lille, Lille, France | [n] University of Virginia School of medicine, Charlottesville, VA, USA | [o] INSERM U614, Faculté de Médecine-Pharmacie de Rouen, Rouen, France | [p] Vanderbilt Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA | [q] Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy | [r] INSERM U897, Victor Segalen University, Bordeaux, France | [s] INSERM U708, Paris, France | [t] UPMC Univ. Paris 06, Paris, France | [u] Memory Clinic and Department of Neurology, ZNA Middelheim, Antwerpen, Belgium | [v] Department of Internal Medicine, Fondazione Policlinico IRCCS, Milan, Italy | [w] Genetic Molecular Unit, Hospital Universitario Central de Asturias, Oviedo, Spain | [x] Section of Clinical Pharmacology, Department of Neuroscience, University of Cagliari, Cagliari, Italy | [y] Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain | [z] Neurology Department, Hospital G. Universitari Vall d'Hebron, Barcelona, Spain | [aa] Alzheimur Foundation, Murcia, Spain | [bb] Dementia Unit. University Hospital Virgen de la Arrixaca, Murcia, Spain | [cc] Memory Unit. University Hospital La Paz- Cantoblanco, Madrid, Spain | [dd] UMR 894, INSERM Faculté de Médecine, Université Paris Descartes, Paris, France | [ee] Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max-Planck Institute for Molecular Genetics, Berlin, Germany | [ff] Servicio de Neurologia, Hospital Universitario La Paz (UAM) and CIBERNED, Madrid, Spain | [gg] Department of Experimental Pathology, School of Medicine, University of Bologna, Bologna, Italy | [hh] Geriatric Unit & Gerontology-Geriatric Research Laboratory, Department of Medical Science, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy | [ii] Department of Internal Medicine Cardiology and Hepatology, University Hospital S. Orsola-Malpighi, Bologna, Italy | [jj] IRCCS Oasi Maria SS, Troina, Italy | [kk] Centre National de Genotypage, Institut Genomique, Commissariat à l'Énergie Atomique, Evry, France | [ll] Fondation Jean Dausset-CEPH, Paris, France | [mm] Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy | [nn] Department of Geriatrics, Centre for Aging Brain, Memory Unit, University of Bari, Policlinico, Bari, Italy | [oo] Department of Neurological and Psychiatric Sciences, Florence, Italy | [pp] Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Roma, Italy | [qq] Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy | [rr] Greater Manchester Neuroscience Centre, University of Manchester, Manchester, UK | [ss] Litwin-Zucker Research Center for the Study of Alzheimer's Disease, Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, USA | [tt] Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA | [uu] Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA | [vv] Molecular Psychiatry Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland, Australia | [ww] Department of Human Genetics and Alzheimer's Disease Research Centre, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: [*] Correspondence to: Jean-Charles Lambert, Unité INSERM 744, Institut Pasteur de Lille BP 245, 1, rue du professeur Calmette, F-59019 Lille cedex, France. Tel.: +33 (0)3 20 87 73 91; Fax: +33 (0)3 20 87 78 94; E-mail: jean-charles.lambert@pasteur-lille.fr

Abstract: The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene.

Keywords: Age at onset, Alzheimer's disease, apolipoprotein E, CALHM1, polymorphism

DOI: 10.3233/JAD-2010-100933

Journal: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 247-255, 2010