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Article Dans Une Revue Molecular Psychiatry Année : 2012

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

Jean-Charles Lambert (1) , Benjamin Grenier-Boley (2) , Denise Harold (3, 4) , Diana Zelenika (5, 6) , Vincent Chouraki (2) , Y. Kamatani (5, 7) , K. Sleegers (8, 9) , M. A. Ikram (10) , M. Hiltunen (11) , C. Reitz (12) , I. Mateo (13) , T. Feulner (14) , M. Bullido (15) , D. Galimberti (16) , L. Concari (17) , V. Alvarez (18) , R. Sims (3) , A. Gerrish (3) , J. Chapman (3) , C. Deniz-Naranjo (19) , V. Solfrizzi (20) , S. Sorbi (21) , B. Arosio (22) , G. Spalletta (23) , G. Siciliano (24) , Jacques Epelbaum (25) , Didier Hannequin (26, 27) , Jean-François Dartigues (28) , Christophe Tzourio (29) , Claudine Berr (30) , E. M. C. Schrijvers (10) , R. Rogers (12) , G. Tosto (12) , F. Pasquier (31) , K. Bettens (8, 9) , C. van Cauwenberghe (8, 9) , L. Fratiglioni (32, 33) , C. Graff (33, 34) , Marc Délépine (5) , R. Ferri (35) , C. A. Reynolds (36) , L. Lannfelt (37) , M. Ingelsson (37) , J. A. Prince (38) , C. Chillotti (39) , A. Pilotto (40) , D. Seripa (40) , Anne Boland (5) , M. Mancuso (24) , P. Bossù (23) , G. Annoni (22) , B. Nacmias (21) , P. Bosco (35) , F. Panza (20) , F. Sanchez-Garcia (19) , M Del Zompo (41) , E. Coto (18) , M. Owen (3) , M. O'Donovan (3) , F. Valdivieso (15) , P. Caffara (17) , E. Scarpini (16) , O. Combarros (13) , Luc Buée (42) , D. Campion (26) , H. Soininen (11) , M. Breteler (10, 43) , M. Riemenschneider (14) , C. van Broeckhoven (8, 9) , A. Alpérovitch (29) , Marc Lathrop (5, 7) , David-Alexandre Trégouët (44, 45) , J. Williams (3) , Philippe Amouyel (2, 31)
1 Inserm U744
2 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
3 Cardiff University
4 Bioinformatics
5 CNG - Centre National de Génotypage
6 INM - Institut des Neurosciences de Montpellier
7 CEPH - Centre d'Etude du Polymorphisme Humain
8 Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium
9 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
10 Erasmus MC - Erasmus University Medical Center [Rotterdam]
11 University of Eastern Finland
12 G.H. Sergievsky Center, Columbia University, New York, NY, USA
13 Universidad de Cantabria [Santander]
14 Department of Psychiatry and Psychotherapy, Universitätsklinikum des Saarlandes, Universität des Saarlandes Saarbruecken, Germany
15 CBMSO - Centro de Biología Molecular Severo Ochoa [Madrid]
16 Centro Dino Ferrari [Milano]
17 Department of Neuroscience, University of Parma, Parma, Italy
18 Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central Asturias, Oviedo, Spain
19 Servicio de Inmunología. Hospital Unviersitario de Gran Canaria Dr Negrín. Bco, Las Palmas de Gran Canaria, Spain
20 Department of Geriatrics, Center for aging brain, Memory unit, University of Bari, Bari, Italy
21 Department of neurological and psychiatric Sciences, University of Florence, Florence, Italy
22 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
23 Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Roma, Italy
24 Neurological clinic, University of Pisa, Pisa, Italy
25 U894 - Centre de Psychiatrie et Neurosciences
26 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
27 GMFC - Génétique du cancer et des maladies neuropsychiatriques
28 Epidémiologie et Biostatistique [Bordeaux]
29 Neuroépidémiologie
30 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
31 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
32 ARC - Aging Research Center [Karolinska Institutet]
33 Karolinska University Hospital [Stockholm]
34 KI-Alzheimer's Disease Reseach Center, Department NVS, Karolinska Institutet, KIADRC, Stockholm, Sweden
35 IRCCS Associazione Oasi Maria SS, Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy
36 Department of Psychology [Riverside]
37 Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
38 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
39 Unit of Clinical Pharmacology, Teaching Hospital of Cagliari, Cagliari, Italy
40 Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, I.R.C.C.S. 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
41 UniCa - Università degli Studi di Cagliari = University of Cagliari
42 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
43 DZNE, Bonn, Germany
44 Génomique cardiovasculaire
45 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
Jean-Charles Lambert
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R. Sims
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A. Gerrish
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J. Chapman
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Jacques Epelbaum
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Christophe Tzourio
Marc Délépine
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Anne Boland
M. Owen
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M. O'Donovan
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J. Williams

Résumé

Recently, several genome wide association studies (GWAS) have led to the discovery of 9 new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches.. We performed a genome wide haplotype association (GWHA) study in the EADI1 study (n=2,025 AD cases and 5,328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2,820 AD cases and 6,356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5,093 AD cases and 4,061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analysed (OR=1.68, 95% CI 1.43- 1.96; p=1.1x10-10). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non demented populations (n=2,579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, p=5.4x10-7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
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Dates et versions

hal-00778632 , version 1 (25-01-2013)

Identifiants

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Jean-Charles Lambert, Benjamin Grenier-Boley, Denise Harold, Diana Zelenika, Vincent Chouraki, et al.. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.. Molecular Psychiatry, 2012, 18, pp.521-521. ⟨10.1038/mp.2012.75⟩. ⟨hal-00778632⟩
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