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

Jean-Charles Lambert; Benjamin Grenier-Boley; Denise Harold; Diana Zelenika; Vincent Chouraki; Y. Kamatani; K. Sleegers; M. A. Ikram; M. Hiltunen; C. Reitz; I. Mateo; T. Feulner; M. Bullido; D. Galimberti; L. Concari; V. Alvarez; R. Sims; A. Gerrish; J. Chapman; C. Deniz-Naranjo; V. Solfrizzi; S. Sorbi; B. Arosio; G. Spalletta; G. Siciliano; Jacques Epelbaum; Didier Hannequin; Jean-François Dartigues; Christophe Tzourio; Claudine Berr; E. M. C. Schrijvers; R. Rogers; G. Tosto; F. Pasquier; K. Bettens; C. van Cauwenberghe; L. Fratiglioni; C. Graff; Marc Délépine; R. Ferri; C. A. Reynolds; L. Lannfelt; M. Ingelsson; J. A. Prince; C. Chillotti; A. Pilotto; D. Seripa; Anne Boland; M. Mancuso; P. Bossù; G. Annoni; B. Nacmias; P. Bosco; F. Panza; F. Sanchez-Garcia; M Del Zompo; E. Coto; M. Owen; M. O'Donovan; F. Valdivieso; P. Caffara; E. Scarpini; O. Combarros; Luc Buée; D. Campion; H. Soininen; M. Breteler; M. Riemenschneider; C. van Broeckhoven; A. Alpérovitch; Marc Lathrop; David-Alexandre Trégouët; J. Williams; Philippe Amouyel

doi:10.1038/mp.2012.75

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

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

Jean-Charles Lambert, Benjamin Grenier-Boley, Denise Harold, Diana Zelenika, Vincent Chouraki, Y. Kamatani, K. Sleegers, M. A. Ikram, M. Hiltunen, C. Reitz, …

Molecular Psychiatry, Vol.18

18/09/2012

DOI: https://doi.org/10.1038/mp.2012.75

PMID: 22986933

Résumé

FRMD4A

genome wide haplotype association study

haplotype

Alzheimer's disease

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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Titre: Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.
Créateurs - sans rôle: Jean-Charles Lambert - Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
Benjamin Grenier-Boley - Institut Pasteur
Denise Harold - Cardiff University
Diana Zelenika - Centre National de Recherche en Génomique Humaine
Vincent Chouraki - Institut Pasteur
Y. Kamatani - Fondation Jean Dausset-CEPH
K. Sleegers - University of Antwerp
M. A. Ikram - Erasmus MC
M. Hiltunen - University of Eastern Finland
C. Reitz - Columbia University
I. Mateo - Universidad de Cantabria
T. Feulner - Universitätsklinikum des Saarlandes
M. Bullido - Centro de Biología Molecular Severo Ochoa
D. Galimberti - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
L. Concari - University of Parma
V. Alvarez - Central University Hospital of Asturias
R. Sims - Cardiff University
A. Gerrish - Cardiff University
J. Chapman - Cardiff University
C. Deniz-Naranjo - Hospital Universitario de Gran Canaria Doctor Negrín
V. Solfrizzi - University of Bari Aldo Moro
S. Sorbi - University of Florence
B. Arosio - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
G. Spalletta - Fondazione Santa Lucia
G. Siciliano - University of Pisa
Jacques Epelbaum - Institut de Psychiatrie et Neurosciences de Paris
Didier Hannequin - Biotherapy of Genetic Diseases, Inflammatory Disorders and Cancers
Jean-François Dartigues - Université de Bordeaux
Christophe Tzourio - Neuroépidémiologie
Claudine Berr - Neuropsychiatrie : Recherche Epidemiologique et Clinique
E. M. C. Schrijvers - Erasmus MC
R. Rogers - Columbia University
G. Tosto - Columbia University
F. Pasquier - Centre Hospitalier Universitaire de Lille
K. Bettens - University of Antwerp
C. van Cauwenberghe - University of Antwerp
L. Fratiglioni - Karolinska Institutet
C. Graff - Karolinska Institutet
Marc Délépine - Centre National de Recherche en Génomique Humaine
R. Ferri - Oasi Maria SS
C. A. Reynolds - University of California, Riverside
L. Lannfelt - Uppsala University
M. Ingelsson - Uppsala University
J. A. Prince - Karolinska Institutet
C. Chillotti - University of Cagliari
A. Pilotto - Casa Sollievo della Sofferenza
D. Seripa - Casa Sollievo della Sofferenza
Anne Boland - Centre National de Recherche en Génomique Humaine
M. Mancuso - University of Pisa
P. Bossù - Fondazione Santa Lucia
G. Annoni - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
B. Nacmias - University of Florence
P. Bosco - Oasi Maria SS
F. Panza - University of Bari Aldo Moro
F. Sanchez-Garcia - Hospital Universitario de Gran Canaria Doctor Negrín
M Del Zompo - University of Cagliari
E. Coto - Central University Hospital of Asturias
M. Owen - Cardiff University
M. O'Donovan - Cardiff University
F. Valdivieso - Centro de Biología Molecular Severo Ochoa
P. Caffara - University of Parma
E. Scarpini - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
O. Combarros - Universidad de Cantabria
Luc Buée - Centre de Recherche Jean Pierre Aubert
D. Campion - Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
H. Soininen - University of Eastern Finland
M. Breteler - Erasmus MC
M. Riemenschneider - Saarland University
C. van Broeckhoven - University of Antwerp
A. Alpérovitch - Neuroépidémiologie
Marc Lathrop - Centre National de Génotypage
David-Alexandre Trégouët - Unité de recherche sur les maladies cardiovasculaires et métaboliques
J. Williams - Cardiff University
Philippe Amouyel - Institut Pasteur
Détails de publication: Molecular Psychiatry, Vol.18
Note de subvention: 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 sur la recherche sur le cerveau) and Rotary.
Identifiants: 99151220709311
Unité académique: Institut des Neurosciences de Montpellier - INM
Langue: English
Type de ressource: Journal article
Champs locaux: hal-00778632