title: Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.
abstract: Recently, several genome-wide association studies (GWASs) have led to the discovery of nine 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 (single-nucleotide polymorphism) 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=2025 AD cases and 5328 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 (2820 AD cases and 6356 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 (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10(-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.
authors.affiliation: INSERM, U744, Lille, France. jean-charles.lambert@pasteur-lille.fr
authors.forename: J-C
authors.initials: JC
authors.lastname: Lambert
authors.forename: B
authors.initials: B
authors.lastname: Grenier-Boley
authors.forename: D
authors.initials: D
authors.lastname: Harold
authors.forename: D
authors.initials: D
authors.lastname: Zelenika
authors.forename: V
authors.initials: V
authors.lastname: Chouraki
authors.forename: Y
authors.initials: Y
authors.lastname: Kamatani
authors.forename: K
authors.initials: K
authors.lastname: Sleegers
authors.forename: M A
authors.initials: MA
authors.lastname: Ikram
authors.forename: M
authors.initials: M
authors.lastname: Hiltunen
authors.forename: C
authors.initials: C
authors.lastname: Reitz
authors.forename: I
authors.initials: I
authors.lastname: Mateo
authors.forename: T
authors.initials: T
authors.lastname: Feulner
authors.forename: M
authors.initials: M
authors.lastname: Bullido
authors.forename: D
authors.initials: D
authors.lastname: Galimberti
authors.forename: L
authors.initials: L
authors.lastname: Concari
authors.forename: V
authors.initials: V
authors.lastname: Alvarez
authors.forename: R
authors.initials: R
authors.lastname: Sims
authors.forename: A
authors.initials: A
authors.lastname: Gerrish
authors.forename: J
authors.initials: J
authors.lastname: Chapman
authors.forename: C
authors.initials: C
authors.lastname: Deniz-Naranjo
authors.forename: V
authors.initials: V
authors.lastname: Solfrizzi
authors.forename: S
authors.initials: S
authors.lastname: Sorbi
authors.forename: B
authors.initials: B
authors.lastname: Arosio
authors.forename: G
authors.initials: G
authors.lastname: Spalletta
authors.forename: G
authors.initials: G
authors.lastname: Siciliano
authors.forename: J
authors.initials: J
authors.lastname: Epelbaum
authors.forename: D
authors.initials: D
authors.lastname: Hannequin
authors.forename: J-F
authors.initials: JF
authors.lastname: Dartigues
authors.forename: C
authors.initials: C
authors.lastname: Tzourio
authors.forename: C
authors.initials: C
authors.lastname: Berr
authors.forename: E M C
authors.initials: EM
authors.lastname: Schrijvers
authors.forename: R
authors.initials: R
authors.lastname: Rogers
authors.forename: G
authors.initials: G
authors.lastname: Tosto
authors.forename: F
authors.initials: F
authors.lastname: Pasquier
authors.forename: K
authors.initials: K
authors.lastname: Bettens
authors.forename: C
authors.initials: C
authors.lastname: Van Cauwenberghe
authors.forename: L
authors.initials: L
authors.lastname: Fratiglioni
authors.forename: C
authors.initials: C
authors.lastname: Graff
authors.forename: M
authors.initials: M
authors.lastname: Delepine
authors.forename: R
authors.initials: R
authors.lastname: Ferri
authors.forename: C A
authors.initials: CA
authors.lastname: Reynolds
authors.forename: L
authors.initials: L
authors.lastname: Lannfelt
authors.forename: M
authors.initials: M
authors.lastname: Ingelsson
authors.forename: J A
authors.initials: JA
authors.lastname: Prince
authors.forename: C
authors.initials: C
authors.lastname: Chillotti
authors.forename: A
authors.initials: A
authors.lastname: Pilotto
authors.forename: D
authors.initials: D
authors.lastname: Seripa
authors.forename: A
authors.initials: A
authors.lastname: Boland
authors.forename: M
authors.initials: M
authors.lastname: Mancuso
authors.forename: P
authors.initials: P
authors.lastname: Bossù
authors.forename: G
authors.initials: G
authors.lastname: Annoni
authors.forename: B
authors.initials: B
authors.lastname: Nacmias
authors.forename: P
authors.initials: P
authors.lastname: Bosco
authors.forename: F
authors.initials: F
authors.lastname: Panza
authors.forename: F
authors.initials: F
authors.lastname: Sanchez-Garcia
authors.forename: M
authors.initials: M
authors.lastname: Del Zompo
authors.forename: E
authors.initials: E
authors.lastname: Coto
authors.forename: M
authors.initials: M
authors.lastname: Owen
authors.forename: M
authors.initials: M
authors.lastname: O'Donovan
authors.forename: F
authors.initials: F
authors.lastname: Valdivieso
authors.forename: P
authors.initials: P
authors.lastname: Caffarra
authors.forename: P
authors.initials: P
authors.lastname: Caffara
authors.forename: E
authors.initials: E
authors.lastname: Scarpini
authors.forename: O
authors.initials: O
authors.lastname: Combarros
authors.forename: L
authors.initials: L
authors.lastname: Buée
authors.forename: D
authors.initials: D
authors.lastname: Campion
authors.forename: H
authors.initials: H
authors.lastname: Soininen
authors.forename: M
authors.initials: M
authors.lastname: Breteler
authors.forename: M
authors.initials: M
authors.lastname: Riemenschneider
authors.forename: C
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: A
authors.initials: A
authors.lastname: Alpérovitch
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.forename: D-A
authors.initials: DA
authors.lastname: Trégouët
authors.forename: J
authors.initials: J
authors.lastname: Williams
authors.forename: P
authors.initials: P
authors.lastname: Amouyel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000097:blood; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C574784:FERM domain-containing protein 4A, human