Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease
J-C Lambert
(1, 2)
,
B Grenier-Boley
(1)
,
D Harold
(3)
,
D Zelenika
(4)
,
V Chouraki
(1)
,
Y Kamatani
(4, 5)
,
K Sleegers
(6, 7)
,
M A Ikram
(8)
,
M Hiltunen
(9, 10)
,
C Reitz
(11)
,
I Mateo
(12, 13)
,
T Feulner
(14)
,
M Bullido
(15, 16)
,
D Galimberti
(17, 18)
,
L Concari
(19)
,
V Alvarez
(20)
,
R Sims
(21)
,
A Gerrish
(21)
,
J Chapman
(21)
,
C Deniz-Naranjo
(22)
,
V Solfrizzi
(23)
,
S Sorbi
(24)
,
B Arosio
(25, 18)
,
G Spalletta
(26)
,
G Siciliano
(27)
,
J Epelbaum
(28)
,
D Hannequin
(29)
,
J-F Dartigues
(30)
,
C Tzourio
(31, 32)
,
C Berr
(33, 34)
,
Emc M C Schrijvers
(8)
,
R Rogers
(11)
,
G Tosto
(11)
,
F Pasquier
(35, 36)
,
K Bettens
(37, 6)
,
C van Cauwenberghe
(37, 6)
,
L Fratiglioni
(38, 39, 40)
,
C Graff
(39, 41)
,
M Delepine
(4, 42)
,
R Ferri
(43)
,
C A Reynolds
(44)
,
L Lannfelt
(45)
,
M Ingelsson
(45)
,
J A Prince
(46)
,
C Chillotti
(47)
,
A Pilotto
(48)
,
D Seripa
(48)
,
A Boland
(42, 4)
,
M Mancuso
(27)
,
P Bossù
(26)
,
G Annoni
(25, 18)
,
B Nacmias
(24)
,
P Bosco
(43)
,
F Panza
(23)
,
F Sanchez-Garcia
(22)
,
M del Zompo
(49)
,
E Coto
(20)
,
M Owen
(21)
,
M O'Donovan
(21)
,
F Valdivieso
(15, 50, 16)
,
P Caffara
(19)
,
E Scarpini
(18, 25)
,
O Combarros
(13, 12)
,
L Buée
(51)
,
D Campion
(29)
,
H Soininen
(9, 10)
,
M Breteler
(8, 52)
,
M Riemenschneider
(14)
,
C van Broeckhoven
(7, 6)
,
A Alpérovitch
(31)
,
M Lathrop
(4, 53)
,
D-A Trégouët
(54, 55)
,
J Williams
(21)
,
P Amouyel
(2, 35, 56)
1
RID-AGE -
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
2 Institut Pasteur de Lille
3 School of Medicine [Cardiff]
4 CNG - Centre National de Génotypage
5 CEPH - Centre d'Etude du Polymorphisme Humain
6 UA - University of Antwerp
7 Institute Born-Bunge [Antwerp, Belgium]
8 Erasmus MC - Erasmus University Medical Center [Rotterdam]
9 University of Eastern Finland
10 KUH - Kuopio University Hospital
11 Columbia University [New York]
12 UC / UniCan - Universidad de Cantabria [Santander] = University of Cantabria [Spain] = Université de Cantabrie [Espagne]
13 Marqués de Valdecilla University Hospital [Santander]
14 Universität des Saarlandes [Saarbrücken] = Saarland University [Saarbrücken]
15 CBMSO - Centro de Biología Molecular Severo Ochoa [Madrid]
16 UAM - Universidad Autónoma de Madrid
17 Centro Dino Ferrari [Milano]
18 UNIMI - Università degli Studi di Milano = University of Milan
19 UNIPR - Università degli studi di Parma = University of Parma
20 HUCA - Hospital Universitario Central de Asturias
21 Cardiff University
22 Hospital Universitario de Gran Canaria Dr Negrin
23 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
24 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
25 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
26 Fondazione Santa Lucia [IRCCS]
27 UniPi - University of Pisa [Italy] = Università di Pisa [Italia] = Université de Pise [Italie]
28 U894 - Centre de Psychiatrie et Neurosciences
29 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
30 Epidémiologie et Biostatistique [Bordeaux]
31 Neuroépidémiologie
32 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie
33 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
34 Hôpital la Colombière [CHU Montpellier]
35 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
36 Université Lille Nord de France (COMUE)
37 Born-Bunge Institute [Anvers]
38 ARC - Aging Research Center [Karolinska Institutet]
39 Karolinska University Hospital [Stockholm]
40 Stockholm University
41 Karolinska Institutet [Stockholm]
42 IG - Institut de Génomique d'Evry
43 I.R.C.C.S. - "Oasi Maria Santissima" Institute for Research and Prevention of Mental Retardation
44 UC Riverside - University of California [Riverside]
45 Uppsala University
46 Karolinska Institute
47 AOUC - Azienda Ospedaliero-Universitaria di Cagliari [Monserrato, Italia]
48 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo]
49 University of Cagliari
50 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
51 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
52 Dendrite Differenciation Group [DZNE - Bonn]
53 Fondation Jean Dausset CEPH
54 Cardiovascular Genomics
55 IHU ICAN - Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière]
56 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
2 Institut Pasteur de Lille
3 School of Medicine [Cardiff]
4 CNG - Centre National de Génotypage
5 CEPH - Centre d'Etude du Polymorphisme Humain
6 UA - University of Antwerp
7 Institute Born-Bunge [Antwerp, Belgium]
8 Erasmus MC - Erasmus University Medical Center [Rotterdam]
9 University of Eastern Finland
10 KUH - Kuopio University Hospital
11 Columbia University [New York]
12 UC / UniCan - Universidad de Cantabria [Santander] = University of Cantabria [Spain] = Université de Cantabrie [Espagne]
13 Marqués de Valdecilla University Hospital [Santander]
14 Universität des Saarlandes [Saarbrücken] = Saarland University [Saarbrücken]
15 CBMSO - Centro de Biología Molecular Severo Ochoa [Madrid]
16 UAM - Universidad Autónoma de Madrid
17 Centro Dino Ferrari [Milano]
18 UNIMI - Università degli Studi di Milano = University of Milan
19 UNIPR - Università degli studi di Parma = University of Parma
20 HUCA - Hospital Universitario Central de Asturias
21 Cardiff University
22 Hospital Universitario de Gran Canaria Dr Negrin
23 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
24 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
25 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
26 Fondazione Santa Lucia [IRCCS]
27 UniPi - University of Pisa [Italy] = Università di Pisa [Italia] = Université de Pise [Italie]
28 U894 - Centre de Psychiatrie et Neurosciences
29 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
30 Epidémiologie et Biostatistique [Bordeaux]
31 Neuroépidémiologie
32 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie
33 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
34 Hôpital la Colombière [CHU Montpellier]
35 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
36 Université Lille Nord de France (COMUE)
37 Born-Bunge Institute [Anvers]
38 ARC - Aging Research Center [Karolinska Institutet]
39 Karolinska University Hospital [Stockholm]
40 Stockholm University
41 Karolinska Institutet [Stockholm]
42 IG - Institut de Génomique d'Evry
43 I.R.C.C.S. - "Oasi Maria Santissima" Institute for Research and Prevention of Mental Retardation
44 UC Riverside - University of California [Riverside]
45 Uppsala University
46 Karolinska Institute
47 AOUC - Azienda Ospedaliero-Universitaria di Cagliari [Monserrato, Italia]
48 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo]
49 University of Cagliari
50 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
51 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
52 Dendrite Differenciation Group [DZNE - Bonn]
53 Fondation Jean Dausset CEPH
54 Cardiovascular Genomics
55 IHU ICAN - Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière]
56 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
Résumé
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.
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