Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

被引：1888

作者：

Lambert, Jean-Charles ^{[1
,2
,3
]}

Heath, Simon ^{[4
]}

Even, Gael ^{[1
,2
]}

Campion, Dominique ^{[5
]}

Sleegers, Kristel ^{[6
,7
]}

Hiltunen, Mikko ^{[8
]}

Combarros, Onofre ^{[9
,10
]}

Zelenika, Diana ^{[4
]}

Bullido, Maria J. ^{[11
,12
]}

Tavernier, Beatrice ^{[13
]}

Letenneur, Luc ^{[14
]}

Bettens, Karolien ^{[6
,7
]}

Berr, Claudine ^{[15
]}

Pasquier, Florence ^{[3
,16
,17
]}

Fievet, Nathalie ^{[1
,2
]}

Barberger-Gateau, Pascale ^{[14
]}

Engelborghs, Sebastiaan ^{[7
,18
,19
]}

De Deyn, Peter ^{[7
,18
,19
]}

Mateo, Ignacio ^{[9
,10
]}

Franck, Ana ^{[20
]}

Helisalmi, Seppo ^{[8
]}

Porcellini, Elisa ^{[21
]}

Hanon, Olivier ^{[22
]}

de Pancorbo, Marian M. ^{[23
]}

Lendon, Corinne ^{[24
]}

Dufouil, Carole ^{[25
]}

Jaillard, Celine ^{[26
]}

Leveillard, Thierry ^{[26
]}

Alvarez, Victoria ^{[27
]}

Bosco, Paolo ^{[28
]}

Mancuso, Michelangelo ^{[29
]}

Panza, Francesco ^{[30
]}

Nacmias, Benedetta ^{[31
]}

Bossu, Paola ^{[32
]}

Piccardi, Paola ^{[33
]}

Annoni, Giorgio ^{[34
]}

Seripa, Davide ^{[35
,36
]}

Galimberti, Daniela ^{[37
]}

Hannequin, Didier ^{[5
]}

Licastro, Federico ^{[21
]}

Soininen, Hilkka ^{[8
]}

Ritchie, Karen ^{[15
]}

Blanche, Helene ^{[38
]}

Dartigues, Jean-Francois ^{[14
]}

Tzourio, Christophe ^{[25
]}

Gut, Ivo ^{[4
]}

Van Broeckhoven, Christine ^{[6
,7
]}

Alperovitch, Annick ^{[25
]}

Lathrop, Mark ^{[4
,38
]}

Amouyel, Philippe ^{[1
,2
,3
,16
,17
]}

机构：

[1] INSERM, U744, F-59045 Lille, France

[2] Inst Pasteur, F-59019 Lille, France

[3] Univ Lille Nord France, Lille, France

[4] Commissariat Energie Atom, Ctr Natl Genotypage, Inst Genom, Evry, France

[5] Fac Med & Pharm Rouen, U614, INSERM, Rouen, France

[6] VIB, Neurodegenerat Brain Dis Grp, Dept Mol Genet, Antwerp, Belgium

[7] Inst Born Bunge, Antwerp, Belgium

[8] Univ Kuopio, Dept Neurol, FIN-70211 Kuopio, Finland

[9] Univ Cantabria, Neurol Serv, Marques de Valdecilla Univ Hosp, E-39005 Santander, Spain

[10] Univ Cantabria, CIBERNED, Marques de Valdecilla Univ Hosp, E-39005 Santander, Spain

[11] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, CSIC, Madrid, Spain

[12] Univ Autonoma Madrid, CIBERNED, Madrid, Spain

[13] Ctr Hosp Univ Dijon, Dept Geriatrie, Dijon, France

[14] Victor Segalen Univ, INSERM, U897, Bordeaux, France

[15] Hop La Colombiere, INSERM, U888, Montpellier, France

[16] Ctr Hosp Reg Univ Lille, Lille, France

[17] Ctr Hosp Reg Univ Lille, Lille, France

[18] Ziekenhuisnetwerk Antwerpen Middelheim, Memory Clin, Antwerp, Belgium

[19] Ziekenhuisnetwerk Antwerpen Middelheim, Dept Neurol, Antwerp, Belgium

[20] Univ Autonoma Madrid, Serv Neurol, Hosp Univ La Paz, Madrid, Spain

[21] Univ Bologna, Sch Med, Dept Expt Pathol, I-40126 Bologna, Italy

[22] Univ Paris 05, INSERM, U894, Fac Med, Paris, France

[23] Univ Basque Country, EHU, Banco ADN, Fac Farm, Vitoria, Spain

[24] Royal Brisbane Hosp, Mol Psychiat Lab, Queensland Inst Med Res, Brisbane, Qld, Australia

[25] INSERM, U708, Paris, France

[26] Univ Paris 06, INSERM, Dept Genet, Inst Vis, Paris, France

[27] Hosp Univ Cent Asturias, Mol Genet Unit, Oviedo, Spain

[28] Inst Res Mental Retardat & Brain Aging, IRCCS, Assoc Oasi Maria Santissima, Troina, Italy

[29] Univ Pisa, Dept Neurosci, Neurol Clin, I-56100 Pisa, Italy

[30] Univ Bari, Dept Geriatr, Ctr Aging Brain, Memory Unit, Bari, Italy

[31] Dept Neurol & Psychiat Sci, Florence, Italy

[32] IRCCS Santa Lucia Fdn, Dept Clin & Behav Neurol, Rome, Italy

[33] Univ Cagliari, Clin Pharmacol Sect, Dept Neurosci, Mol Genet Lab, I-09124 Cagliari, Italy

[34] Univ Milano Bicocca, Dept Clin Med & Prevent, Monza, Italy

[35] IRCCS Casa Sollievo Sofferenza, Geriatr Unit, Dept Med Sci, San Giovanni Rotondo, Italy

[36] IRCCS Casa Sollievo Sofferenza, Gerontol Geriatr Res Lab, Dept Med Sci, San Giovanni Rotondo, Italy

[37] Univ Milan, Dept Neurol Sci, Dino Ferrari Ctr, IRCCS Osped Maggiore Policlin, Milan, Italy

[38] Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, F-75010 Paris, France

来源：

NATURE GENETICS | 2009年 / 41卷 / 10期

基金：

芬兰科学院;

关键词：

AMYLOID-BETA-PEPTIDE; APOLIPOPROTEIN-J; GENETIC-HETEROGENEITY; PLAQUE-FORMATION; MOUSE MODEL; A-BETA; COMPLEMENT; CLUSTERIN; EXPRESSION; RISK;

D O I：

10.1038/ng.439

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10(-5)) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81-0.90, P = 7.5 x 10(-9) for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14-1.29, P = 3.7 x 10(-9) for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of. amyloid (A.) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease.

引用

页码：1094 / U68

页数：7

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