Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

被引：1883

作者：

Kunkle, Brian W. ^{[1
]}

Grenier-Boley, Benjamin ^{[2
,3
,4
]}

Sims, Rebecca ^{[5
,6
]}

Bis, Joshua C. ^{[7
]}

Damotte, Vincent ^{[2
,3
,4
]}

Naj, Adam C. ^{[8
]}

Boland, Anne ^{[9
,10
]}

Vronskaya, Maria ^{[5
]}

van der Lee, Sven J. ^{[11
]}

Amlie-Wolf, Alexandre ^{[12
]}

Bellenguez, Celine ^{[2
,3
,4
]}

Frizatti, Aura ^{[5
]}

Chouraki, Vincent ^{[2
,3
,4
,13
,14
]}

Martin, Eden R. ^{[1
]}

Sleegers, Kristel ^{[15
,16
]}

Badarinarayan, Nandini ^{[5
]}

Jakobsdottir, Johanna ^{[17
]}

Hamilton-Nelson, Kara L. ^{[1
]}

Moreno-Grau, Sonia ^{[18
,19
]}

Olaso, Robert ^{[9
,10
]}

Raybould, Rachel ^{[5
,6
]}

Chen, Yuning ^{[20
]}

Kuzma, Amanda B. ^{[12
]}

Hiltunen, Mikko ^{[21
,22
]}

Morgan, Taniesha ^{[5
]}

Ahmad, Shahzad ^{[11
]}

Vardarajan, Badri N. ^{[23
,24
,25
]}

Epelbaum, Jacques ^{[26
]}

Hoffmann, Per ^{[27
,28
,29
,30
]}

Boada, Merce ^{[18
,19
]}

Beecham, Gary W. ^{[1
]}

Garnier, Jean-Guillaume ^{[9
,10
]}

Harold, Denise ^{[31
]}

Fitzpatrick, Annette L. ^{[32
,33
]}

Valladares, Otto ^{[12
]}

Moutet, Marie-Laure ^{[9
,10
]}

Gerrish, Amy ^{[34
]}

Smith, Albert, V ^{[35
,36
]}

Qu, Liming ^{[12
]}

Bacq, Delphine ^{[9
,10
]}

Denning, Nicola ^{[5
,6
]}

Jian, Xueqiu ^{[37
]}

Zhao, Yi ^{[12
]}

Del Zompo, Maria ^{[38
]}

Fox, Nick C. ^{[34
,39
]}

Choi, Seung-Hoan ^{[18
]}

Mateo, Ignacio ^{[40
,41
,42
]}

Hughes, Joseph T. ^{[43
]}

Adams, Hieab H. ^{[11
]}

Malamon, John ^{[12
]}

机构：

[1] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA

[2] Inserm, RID AGE Risk Factors & Mol Determinants Aging Rel, U1167, Lille, France

[3] Inst Pasteur, Lille, France

[4] Univ Lille, U1167, Excellence Lab LabEx DISTALZ, Lille, France

[5] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Div Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales

[6] Cardiff Univ, UK Dementia Res Inst Cardiff, Cardiff, S Glam, Wales

[7] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[8] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[9] Univ Paris Saclay, CEA, Inst Biol Francois Jacob, Ctr Natl Rech Genom Humaine, Evry, France

[10] LabEx GENMED, Evry, France

[11] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[12] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Penn Neurodegenerat Genom Ctr, Philadelphia, PA 19104 USA

[13] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[14] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[15] VIB, Ctr Mol Neurol, Neurodegenerat Brain Dis Grp, Antwerp, Belgium

[16] Univ Antwerp, Inst Born Bunge, Lab Neurogenet, Antwerp, Belgium

[17] Iceland Heart Assoc, Kopavogur, Iceland

[18] Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin Fundacio ACE, Barcelona, Spain

[19] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain

[20] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[21] Univ Eastern Finland, Inst Biomed, Kuopio, Finland

[22] Kuopio Univ Hosp, Dept Neurol, Kuopio, Finland

[23] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA

[24] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA

[25] Columbia Univ, Dept Neurol, New York, NY USA

[26] Univ Paris 05, Inserm, Ctr Psychiat & Neurosci, UMR 894, Paris, France

[27] Univ Bonn, Inst Human Genet, Bonn, Germany

[28] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany

[29] Univ Basel, Univ Hosp, Div Med Genet, Basel, Switzerland

[30] Univ Basel, Dept Biomed, Basel, Switzerland

[31] Dublin City Univ, Sch Biotechnol, Dublin, Ireland

[32] Univ Washington, Dept Family Med, Seattle, WA 98195 USA

[33] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[34] UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London, England

[35] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[36] Univ Iceland, Fac Med, Reykjavik, Iceland

[37] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA

[38] Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy

[39] UCL Inst Neurol, UK Dementia Res Inst UCL, Dept Neurodegenerat Dis, London, England

[40] Univ Cantabria, Marques de Valdecilla Univ Hosp, Neurol Serv, Santander, Spain

[41] Univ Cantabria, Marques de Valdecilla Univ Hosp, CIBERNED, Santander, Spain

[42] IDIVAL, Santander, Spain

[43] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Basic & Clin Neurosci, London, England

[44] Hosp Univ Doctor Negrin, Dept Immunol, Las Palmas Gran Canaria, Spain

[45] Aristotle Univ Thessaloniki, Med Sch, Dept Neurol, Thessaloniki, Greece

[46] Univ Washington, Dept Med, Seattle, WA USA

[47] Normandie Univ, UNIROUEN, Inserm U1245, Rouen, France

[48] Rouen Univ Hosp, Dept Neurol, Dept Genet, Rouen, France

[49] CNR MAJ, Normandy Ctr Genom & Personalized Med, Rouen, France

[50] Inst Prion Dis, MRC Prion Unit UCL, Dept Neurodegenerat Dis, London, England

来源：

NATURE GENETICS | 2019年 / 51卷 / 03期

关键词：

GENOME-WIDE ASSOCIATION; DOMAIN-CONTAINING OXIDOREDUCTASE; ANGIOTENSIN-CONVERTING ENZYME; AMYLOID-BETA; TRANSCRIPTION FACTOR; GENOTYPE IMPUTATION; APOLIPOPROTEIN-E; COMMON VARIANTS; ONSET; MUTATIONS;

D O I：

10.1038/s41588-019-0358-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A beta processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 x 10(-7)), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

引用

页码：414 / +

页数：20

共 183 条

[1] A method and server for predicting damaging missense mutations [J].

Adzhubei, Ivan A. ;

Schmidt, Steffen ;

Peshkin, Leonid ;

Ramensky, Vasily E. ;

Gerasimova, Anna ;

Bork, Peer ;

Kondrashov, Alexey S. ;

Sunyaev, Shamil R. .

NATURE METHODS, 2010, 7 (04) :248-249

[2] Genetic effects on gene expression across human tissues [J].

Aguet, Francois ;

Brown, Andrew A. ;

Castel, Stephane E. ;

Davis, Joe R. ;

He, Yuan ;

Jo, Brian ;

Mohammadi, Pejman ;

Park, Yoson ;

Parsana, Princy ;

Segre, Ayellet V. ;

Strober, Benjamin J. ;

Zappala, Zachary ;

Cummings, Beryl B. ;

Gelfand, Ellen T. ;

Hadley, Kane ;

Huang, Katherine H. ;

Lek, Monkol ;

Li, Xiao ;

Nedzel, Jared L. ;

Nguyen, Duyen Y. ;

Noble, Michael S. ;

Sullivan, Timothy J. ;

Tukiainen, Taru ;

MacArthur, Daniel G. ;

Getz, Gad ;

Management, Nih Program ;

Addington, Anjene ;

Guan, Ping ;

Koester, Susan ;

Little, A. Roger ;

Lockhart, Nicole C. ;

Moore, Helen M. ;

Rao, Abhi ;

Struewing, Jeffery P. ;

Volpi, Simona ;

Collection, Biospecimen ;

Brigham, Lori E. ;

Hasz, Richard ;

Hunter, Marcus ;

Johns, Christopher ;

Johnson, Mark ;

Kopen, Gene ;

Leinweber, William F. ;

Lonsdale, John T. ;

McDonald, Alisa ;

Mestichelli, Bernadette ;

Myer, Kevin ;

Roe, Bryan ;

Salvatore, Michael ;

Shad, Saboor .

NATURE, 2017, 550 (7675) :204-+

[3] INFERNO: inferring the molecular mechanisms of noncoding genetic variants [J].

Amlie-Wolf, Alexandre ;

Tang, Mitchell ;

Mlynarski, Elisabeth E. ;

Kuksa, Pavel P. ;

Valladares, Otto ;

Katanic, Zivadin ;

Tsuang, Debby ;

Brown, Christopher D. ;

Schellenberg, Gerard D. ;

Wang, Li-San .

NUCLEIC ACIDS RESEARCH, 2018, 46 (17) :8740-8753

[4]

[Anonymous], 2017, BioRxiv, June, DOI [DOI 10.1101/148353, 10.1101/148353]

[5]

[Anonymous], PLOS ONE

[6]

[Anonymous], PLOS MED

[7]

[Anonymous], BIOINFORMATICS

[8]

[Anonymous], 2012, NATURE, DOI DOI 10.1038/nature11632

[9]

[Anonymous], HAPLO STATS V 1 7 9

[10]

[Anonymous], J ALZHEIMERS DIS

← 1 2 3 4 5 6 7 8 9 10 →