Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk

被引：1508

作者：

Jansen, Iris E. ^{[1
,2
]}

Savage, Jeanne E. ^{[1
]}

Watanabe, Kyoko ^{[1
]}

Bryois, Julien ^{[3
]}

Williams, Dylan M. ^{[3
]}

Steinberg, Stacy ^{[4
]}

Sealock, Julia ^{[5
]}

Karlsson, Ida K. ^{[3
,6
]}

Hagg, Sara ^{[3
]}

Athanasiu, Lavinia ^{[7
,8
]}

Voyle, Nicola ^{[9
]}

Proitsi, Petroula ^{[9
]}

Witoelar, Aree ^{[7
,10
]}

Stringer, Sven ^{[1
]}

Aarsland, Dag ^{[9
,11
]}

Almdahl, Ina S. ^{[12
,13
,14
]}

Andersen, Fred ^{[15
]}

Bergh, Sverre ^{[16
,17
]}

Bettella, Francesco ^{[7
,10
]}

Bjornsson, Sigurbjorn ^{[18
]}

Braekhus, Anne ^{[16
,19
]}

Brathen, Geir ^{[20
,21
]}

de Leeuw, Christiaan ^{[1
]}

Desikan, Rahul S. ^{[22
]}

Djurovic, Srdjan ^{[7
,23
]}

Dumitrescu, Logan ^{[24
,25
]}

Fladby, Tormod ^{[12
,13
]}

Hohman, Timothy J. ^{[24
,25
]}

Jonsson, Palmi, V ^{[18
,26
]}

Kiddle, Steven J. ^{[27
]}

Rongve, Arvid ^{[28
,29
]}

Saltvedt, Ingvild ^{[20
,30
]}

Sando, Sigrid B. ^{[20
,21
]}

Selbaek, Geir ^{[16
,31
]}

Shoai, Maryam ^{[32
]}

Skene, Nathan G. ^{[33
,34
]}

Snaedal, Jon ^{[18
]}

Stordal, Eystein ^{[35
,36
]}

Ulstein, Ingun D. ^{[37
]}

Wang, Yunpeng ^{[7
,10
]}

White, Linda R. ^{[20
,21
]}

Hardy, John ^{[32
]}

Hjerling-Leffler, Jens ^{[33
]}

Sullivan, Patrick F. ^{[3
,38
,39
]}

van der Flier, Wiesje M. ^{[2
]}

Dobson, Richard ^{[9
,40
,41
,42
,43
]}

Davis, Lea K. ^{[25
,44
]}

Stefansson, Hreinn ^{[4
]}

Stefansson, Kari ^{[4
]}

Pedersen, Nancy L. ^{[3
]}

机构：

[1] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, Amsterdam Neurosci, Amsterdam, Netherlands

[2] Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands

[3] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[4] deCODE Genet Amgen, Reykjavik, Iceland

[5] Vanderbilt Univ, Interdisciplinary Grad Program, 221 Kirkland Hall, Nashville, TN 37235 USA

[6] Jonkoping Univ, Sch Hlth & Welf, Inst Gerontol & Aging Res Network Jonkoping ARN J, Jonkoping, Sweden

[7] Univ Oslo, KG Jebsen Ctr Psychosis Res, Inst Clin Med, NORMENT, Oslo, Norway

[8] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[9] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England

[10] Univ Oslo, Inst Clin Med, Oslo, Norway

[11] Stavanger Univ Hosp, Ctr Age Related Dis, Stavanger, Norway

[12] Akershus Univ Hosp, Dept Neurol, Lorenskog, Norway

[13] Univ Oslo, AHUS Campus, Oslo, Norway

[14] Oslo Univ Hosp, Dept Psychiat Old Age, Oslo, Norway

[15] Univ Tromso, Dept Community Med, Tromso, Norway

[16] Vestfold Hosp Trust, Norwegian Natl Advisory Unit Ageing & Hlth, Tonsberg, Norway

[17] Innlandet Hosp Trust, Ctr Old Age Psychiat Res, Ottestad, Norway

[18] Landspitali Univ Hosp, Dept Geriatr Med, Reykjavik, Iceland

[19] Oslo Univ Hosp, Geriatr Dept, Oslo, Norway

[20] Norwegian Univ Sci & Technol, Dept Neuromed & Movement Sci, Trondheim, Norway

[21] Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Neurol, Trondheim, Norway

[22] Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA

[23] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[24] Vanderbilt Univ, Med Ctr, Dept Neurol, Vanderbilt Memory & Alzheimers Ctr, Nashville, TN USA

[25] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN USA

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

[27] Univ Cambridge, Cambridge Inst Publ Hlth, MRC Biostat Unit, Cambridge, England

[28] Helse Fonna, Dept Res & Innovat, Haugesund, Norway

[29] Univ Bergen, Dept Clin Med, Bergen, Norway

[30] Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Geriatr, Trondheim, Norway

[31] Univ Oslo, Inst Hlth & Soc, Oslo, Norway

[32] UCL, Dept Neurodegenerat Disorders, Inst Neurol, London, England

[33] Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Stockholm, Sweden

[34] UCL, Inst Neurol, Dept Neuromuscular Dis, London, England

[35] Namsos Hosp, Dept Psychiat, Namsos, Norway

[36] Norwegian Univ Sci & Technol, Dept Mental Hlth, Trondheim, Norway

[37] Oslo Univ Hosp, Geriatr Dept, Memory Clin, Oslo, Norway

[38] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA

[39] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA

[40] South London & Maudsley NHS Fdn Trust, NIHR Biomed Res Ctr, London, England

[41] Kings Coll London, London, England

[42] UCL, Inst Hlth Informat Res, London, England

[43] UCL, Hlth Data Res UK London, London, England

[44] Vanderbilt Univ, Med Ctr, Dept Med, Div Genet Med, Nashville, TN USA

[45] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[46] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[47] Charite, Dept Psychiat & Psychotherapy, Berlin, Germany

[48] Vrije Univ Amsterdam, Dept Clin Genet, Med Ctr, Amsterdam, Netherlands

来源：

NATURE GENETICS | 2019年 / 51卷 / 03期

关键词：

POLYGENIC RISK; MISSENSE MUTATIONS; COGNITIVE RESERVE; GENE-EXPRESSION; VARIANTS; ASSOCIATION; RARE; ANNOTATION; DISCOVERY; DEMENTIA;

D O I：

10.1038/s41588-018-0311-9

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (r(g) = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

引用

页码：404 / +

页数：13

共 65 条

[1] Height as a marker of childhood development and late-life cognitive function: The Honolulu-Asia Aging Study [J].

Abbott, RD ;

White, LR ;

Ross, GW ;

Petrovitch, H ;

Masaki, KH ;

Snowdon, DA ;

Curb, JD .

PEDIATRICS, 1998, 102 (03) :602-609

[2] Novel genetic loci underlying human intracranial volume identified through genome-wide association [J].

Adams, Hieab H. H. ;

Hibar, Derrek P. ;

Chouraki, Vincent ;

Stein, Jason L. ;

Nyquist, Paul A. ;

Renteria, Miguel E. ;

Trompet, Stella ;

Arias-Vasquez, Alejandro ;

Seshadri, Sudha ;

Desrivieres, Sylvane ;

Beecham, Ashley H. ;

Jahanshad, Neda ;

Wittfeld, Katharine ;

Van der Lee, Sven J. ;

Abramovic, Lucija ;

Alhusaini, Saud ;

Amin, Najaf ;

Andersson, Micael ;

Arfanakis, Konstantinos ;

Aribisala, Benjamin S. ;

Armstrong, Nicola J. ;

Athanasiu, Lavinia ;

Axelsson, Tomas ;

Beiser, Alexa ;

Bernard, Manon ;

Bis, Joshua C. ;

Blanken, Laura M. E. ;

Blanton, Susan H. ;

Bohlken, Marc M. ;

Boks, Marco P. ;

Bralten, Janita ;

Brickman, Adam M. ;

Carmichael, Owen ;

Chakravarty, M. Mallar ;

Chauhan, Ganesh ;

Chen, Qiang ;

Ching, Christopher R. K. ;

Cuellar-Partida, Gabriel ;

Den Braber, Anouk ;

Doan, Nhat Trung ;

Ehrlich, Stefan ;

Filippi, Irina ;

Ge, Tian ;

Giddaluru, Sudheer ;

Goldman, Aaron L. ;

Gottesman, Rebecca F. ;

Greven, Corina U. ;

Grimm, Oliver ;

Griswold, Michael E. ;

Guadalupe, Tulio .

NATURE NEUROSCIENCE, 2016, 19 (12) :1569-1582

[3] Actionable exomic incidental findings in 6503 participants: challenges of variant classification [J].

Amendola, Laura M. ;

Dorschner, Michael O. ;

Robertson, Peggy D. ;

Salama, Joseph S. ;

Hart, Ragan ;

Shirts, Brian H. ;

Murray, Mitzi L. ;

Tokita, Mari J. ;

Gallego, Carlos J. ;

Kim, Daniel Seung ;

Bennett, James T. ;

Crosslin, David R. ;

Ranchalis, Jane ;

Jones, Kelly L. ;

Rosenthal, Elisabeth A. ;

Jarvik, Ella R. ;

Itsara, Andy ;

Turner, Emily H. ;

Herman, Daniel S. ;

Schleit, Jennifer ;

Burt, Amber ;

Jamal, Seema M. ;

Abrudan, Jenica L. ;

Johnson, Andrew D. ;

Conlin, Laura K. ;

Dulik, Matthew C. ;

Santani, Avni ;

Metterville, Danielle R. ;

Kelly, Melissa ;

Foreman, Ann Katherine M. ;

Lee, Kristy ;

Taylor, Kent D. ;

Guo, Xiuqing ;

Crooks, Kristy ;

Kiedrowski, Lesli A. ;

Raffe, Leslie J. ;

Gordon, Ora ;

Machini, Kalotina ;

Desnick, Robe ;

Biesecker, Leslie G. ;

Lubitz, Steven A. ;

Mulchandani, Surabhi ;

Cooper, Greg M. ;

Joffe, Steven ;

Richards, C. Sue ;

Yang, Yaoping ;

Rotter, Jerome I. ;

Rich, Stephen S. ;

O'Donne, Christopher J. ;

Berg, Jonathan S. .

GENOME RESEARCH, 2015, 25 (03) :305-315

[4]

[Anonymous], 2015, J IMMUNOL RES

[5] Analysis of shared heritability in common disorders of the brain [J].

Anttila, Verneri ;

Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Walters, Raymond K. ;

Bras, Jose ;

Duncan, Laramie ;

Escott-Price, Valentina ;

Falcone, Guido J. ;

Gormley, Padhraig ;

Malik, Rainer ;

Patsopoulos, Nikolaos A. ;

Ripke, Stephan ;

Wei, Zhi ;

Yu, Dongmei ;

Lee, Phil H. ;

Turley, Patrick ;

Grenier-Boley, Benjamin ;

Chouraki, Vincent ;

Kamatani, Yoichiro ;

Berr, Claudine ;

Letenneur, Luc ;

Hannequin, Didier ;

Amouyel, Philippe ;

Boland, Anne ;

Deleuze, Jean-Francois ;

Duron, Emmanuelle ;

Vardarajan, Badri N. ;

Reitz, Christiane ;

Goate, Alison M. ;

Huentelman, Matthew J. ;

Kamboh, M. Ilyas ;

Larson, Eric B. ;

Rogaeva, Ekaterina ;

St George-Hyslop, Peter ;

Hakonarson, Hakon ;

Kukull, Walter A. ;

Farrer, Lindsay A. ;

Barnes, Lisa L. ;

Beach, Thomas G. ;

Demirci, F. Yesim ;

Head, Elizabeth ;

Hulette, Christine M. ;

Jicha, Gregory A. ;

Kauwe, John S. K. ;

Kaye, Jeffrey A. ;

Leverenz, James B. ;

Levey, Allan I. ;

Lieberman, Andrew P. ;

Pankratz, Vernon S. ;

Poon, Wayne W. .

SCIENCE, 2018, 360 (6395) :1313-+

[6] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[7] Annotation of functional variation in personal genomes using RegulomeDB [J].

Boyle, Alan P. ;

Hong, Eurie L. ;

Hariharan, Manoj ;

Cheng, Yong ;

Schaub, Marc A. ;

Kasowski, Maya ;

Karczewski, Konrad J. ;

Park, Julie ;

Hitz, Benjamin C. ;

Weng, Shuai ;

Cherry, J. Michael ;

Snyder, Michael .

GENOME RESEARCH, 2012, 22 (09) :1790-1797

[8] An atlas of genetic correlations across human diseases and traits [J].

Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Anttila, Verneri ;

Gusev, Alexander ;

Day, Felix R. ;

Loh, Po-Ru ;

Duncan, Laramie ;

Perry, John R. B. ;

Patterson, Nick ;

Robinson, Elise B. ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (11) :1236-+

[9] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[10] Molecular genetics of early-onset Alzheimer's disease revisited [J].

Cacace, Rita ;

Sleegers, Kristel ;

Van Broeckhoven, Christine .

ALZHEIMERS & DEMENTIA, 2016, 12 (06) :733-748

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