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

被引：1307

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

下载

页码：404 / +

页数：13

共 50 条

[31] Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis
Lavinia Paternoster
Marie Standl
Chih-Mei Chen
Adaikalavan Ramasamy
Klaus Bønnelykke
Liesbeth Duijts
Manuel A Ferreira
Alexessander Couto Alves
Jacob P Thyssen
Eva Albrecht
Hansjörg Baurecht
Bjarke Feenstra
Patrick M A Sleiman
Pirro Hysi
Nicole M Warrington
Ivan Curjuric
Ronny Myhre
John A Curtin
Maria M Groen-Blokhuis
Marjan Kerkhof
Annika Sääf
Andre Franke
David Ellinghaus
Regina Fölster-Holst
Emmanouil Dermitzakis
Stephen B Montgomery
Holger Prokisch
Katharina Heim
Anna-Liisa Hartikainen
Anneli Pouta
Juha Pekkanen
Alexandra I F Blakemore
Jessica L Buxton
Marika Kaakinen
David L Duffy
Pamela A Madden
Andrew C Heath
Grant W Montgomery
Philip J Thompson
Melanie C Matheson
Peter Le Souëf
Beate St. Pourcain
George Davey Smith
John Henderson
John P Kemp
Nicholas J Timpson
Panos Deloukas
Susan M Ring
H-Erich Wichmann
Martina Müller-Nurasyid
Nature Genetics, 2012, 44 : 187 - 192
[32] Genome-wide meta-analysis identifies novel loci conferring risk of acne vulgaris
Teder-Laving, Maris
Kals, Mart
Reigo, Anu
Nikopensius, Tiit
Objartel, Telver
Ehin, Riin
Vaht, Mariliis
Metspalu, Andres
Kingo, Kulli
EUROPEAN JOURNAL OF HUMAN GENETICS, 2024, 32 : 773 - 773
[33] Genome-wide meta-analysis identifies novel loci conferring risk of acne vulgaris
Teder-Laving, Maris
Kals, Mart
Reigo, Anu
Ehin, Riin
Objaertel, Telver
Vaht, Mariliis
Nikopensius, Tiit
Metspalu, Andres
Kingo, Kulli
EUROPEAN JOURNAL OF HUMAN GENETICS, 2023, 32 (9) : 1136 - 1143
[34] Genome-wide meta-analysis of keratinocytic cancers identifies 26 novel risk loci
Liyanage, Upekha E.
Law, Matthew H.
Han, Xikun
An, Jiyuan
Ong, Jue-Sheng
Gharahkhani, Puya
Iles, Mark M.
Neale, Rachel E.
Olsen, Catherine
Macgregor, Stuart
Whiteman, David C.
CANCER RESEARCH, 2019, 79 (13)
[35] Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease
DeMichele-Sweet, Mary Ann A.
Klei, Lambertus
Creese, Byron
Harwood, Janet C.
Weamer, Elise A.
McClain, Lora
Sims, Rebecca
Hernandez, Isabel
Moreno-Grau, Sonia
Tarraga, Lluis
Boada, Merce
Alarcon-Martin, Emilio
Valero, Sergi
Liu, Yushi
Hooli, Basavaraj
Aarsland, Dag
Selbaek, Geir
Bergh, Sverre
Rongve, Arvid
Saltvedt, Ingvild
Skjellegrind, Havard K.
Engdahl, Bo
Stordal, Eystein
Andreassen, Ole A.
Djurovic, Srdjan
Athanasiu, Lavinia
Seripa, Davide
Borroni, Barbara
Albani, Diego
Forloni, Gianluigi
Mecocci, Patrizia
Serretti, Alessandro
De Ronchi, Diana
Politis, Antonis
Williams, Julie
Mayeux, Richard
Foroud, Tatiana
Ruiz, Agustin
Ballard, Clive
Holmans, Peter
Lopez, Oscar L.
Kamboh, M. Ilyas
Devlin, Bernie
Sweet, Robert A.
MOLECULAR PSYCHIATRY, 2021, 26 (10) : 5797 - 5811
[36] Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease
Mary Ann A. DeMichele-Sweet
Lambertus Klei
Byron Creese
Janet C. Harwood
Elise A. Weamer
Lora McClain
Rebecca Sims
Isabel Hernandez
Sonia Moreno-Grau
Lluís Tárraga
Mercè Boada
Emilio Alarcón-Martín
Sergi Valero
Yushi Liu
Basavaraj Hooli
Dag Aarsland
Geir Selbaek
Sverre Bergh
Arvid Rongve
Ingvild Saltvedt
Håvard K. Skjellegrind
Bo Engdahl
Eystein Stordal
Ole A. Andreassen
Srdjan Djurovic
Lavinia Athanasiu
Davide Seripa
Barbara Borroni
Diego Albani
Gianluigi Forloni
Patrizia Mecocci
Alessandro Serretti
Diana De Ronchi
Antonis Politis
Julie Williams
Richard Mayeux
Tatiana Foroud
Agustin Ruiz
Clive Ballard
Peter Holmans
Oscar L. Lopez
M. Ilyas Kamboh
Bernie Devlin
Robert A. Sweet
Molecular Psychiatry, 2021, 26 : 5797 - 5811
[37] Genome-wide association meta-analysis identifies 29 new acne susceptibility loci
Brittany L. Mitchell
Jake R. Saklatvala
Nick Dand
Fiona A. Hagenbeek
Xin Li
Josine L. Min
Laurent Thomas
Meike Bartels
Jouke Jan Hottenga
Michelle K. Lupton
Dorret I. Boomsma
Xianjun Dong
Kristian Hveem
Mari Løset
Nicholas G. Martin
Jonathan N. Barker
Jiali Han
Catherine H. Smith
Miguel E. Rentería
Michael A. Simpson
Nature Communications, 13
[38] Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
Klein, Alison P.
Wolpin, Brian M.
Risch, Harvey A.
Stolzenberg-Solomon, Rachael Z.
Mocci, Evelina
Zhang, Mingfeng
Canzian, Federico
Childs, Erica J.
Hoskins, Jason W.
Jermusyk, Ashley
Zhong, Jun
Chen, Fei
Albanes, Demetrius
Andreotti, Gabriella
Arslan, Alan A.
Babic, Ana
Bamlet, William R.
Beane-Freeman, Laura
Berndt, Sonja I.
Blackford, Amanda
Borges, Michael
Borgida, Ayelet
Bracci, Paige M.
Brais, Lauren
Brennan, Paul
Brenner, Hermann
Bueno-de-Mesquita, Bas
Buring, Julie
Campa, Daniele
Capurso, Gabriele
Cavestro, Giulia Martina
Chaffee, Kari G.
Chung, Charles C.
Cleary, Sean
Cotterchio, Michelle
Dijk, Frederike
Duell, Eric J.
Foretova, Lenka
Fuchs, Charles
Funel, Niccola
Gallinger, Steven
Gaziano, J. Michael M.
Gazouli, Maria
Giles, Graham G.
Giovannucci, Edward
Goggins, Michael
Goodman, Gary E.
Goodman, Phyllis J.
Hackert, Thilo
Haiman, Christopher
NATURE COMMUNICATIONS, 2018, 9
[39] Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
Alison P. Klein
Brian M. Wolpin
Harvey A. Risch
Rachael Z. Stolzenberg-Solomon
Evelina Mocci
Mingfeng Zhang
Federico Canzian
Erica J. Childs
Jason W. Hoskins
Ashley Jermusyk
Jun Zhong
Fei Chen
Demetrius Albanes
Gabriella Andreotti
Alan A. Arslan
Ana Babic
William R. Bamlet
Laura Beane-Freeman
Sonja I. Berndt
Amanda Blackford
Michael Borges
Ayelet Borgida
Paige M. Bracci
Lauren Brais
Paul Brennan
Hermann Brenner
Bas Bueno-de-Mesquita
Julie Buring
Daniele Campa
Gabriele Capurso
Giulia Martina Cavestro
Kari G. Chaffee
Charles C. Chung
Sean Cleary
Michelle Cotterchio
Frederike Dijk
Eric J. Duell
Lenka Foretova
Charles Fuchs
Niccola Funel
Steven Gallinger
J. Michael M. Gaziano
Maria Gazouli
Graham G. Giles
Edward Giovannucci
Michael Goggins
Gary E. Goodman
Phyllis J. Goodman
Thilo Hackert
Christopher Haiman
Nature Communications, 9
[40] Genome-wide association meta-analysis identifies 29 new acne susceptibility loci
Mitchell, Brittany L.
Saklatvala, Jake R.
Dand, Nick
Hagenbeek, Fiona A.
Li, Xin
Min, Josine L.
Thomas, Laurent
Bartels, Meike
Hottenga, Jouke Jan
Lupton, Michelle K.
Boomsma, Dorret, I
Dong, Xianjun
Hveem, Kristian
Loset, Mari
Martin, Nicholas G.
Barker, Jonathan N.
Han, Jiali
Smith, Catherine H.
Renteria, Miguel E.
Simpson, Michael A.
NATURE COMMUNICATIONS, 2022, 13 (01)

← 1 2 3 4 5 →