Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

被引：240

作者：

Chia, Ruth ^{[1
]}

Sabir, Marya S. ^{[2
]}

Bandres-Ciga, Sara ^{[3
]}

Saez-Atienzar, Sara ^{[1
]}

Reynolds, Regina H. ^{[4
,5
,6
]}

Gustavsson, Emil ^{[5
,6
]}

Walton, Ronald L. ^{[7
]}

Ahmed, Sarah ^{[2
]}

Viollet, Coralie ^{[8
,9
]}

Ding, Jinhui ^{[10
]}

Makarious, Mary B. ^{[2
]}

Diez-Fairen, Monica ^{[11
]}

Portley, Makayla K. ^{[2
]}

Shah, Zalak ^{[2
]}

Abramzon, Yevgeniya ^{[1
,12
]}

Hernandez, Dena G. ^{[3
]}

Blauwendraat, Cornelis ^{[3
]}

Stone, David J. ^{[13
]}

Eicher, John ^{[14
]}

Parkkinen, Laura ^{[15
]}

Ansorge, Olaf ^{[15
]}

Clark, Lorraine ^{[16
,17
]}

Honig, Lawrence S. ^{[18
,19
]}

Marder, Karen ^{[18
,19
]}

Lemstra, Afina ^{[20
,21
]}

St George-Hyslop, Peter ^{[22
,23
]}

Londos, Elisabet ^{[24
]}

Morgan, Kevin ^{[25
]}

Lashley, Tammaryn ^{[4
,26
]}

Warner, Thomas T. ^{[12
,26
]}

Jaunmuktane, Zane ^{[26
]}

Galasko, Douglas ^{[27
,28
]}

Santana, Isabel ^{[29
,30
,31
,32
]}

Tienari, Pentti J. ^{[33
,34
]}

Myllykangas, Liisa ^{[35
,36
]}

Oinas, Minna ^{[37
]}

Cairns, Nigel J. ^{[38
]}

Morris, John C. ^{[38
]}

Halliday, Glenda M. ^{[39
,40
,41
]}

Van Deerlin, Vivianna M. ^{[42
]}

Trojanowski, John Q. ^{[42
]}

Grassano, Maurizio ^{[1
,43
]}

Calvo, Andrea ^{[43
,44
]}

Mora, Gabriele ^{[45
]}

Canosa, Antonio ^{[43
,44
]}

Floris, Gianluca ^{[46
]}

Bohannan, Ryan C. ^{[47
]}

Brett, Francesca ^{[48
]}

Gan-Or, Ziv ^{[49
]}

Geiger, Joshua T. ^{[2
]}

机构：

[1] NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD 20892 USA

[2] NINDS, Neurodegenerat Dis Res Unit, Lab Neurogenet, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[3] NIA, Mol Genet Sect, Lab Neurogenet, Bethesda, MD 20892 USA

[4] UCL, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London, England

[5] UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England

[6] UCL, Great Ormond St Inst Child Hlth Genet & Genom Med, London, England

[7] Mayo Clin, Dept Neurosci, Jacksonville, FL USA

[8] Uniformed Serv Univ Hlth Sci, Collaborat Hlth Initiat Res Program, Bethesda, MD 20814 USA

[9] Henry M Jackson Fdn Adv Mil Med Inc, Bethesda, MD USA

[10] NIA, Computat Biol Grp, Lab Neurogenet, Bethesda, MD 20892 USA

[11] Univ Hosp Mutua Terrassa, Dept Neurol, Memory & Movement Disorders Units, Barcelona, Spain

[12] UCL, Reta Lila Weston Inst, UCL Queen Sq Inst Neurol, London, England

[13] Cerevel Therapeut, Boston, MA USA

[14] Merck & Co Inc, Genet & Pharmacogen, West Point, PA USA

[15] Univ Oxford, Oxford Parkinsons Dis Ctr, Nuffield Dept Clin Neurosci, Oxford, England

[16] Columbia Univ, Taub Inst Alzheimer Dis & Aging Brain, New York, NY USA

[17] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA

[18] Columbia Univ, GH Sergievsky Ctr, Taub Inst Alzheimer Dis & Aging Brain, New York, NY USA

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

[20] Neurosci Campus Amsterdam, Dept Neurol, Amsterdam, Netherlands

[21] Neurosci Campus Amsterdam, Alzheimer Ctr, Amsterdam, Netherlands

[22] Univ Cambridge, Cambridge Inst Med Res, Dept Clin Neurosci, Cambridge, England

[23] Univ Toronto, Dept Med, Toronto, ON, Canada

[24] Lund Univ, Inst Clin Sci Malmo, Clin Memory Res Unit, Lund, Sweden

[25] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Nottingham, England

[26] UCL, UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, Queen Sq Brain Bank Neurol Disorders, London, England

[27] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[28] Vet Affairs San Diego Healthcare Syst, La Jolla, CA USA

[29] Univ Coimbra Hosp, Neurol Serv, Coimbra, Portugal

[30] Ctr Hosp & Univ Coimbra, Coimbra, Portugal

[31] Univ Coimbra, Fac Med, Coimbra, Portugal

[32] Univ Coimbra, Ctr Innovat Biomed & Biotechnol, Coimbra, Portugal

[33] Univ Helsinki, Res Programs Unit, Translat Immunol, Helsinki, Finland

[34] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland

[35] Univ Helsinki, Dept Pathol, Med, Helsinki, Finland

[36] Helsinki Univ Hosp, HUS Diagnost Ctr, Helsinki, Finland

[37] UiT Arctic Univ Norway, Fac Hlth, Dept Clin Med, Tromso, Norway

[38] Washington Univ, Sch Med, Dept Neurol, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA

[39] Neurosci Res Australia, Sydney, NSW, Australia

[40] Univ New South Wales, Fac Med, Sch Med Sci, Sydney, NSW, Australia

[41] Univ Sydney, Brain & Mind Ctr, Sydney Med Sch, Sydney, NSW, Australia

[42] Univ Penn, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Philadelphia, PA USA

[43] Univ Turin, Rita Levi Montalcini Dept Neurosci, Turin, Italy

[44] Azienda Osped Univ Citt Salute & Sci, Turin, Italy

[45] IRCCS, Ist Clin Sci Maugeri, Milan, Italy

[46] Univ Hosp Cagliari, Dept Neurol, Cagliari, Italy

[47] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA USA

[48] Beaumont Hosp, Neuropathol Dept, Dublin Brain Bank, Dublin, Ireland

[49] McGill Univ, Montreal Neurol Inst & Hosp, Dept Neurol & Neurosurg, Montreal, PQ, Canada

[50] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Sur Alzette, Luxembourg

来源：

NATURE GENETICS | 2021年 / 53卷 / 03期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

ALZHEIMERS-DISEASE; GLUCOCEREBROSIDASE MUTATIONS; RISK LOCI; BODIES; METAANALYSIS; BETA; MULTICENTER; PATHOLOGY; EFFICIENT; RESOURCE;

D O I：

10.1038/s41588-021-00785-3

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

引用

页码：294 / +

页数：24

共 60 条

[1] Integrating common and rare genetic variation in diverse human populations [J].

Altshuler, David M. ;

Gibbs, Richard A. ;

Peltonen, Leena ;

Dermitzakis, Emmanouil ;

Schaffner, Stephen F. ;

Yu, Fuli ;

Bonnen, Penelope E. ;

de Bakker, Paul I. W. ;

Deloukas, Panos ;

Gabriel, Stacey B. ;

Gwilliam, Rhian ;

Hunt, Sarah ;

Inouye, Michael ;

Jia, Xiaoming ;

Palotie, Aarno ;

Parkin, Melissa ;

Whittaker, Pamela ;

Chang, Kyle ;

Hawes, Alicia ;

Lewis, Lora R. ;

Ren, Yanru ;

Wheeler, David ;

Muzny, Donna Marie ;

Barnes, Chris ;

Darvishi, Katayoon ;

Hurles, Matthew ;

Korn, Joshua M. ;

Kristiansson, Kati ;

Lee, Charles ;

McCarroll, Steven A. ;

Nemesh, James ;

Keinan, Alon ;

Montgomery, Stephen B. ;

Pollack, Samuela ;

Price, Alkes L. ;

Soranzo, Nicole ;

Gonzaga-Jauregui, Claudia ;

Anttila, Verneri ;

Brodeur, Wendy ;

Daly, Mark J. ;

Leslie, Stephen ;

McVean, Gil ;

Moutsianas, Loukas ;

Nguyen, Huy ;

Zhang, Qingrun ;

Ghori, Mohammed J. R. ;

McGinnis, Ralph ;

McLaren, William ;

Takeuchi, Fumihiko ;

Grossman, Sharon R. .

NATURE, 2010, 467 (7311) :52-58

[2] 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

[3] The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease [J].

Bandres-Ciga, Sara ;

Saez-Atienzar, Sara ;

Bonet-Ponce, Luis ;

Billingsley, Kimberley ;

Vitale, Dan ;

Blauwendraat, Cornelis ;

Gibbs, Jesse Raphael ;

Pihistrom, Lasse ;

Gan-Or, Ziv ;

Cookson, Mark R. ;

Nails, Mike A. ;

Singleton, Andrew B. .

MOVEMENT DISORDERS, 2019, 34 (04) :460-468

[4] Reactome from a WikiPathways Perspective [J].

Bohler, Anwesha ;

Wu, Guanming ;

Kutmon, Martina ;

Pradhana, Leontius Adhika ;

Coort, Susan L. ;

Hanspers, Kristina ;

Haw, Robin ;

Pico, Alexander R. ;

Evelo, Chris T. .

PLOS COMPUTATIONAL BIOLOGY, 2016, 12 (05)

[5] Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry [J].

Braak, Heiko ;

Alafuzoff, Irina ;

Arzberger, Thomas ;

Kretzschmar, Hans ;

Del Tredici, Kelly .

ACTA NEUROPATHOLOGICA, 2006, 112 (04) :389-404

[6] Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson's disease [J].

Bryois, Julien ;

Skene, Nathan G. ;

Hansen, Thomas Folkmann ;

Kogelman, Lisette J. A. ;

Watson, Hunna J. ;

Liu, Zijing ;

Brueggeman, Leo ;

Breen, Gerome ;

Bulik, Cynthia M. ;

Arenas, Ernest ;

Hjerling-Leffler, Jens ;

Sullivan, Patrick F. .

NATURE GENETICS, 2020, 52 (05) :482-+

[7] Loss of Bin1 Promotes the Propagation of Tau Pathology [J].

Calafate, Sara ;

Flavin, William ;

Verstreken, Patrik ;

Moechars, Diederik .

CELL REPORTS, 2016, 17 (04) :931-940

[8] Second-generation PLINK: rising to the challenge of larger and richer datasets [J].

Chang, Christopher C. ;

Chow, Carson C. ;

Tellier, Laurent C. A. M. ;

Vattikuti, Shashaank ;

Purcell, Shaun M. ;

Lee, James J. .

GIGASCIENCE, 2015, 4

[9] GENE DOSE OF APOLIPOPROTEIN-E TYPE-4 ALLELE AND THE RISK OF ALZHEIMERS-DISEASE IN LATE-ONSET FAMILIES [J].

CORDER, EH ;

SAUNDERS, AM ;

STRITTMATTER, WJ ;

SCHMECHEL, DE ;

GASKELL, PC ;

SMALL, GW ;

ROSES, AD ;

HAINES, JL ;

PERICAKVANCE, MA .

SCIENCE, 1993, 261 (5123) :921-923

[10] Next-generation genotype imputation service and methods [J].

Das, Sayantan ;

Forer, Lukas ;

Schoenherr, Sebastian ;

Sidore, Carlo ;

Locke, Adam E. ;

Kwong, Alan ;

Vrieze, Scott I. ;

Chew, Emily Y. ;

Levy, Shawn ;

McGue, Matt ;

Schlessinger, David ;

Stambolian, Dwight ;

Loh, Po-Ru ;

Iacono, William G. ;

Swaroop, Anand ;

Scott, Laura J. ;

Cucca, Francesco ;

Kronenberg, Florian ;

Boehnke, Michael ;

Abecasis, Goncalo R. ;

Fuchsberger, Christian .

NATURE GENETICS, 2016, 48 (10) :1284-1287

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