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

Authors:
Brian W Kunkle Benjamin Grenier-Boley Rebecca Sims Joshua C Bis Vincent Damotte Adam C Naj Anne Boland Maria Vronskaya Sven J van der Lee Alexandre Amlie-Wolf Céline Bellenguez Aura Frizatti Vincent Chouraki Eden R Martin Kristel Sleegers Nandini Badarinarayan Johanna Jakobsdottir Kara L Hamilton-Nelson Sonia Moreno-Grau Robert Olaso Rachel Raybould Yuning Chen Amanda B Kuzma Mikko Hiltunen Taniesha Morgan Shahzad Ahmad Badri N Vardarajan Jacques Epelbaum Per Hoffmann Merce Boada Gary W Beecham Jean-Guillaume Garnier Denise Harold Annette L Fitzpatrick Otto Valladares Marie-Laure Moutet Amy Gerrish Albert V Smith Liming Qu Delphine Bacq Nicola Denning Xueqiu Jian Yi Zhao Maria Del Zompo Nick C Fox Seung-Hoan Choi Ignacio Mateo Joseph T Hughes Hieab H Adams John Malamon Florentino Sanchez-Garcia Yogen Patel Jennifer A Brody Beth A Dombroski Maria Candida Deniz Naranjo Makrina Daniilidou Gudny Eiriksdottir Shubhabrata Mukherjee David Wallon James Uphill Thor Aspelund Laura B Cantwell Fabienne Garzia Daniela Galimberti Edith Hofer Mariusz Butkiewicz Bertrand Fin Elio Scarpini Chloe Sarnowski Will S Bush Stéphane Meslage Johannes Kornhuber Charles C White Yuenjoo Song Robert C Barber Sebastiaan Engelborghs Sabrina Sordon Dina Voijnovic Perrie M Adams Rik Vandenberghe Manuel Mayhaus L Adrienne Cupples Marilyn S Albert Peter P De Deyn Wei Gu Jayanadra J Himali Duane Beekly Alessio Squassina Annette M Hartmann Adelina Orellana Deborah Blacker Eloy Rodriguez-Rodriguez Simon Lovestone Melissa E Garcia Rachelle S Doody Carmen Munoz-Fernadez Rebecca Sussams Honghuang Lin Thomas J Fairchild Yolanda A Benito Clive Holmes Hata Karamujić-Čomić Matthew P Frosch Hakan Thonberg Wolfgang Maier Gennady Roshchupkin Bernardino Ghetti Vilmantas Giedraitis Amit Kawalia Shuo Li Ryan M Huebinger Lena Kilander Susanne Moebus Isabel Hernández M Ilyas Kamboh RoseMarie Brundin James Turton Qiong Yang Mindy J Katz Letizia Concari Jenny Lord Alexa S Beiser C Dirk Keene Seppo Helisalmi Iwona Kloszewska Walter A Kukull Anne Maria Koivisto Aoibhinn Lynch Lluís Tarraga Eric B Larson Annakaisa Haapasalo Brian Lawlor Thomas H Mosley Richard B Lipton Vincenzo Solfrizzi Michael Gill W T Longstreth Thomas J Montine Vincenza Frisardi Monica Diez-Fairen Fernando Rivadeneira Ronald C Petersen Vincent Deramecourt Ignacio Alvarez Francesca Salani Antonio Ciaramella Eric Boerwinkle Eric M Reiman Nathalie Fievet Jerome I Rotter Joan S Reisch Olivier Hanon Chiara Cupidi A G Andre Uitterlinden Donald R Royall Carole Dufouil Raffaele Giovanni Maletta Itziar de Rojas Mary Sano Alexis Brice Roberta Cecchetti Peter St George-Hyslop Karen Ritchie Magda Tsolaki Debby W Tsuang Bruno Dubois David Craig Chuang-Kuo Wu Hilkka Soininen Despoina Avramidou Roger L Albin Laura Fratiglioni Antonia Germanou Liana G Apostolova Lina Keller Maria Koutroumani Steven E Arnold Francesco Panza Olymbia Gkatzima Sanjay Asthana Didier Hannequin Patrice Whitehead Craig S Atwood Paolo Caffarra Harald Hampel Inés Quintela Ángel Carracedo Lars Lannfelt David C Rubinsztein Lisa L Barnes Florence Pasquier Lutz Frölich Sandra Barral Bernadette McGuinness Thomas G Beach Janet A Johnston James T Becker Peter Passmore Eileen H Bigio Jonathan M Schott Thomas D Bird Jason D Warren Bradley F Boeve Michelle K Lupton James D Bowen Petra Proitsi Adam Boxer John F Powell James R Burke John S K Kauwe Jeffrey M Burns Michelangelo Mancuso Joseph D Buxbaum Ubaldo Bonuccelli Nigel J Cairns Andrew McQuillin Chuanhai Cao Gill Livingston Chris S Carlson Nicholas J Bass Cynthia M Carlsson John Hardy Regina M Carney Jose Bras Minerva M Carrasquillo Rita Guerreiro Mariet Allen Helena C Chui Elizabeth Fisher Carlo Masullo Elizabeth A Crocco Charles DeCarli Gina Bisceglio Malcolm Dick Li Ma Ranjan Duara Neill R Graff-Radford Denis A Evans Angela Hodges Kelley M Faber Martin Scherer Kenneth B Fallon Matthias Riemenschneider David W Fardo Reinhard Heun Martin R Farlow Heike Kölsch Steven Ferris Markus Leber Tatiana M Foroud Isabella Heuser Douglas R Galasko Ina Giegling Marla Gearing Michael Hüll Daniel H Geschwind John R Gilbert John Morris Robert C Green Kevin Mayo John H Growdon Thomas Feulner Ronald L Hamilton Lindy E Harrell Dmitriy Drichel Lawrence S Honig Thomas D Cushion Matthew J Huentelman Paul Hollingworth Christine M Hulette Bradley T Hyman Rachel Marshall Gail P Jarvik Alun Meggy Erin Abner Georgina E Menzies Lee-Way Jin Ganna Leonenko Luis M Real Gyungah R Jun Clinton T Baldwin Detelina Grozeva Anna Karydas Giancarlo Russo Jeffrey A Kaye Ronald Kim Frank Jessen Neil W Kowall Bruno Vellas Joel H Kramer Emma Vardy Frank M LaFerla Karl-Heinz Jöckel James J Lah Martin Dichgans James B Leverenz David Mann Allan I Levey Stuart Pickering-Brown Andrew P Lieberman Norman Klopp Kathryn L Lunetta H-Erich Wichmann Constantine G Lyketsos Kevin Morgan Daniel C Marson Kristelle Brown Frank Martiniuk Christopher Medway Deborah C Mash Markus M Nöthen Eliezer Masliah Nigel M Hooper Wayne C McCormick Antonio Daniele Susan M McCurry Anthony Bayer Andrew N McDavid John Gallacher Ann C McKee Hendrik van den Bussche Marsel Mesulam Carol Brayne Bruce L Miller Steffi Riedel-Heller Carol A Miller Joshua W Miller Ammar Al-Chalabi John C Morris Christopher E Shaw Amanda J Myers Jens Wiltfang Sid O'Bryant John M Olichney Victoria Alvarez Joseph E Parisi Andrew B Singleton Henry L Paulson John Collinge William R Perry Simon Mead Elaine Peskind David H Cribbs Martin Rossor Aimee Pierce Natalie S Ryan Wayne W Poon Benedetta Nacmias Huntington Potter Sandro Sorbi Joseph F Quinn Eleonora Sacchinelli Ashok Raj Gianfranco Spalletta Murray Raskind Carlo Caltagirone Paola Bossù Maria Donata Orfei Barry Reisberg Robert Clarke Christiane Reitz A David Smith John M Ringman Donald Warden Erik D Roberson Gordon Wilcock Ekaterina Rogaeva Amalia Cecilia Bruni Howard J Rosen Maura Gallo Roger N Rosenberg Yoav Ben-Shlomo Mark A Sager Patrizia Mecocci Andrew J Saykin Pau Pastor Michael L Cuccaro Jeffery M Vance Julie A Schneider Lori S Schneider Susan Slifer William W Seeley Amanda G Smith Joshua A Sonnen Salvatore Spina Robert A Stern Russell H Swerdlow Mitchell Tang Rudolph E Tanzi John Q Trojanowski Juan C Troncoso Vivianna M Van Deerlin Linda J Van Eldik Harry V Vinters Jean Paul Vonsattel Sandra Weintraub Kathleen A Welsh-Bohmer Kirk C Wilhelmsen Jennifer Williamson Thomas S Wingo Randall L Woltjer Clinton B Wright Chang-En Yu Lei Yu Yasaman Saba Alberto Pilotto Maria J Bullido Oliver Peters Paul K Crane David Bennett Paola Bosco Eliecer Coto Virginia Boccardi Phil L De Jager Alberto Lleo Nick Warner Oscar L Lopez Martin Ingelsson Panagiotis Deloukas Carlos Cruchaga Caroline Graff Rhian Gwilliam Myriam Fornage Alison M Goate Pascual Sanchez-Juan Patrick G Kehoe Najaf Amin Nilifur Ertekin-Taner Claudine Berr Stéphanie Debette Seth Love Lenore J Launer Steven G Younkin Jean-Francois Dartigues Chris Corcoran M Arfan Ikram Dennis W Dickson Gael Nicolas Dominique Campion JoAnn Tschanz Helena Schmidt Hakon Hakonarson Jordi Clarimon Ron Munger Reinhold Schmidt Lindsay A Farrer Christine Van Broeckhoven Michael C O'Donovan Anita L DeStefano Lesley Jones Jonathan L Haines Jean-Francois Deleuze Michael J Owen Vilmundur Gudnason Richard Mayeux Valentina Escott-Price Bruce M Psaty Alfredo Ramirez Li-San Wang Agustin Ruiz Cornelia M van Duijn Peter A Holmans Sudha Seshadri Julie Williams Phillippe Amouyel Gerard D Schellenberg Jean-Charles Lambert Margaret A Pericak-Vance

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

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 Aβ 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 × 10), 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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019
36 Reads
29.352 Impact Factor

Publication Analysis

Top Keywords

alzheimer's disease
12
risk loci
12
disease load
8
rare variants
8
immunity lipid
8
genome-wide association
8
load risk
8
load
7
risk
6
factor load
4
haplotype hla-dr15
4
hla-dr15 risk
4
risk factor
4
load pathway
4
analysis implicates
4
binding proteins
4
proteins amyloid
4
amyloid precursor
4
tau binding
4
metabolism tau
4

References

(Supplied by CrossRef)
Article in Nat. Genet.
JC Lambert et al.
Nat. Genet. 2013
Article in Neurobiol. Aging.
PM Adams et al.
Neurobiol. Aging. 2016
Article in Arch. Gen. Psychiatry
M Gatz et al.
Arch. Gen. Psychiatry 2006
Article in Nat. Genet.
AC Naj et al.
Nat. Genet. 2011
Article in JAMA
S Seshadri et al.
JAMA 2010
Article in Nat. Genet.
P Hollingworth et al.
Nat. Genet. 2011
Article in N. Engl. J. Med.
T Jonsson et al.
N. Engl. J. Med. 2013
Article in N. Engl. J. Med.
R Guerreiro et al.
N. Engl. J. Med. 2013
Article in Arch. Neurol.
G Jun et al.
Arch. Neurol. 2010
Article in Nat. Genet.
D Harold et al.
Nat. Genet. 2009
Article in Nat. Genet.
JC Lambert et al.
Nat. Genet. 2009

Similar Publications