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Meta-Analysis
. 2019 Mar;51(3):414-430.
doi: 10.1038/s41588-019-0358-2. Epub 2019 Feb 28.

Genetic Meta-Analysis of Diagnosed Alzheimer's Disease Identifies New Risk Loci and Implicates Aβ, Tau, Immunity and Lipid Processing

Brian W Kunkle  1 Benjamin Grenier-Boley  2   3   4 Rebecca Sims  5   6 Joshua C Bis  7 Vincent Damotte  2   3   4 Adam C Naj  8 Anne Boland  9 Maria Vronskaya  5 Sven J van der Lee  10 Alexandre Amlie-Wolf  11 Céline Bellenguez  2   3   4 Aura Frizatti  5 Vincent Chouraki  2   3   4   12   13 Eden R Martin  14 Kristel Sleegers  15   16 Nandini Badarinarayan  5 Johanna Jakobsdottir  17 Kara L Hamilton-Nelson  14 Sonia Moreno-Grau  18   19 Robert Olaso  9 Rachel Raybould  5   6 Yuning Chen  20 Amanda B Kuzma  11 Mikko Hiltunen  21   22 Taniesha Morgan  5 Shahzad Ahmad  10 Badri N Vardarajan  23   24   25 Jacques Epelbaum  26 Per Hoffmann  27   28   29 Merce Boada  18   19 Gary W Beecham  14 Jean-Guillaume Garnier  9 Denise Harold  30 Annette L Fitzpatrick  31   32 Otto Valladares  11 Marie-Laure Moutet  9 Amy Gerrish  33 Albert V Smith  34   35 Liming Qu  11 Delphine Bacq  9 Nicola Denning  5   6 Xueqiu Jian  36 Yi Zhao  11 Maria Del Zompo  37 Nick C Fox  33   38 Seung-Hoan Choi  18 Ignacio Mateo  39 Joseph T Hughes  40 Hieab H Adams  10 John Malamon  11 Florentino Sanchez-Garcia  41 Yogen Patel  40 Jennifer A Brody  7 Beth A Dombroski  11 Maria Candida Deniz Naranjo  41 Makrina Daniilidou  42 Gudny Eiriksdottir  17 Shubhabrata Mukherjee  43 David Wallon  44 James Uphill  45 Thor Aspelund  17   46 Laura B Cantwell  11 Fabienne Garzia  9 Daniela Galimberti  47   48 Edith Hofer  49   50 Mariusz Butkiewicz  51 Bertrand Fin  9 Elio Scarpini  47   48 Chloe Sarnowski  20 Will S Bush  51 Stéphane Meslage  9 Johannes Kornhuber  52 Charles C White  53 Yuenjoo Song  51 Robert C Barber  54 Sebastiaan Engelborghs  55   56 Sabrina Sordon  57 Dina Voijnovic  10 Perrie M Adams  58 Rik Vandenberghe  59 Manuel Mayhaus  57 L Adrienne Cupples  12   20 Marilyn S Albert  60 Peter P De Deyn  55   56 Wei Gu  57 Jayanadra J Himali  12   13   20 Duane Beekly  61 Alessio Squassina  37 Annette M Hartmann  62 Adelina Orellana  18 Deborah Blacker  63   64 Eloy Rodriguez-Rodriguez  39 Simon Lovestone  65 Melissa E Garcia  66 Rachelle S Doody  67 Carmen Munoz-Fernadez  41 Rebecca Sussams  68 Honghuang Lin  69 Thomas J Fairchild  70 Yolanda A Benito  41 Clive Holmes  68 Hata Karamujić-Čomić  10 Matthew P Frosch  71 Hakan Thonberg  72   73 Wolfgang Maier  74   75 Gennady Roshchupkin  10 Bernardino Ghetti  76 Vilmantas Giedraitis  77 Amit Kawalia  78 Shuo Li  20 Ryan M Huebinger  79 Lena Kilander  77 Susanne Moebus  80 Isabel Hernández  18   19 M Ilyas Kamboh  81   82   83 RoseMarie Brundin  77 James Turton  84 Qiong Yang  20 Mindy J Katz  85 Letizia Concari  86   87 Jenny Lord  84 Alexa S Beiser  12   13   20 C Dirk Keene  88 Seppo Helisalmi  21   22 Iwona Kloszewska  89 Walter A Kukull  32 Anne Maria Koivisto  21   22 Aoibhinn Lynch  90   91 Lluís Tarraga  18   19 Eric B Larson  92 Annakaisa Haapasalo  93 Brian Lawlor  90   91 Thomas H Mosley  94 Richard B Lipton  85 Vincenzo Solfrizzi  95 Michael Gill  90   91 W T Longstreth Jr  32   96 Thomas J Montine  88 Vincenza Frisardi  97 Monica Diez-Fairen  98   99 Fernando Rivadeneira  10   100   101 Ronald C Petersen  102 Vincent Deramecourt  103 Ignacio Alvarez  98   99 Francesca Salani  104 Antonio Ciaramella  104 Eric Boerwinkle  105   106 Eric M Reiman  107   108   109   110 Nathalie Fievet  2   3   4 Jerome I Rotter  111 Joan S Reisch  112 Olivier Hanon  113 Chiara Cupidi  114 A G Andre Uitterlinden  10   100   101 Donald R Royall  115 Carole Dufouil  116   117 Raffaele Giovanni Maletta  114 Itziar de Rojas  18   19 Mary Sano  118 Alexis Brice  119   120 Roberta Cecchetti  121 Peter St George-Hyslop  122   123 Karen Ritchie  124   125   126 Magda Tsolaki  42 Debby W Tsuang  127   128 Bruno Dubois  129   130   131   132 David Craig  133 Chuang-Kuo Wu  134 Hilkka Soininen  21   22 Despoina Avramidou  42 Roger L Albin  135   136   137 Laura Fratiglioni  138 Antonia Germanou  42 Liana G Apostolova  139   140   141   142 Lina Keller  138 Maria Koutroumani  42 Steven E Arnold  143 Francesco Panza  97 Olymbia Gkatzima  42 Sanjay Asthana  144   145   146 Didier Hannequin  40 Patrice Whitehead  14 Craig S Atwood  140   141   142 Paolo Caffarra  83   84 Harald Hampel  147   148   149   150 Inés Quintela  151 Ángel Carracedo  151 Lars Lannfelt  77 David C Rubinsztein  122   152 Lisa L Barnes  153   154   155 Florence Pasquier  103 Lutz Frölich  156 Sandra Barral  23   24   25 Bernadette McGuinness  133 Thomas G Beach  157 Janet A Johnston  133 James T Becker  81   158   159 Peter Passmore  133 Eileen H Bigio  160   161 Jonathan M Schott  33 Thomas D Bird  96   127 Jason D Warren  33 Bradley F Boeve  102 Michelle K Lupton  40   162 James D Bowen  163 Petra Proitsi  40 Adam Boxer  164 John F Powell  40 James R Burke  165 John S K Kauwe  166 Jeffrey M Burns  167 Michelangelo Mancuso  168 Joseph D Buxbaum  118   169   170 Ubaldo Bonuccelli  168 Nigel J Cairns  171 Andrew McQuillin  172 Chuanhai Cao  173 Gill Livingston  172 Chris S Carlson  145   146 Nicholas J Bass  172 Cynthia M Carlsson  174 John Hardy  175 Regina M Carney  176 Jose Bras  38   177 Minerva M Carrasquillo  178 Rita Guerreiro  38   177 Mariet Allen  178 Helena C Chui  179 Elizabeth Fisher  177 Carlo Masullo  180 Elizabeth A Crocco  181 Charles DeCarli  182 Gina Bisceglio  178 Malcolm Dick  183 Li Ma  178 Ranjan Duara  184 Neill R Graff-Radford  178 Denis A Evans  185 Angela Hodges  186 Kelley M Faber  139 Martin Scherer  187 Kenneth B Fallon  188 Matthias Riemenschneider  57 David W Fardo  189 Reinhard Heun  75 Martin R Farlow  141 Heike Kölsch  75 Steven Ferris  190 Markus Leber  191 Tatiana M Foroud  139 Isabella Heuser  192 Douglas R Galasko  193 Ina Giegling  62 Marla Gearing  194   195 Michael Hüll  196 Daniel H Geschwind  197 John R Gilbert  14 John Morris  198   199 Robert C Green  200 Kevin Mayo  198   201   202 John H Growdon  203 Thomas Feulner  57 Ronald L Hamilton  204 Lindy E Harrell  205 Dmitriy Drichel  206 Lawrence S Honig  23 Thomas D Cushion  5   6 Matthew J Huentelman  107 Paul Hollingworth  5 Christine M Hulette  207 Bradley T Hyman  203 Rachel Marshall  5 Gail P Jarvik  208   209 Alun Meggy  5 Erin Abner  210 Georgina E Menzies  5   6 Lee-Way Jin  211 Ganna Leonenko  5 Luis M Real  211 Gyungah R Jun  212 Clinton T Baldwin  212 Detelina Grozeva  5 Anna Karydas  163 Giancarlo Russo  213 Jeffrey A Kaye  214   215 Ronald Kim  216 Frank Jessen  74   75   191 Neil W Kowall  13   217 Bruno Vellas  218 Joel H Kramer  219 Emma Vardy  220 Frank M LaFerla  221 Karl-Heinz Jöckel  80 James J Lah  222 Martin Dichgans  223   224 James B Leverenz  225 David Mann  226 Allan I Levey  222 Stuart Pickering-Brown  226 Andrew P Lieberman  227 Norman Klopp  228 Kathryn L Lunetta  20 H-Erich Wichmann  229   230   231 Constantine G Lyketsos  232 Kevin Morgan  233 Daniel C Marson  205 Kristelle Brown  84 Frank Martiniuk  234 Christopher Medway  84 Deborah C Mash  235 Markus M Nöthen  27   28 Eliezer Masliah  193   236 Nigel M Hooper  226 Wayne C McCormick  43 Antonio Daniele  237 Susan M McCurry  238 Anthony Bayer  239 Andrew N McDavid  173 John Gallacher  65 Ann C McKee  13   217 Hendrik van den Bussche  187 Marsel Mesulam  161   240 Carol Brayne  241 Bruce L Miller  242 Steffi Riedel-Heller  243 Carol A Miller  244 Joshua W Miller  245 Ammar Al-Chalabi  246 John C Morris  171   201 Christopher E Shaw  246   247 Amanda J Myers  181 Jens Wiltfang  248   249   250 Sid O'Bryant  54 John M Olichney  182 Victoria Alvarez  251 Joseph E Parisi  252 Andrew B Singleton  253 Henry L Paulson  135   137 John Collinge  45 William R Perry  14 Simon Mead  45 Elaine Peskind  128 David H Cribbs  254 Martin Rossor  33 Aimee Pierce  254 Natalie S Ryan  45 Wayne W Poon  183 Benedetta Nacmias  255   256 Huntington Potter  257 Sandro Sorbi  255   258 Joseph F Quinn  187   188 Eleonora Sacchinelli  104 Ashok Raj  173 Gianfranco Spalletta  259   260 Murray Raskind  128 Carlo Caltagirone  259 Paola Bossù  104 Maria Donata Orfei  259 Barry Reisberg  190   261 Robert Clarke  262 Christiane Reitz  23   24   263 A David Smith  264 John M Ringman  265 Donald Warden  264 Erik D Roberson  205 Gordon Wilcock  264 Ekaterina Rogaeva  123 Amalia Cecilia Bruni  114 Howard J Rosen  164 Maura Gallo  114 Roger N Rosenberg  266 Yoav Ben-Shlomo  267 Mark A Sager  145 Patrizia Mecocci  121 Andrew J Saykin  139   141 Pau Pastor  98   99 Michael L Cuccaro  14 Jeffery M Vance  14 Julie A Schneider  153   155   268 Lori S Schneider  179   269 Susan Slifer  14 William W Seeley  164 Amanda G Smith  173 Joshua A Sonnen  88 Salvatore Spina  76 Robert A Stern  13 Russell H Swerdlow  167 Mitchell Tang  11 Rudolph E Tanzi  203 John Q Trojanowski  270 Juan C Troncoso  271 Vivianna M Van Deerlin  270 Linda J Van Eldik  272 Harry V Vinters  273   274 Jean Paul Vonsattel  275 Sandra Weintraub  161   276 Kathleen A Welsh-Bohmer  165   277 Kirk C Wilhelmsen  278 Jennifer Williamson  23 Thomas S Wingo  222   279 Randall L Woltjer  280 Clinton B Wright  281 Chang-En Yu  43 Lei Yu  153   155 Yasaman Saba  282 Alberto Pilotto  283   284 Maria J Bullido  19   285   286 Oliver Peters  192   287 Paul K Crane  43 David Bennett  153   155 Paola Bosco  288 Eliecer Coto  251 Virginia Boccardi  121 Phil L De Jager  289 Alberto Lleo  19   290 Nick Warner  291 Oscar L Lopez  81   83   158 Martin Ingelsson  77 Panagiotis Deloukas  292 Carlos Cruchaga  198   199 Caroline Graff  72   73 Rhian Gwilliam  292 Myriam Fornage  36 Alison M Goate  169   293 Pascual Sanchez-Juan  39 Patrick G Kehoe  294 Najaf Amin  10 Nilifur Ertekin-Taner  178   295 Claudine Berr  124   125 Stéphanie Debette  119   120 Seth Love  294 Lenore J Launer  66 Steven G Younkin  178   295 Jean-Francois Dartigues  296 Chris Corcoran  297 M Arfan Ikram  10   298   299 Dennis W Dickson  178 Gael Nicolas  44 Dominique Campion  44   300 JoAnn Tschanz  297 Helena Schmidt  282   301 Hakon Hakonarson  302   303 Jordi Clarimon  19   290 Ron Munger  297 Reinhold Schmidt  49 Lindsay A Farrer  13   20   212   304   305 Christine Van Broeckhoven  15   16 Michael C O'Donovan  5 Anita L DeStefano  13   20 Lesley Jones  5   6 Jonathan L Haines  51 Jean-Francois Deleuze  9 Michael J Owen  5 Vilmundur Gudnason  17   35 Richard Mayeux  23   24   25 Valentina Escott-Price  5   6 Bruce M Psaty  7   32   306   307 Alfredo Ramirez  78   191 Li-San Wang  11 Agustin Ruiz  18   19 Cornelia M van Duijn  10 Peter A Holmans  5 Sudha Seshadri  12   13   308 Julie Williams  5   6 Phillippe Amouyel  2   3   4   309 Gerard D Schellenberg  11 Jean-Charles Lambert  310   311   312 Margaret A Pericak-Vance  313 Alzheimer Disease Genetics Consortium (ADGC),European Alzheimer’s Disease Initiative (EADI),Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE),Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES),
Affiliations
Free PMC article
Meta-Analysis

Genetic Meta-Analysis of Diagnosed Alzheimer's Disease Identifies New Risk Loci and Implicates Aβ, Tau, Immunity and Lipid Processing

Brian W Kunkle et al. Nat Genet. .
Free PMC article

Erratum in

  • Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.
    Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fitzpatrick AL, Valladares O, Moutet ML, Gerrish A, Smith AV, Qu L, Bacq D, Denning N, Jian X, Zhao Y, Del Zompo M, Fox NC, Choi SH, Mateo I, Hughes JT, Adams HH, Malamon J, Sanchez-Garcia F, Patel Y, Brody JA, Dombroski BA, Naranjo MCD, Daniilidou M, Eiriksdottir G, Mukherjee S, Wallon D, Uphill J, Aspelund T, Cantwell LB, Garzia F, Galimberti D, Hofer E, Butkiewicz M, Fin B, Scarpini E, Sarnowski C, Bush WS, Meslage S, Kornhuber J, White CC, Song Y, Barber RC, Engelborghs S, Sordon S, Voijnovic D, Adams PM, Vandenberghe R, Mayhaus M, Cupples LA, Albert MS, De Deyn PP, Gu W, Himali JJ, Beekly D, Squassina A, Hartmann AM, Orellana A, Blacker D, Rodriguez-Rodriguez E, Lovestone S, Garcia ME, Doody RS, Munoz-Fernadez C, Sussams R, Lin H, Fairchild TJ, Benito YA, Holmes C, Karamujić-Čomić H, Frosch MP, Thonberg H, Maier W, Roshchupkin G, Ghetti B, Giedraitis V, Kawalia A, Li S, Huebinger RM, Kilander L, Moebus S, Hernández I, Kamboh MI, Brundin R, Turton J, Yang Q, Katz MJ, Concari L, Lord J, Beiser AS, Keene CD, Helisalmi S, Kloszewska I, Kukull WA, Koivisto AM, Lynch A, Tarraga L, Larson EB, Haapasalo A, Lawlor B, Mosley TH, Lipton RB, Solfrizzi V, Gill M, Longstreth WT Jr, Montine TJ, Frisardi V, Diez-Fairen M, Rivadeneira F, Petersen RC, Deramecourt V, Alvarez I, Salani F, Ciaramella A, Boerwinkle E, Reiman EM, Fievet N, Rotter JI, Reisch JS, Hanon O, Cupidi C, Uitterlinden AGA, Royall DR, Dufouil C, Maletta RG, de Rojas I, Sano M, Brice A, Cecchetti R, George-Hyslop PS, Ritchie K, Tsolaki M, Tsuang DW, Dubois B, Craig D, Wu CK, Soininen H, Avramidou D, Albin RL, Fratiglioni L, Germanou A, Apostolova LG, Keller L, Koutroumani M, Arnold SE, Panza F, Gkatzima O, Asthana S, Hannequin D, Whitehead P, Atwood CS, Caffarra P, Hampel H, Quintela I, Carracedo Á, Lannfelt L, Rubinsztein DC, Barnes LL, Pasquier F, Frölich L, Barral S, McGuinness B, Beach TG, Johnston JA, Becker JT, Passmore P, Bigio EH, Schott JM, Bird TD, Warren JD, Boeve BF, Lupton MK, Bowen JD, Proitsi P, Boxer A, Powell JF, Burke JR, Kauwe JSK, Burns JM, Mancuso M, Buxbaum JD, Bonuccelli U, Cairns NJ, McQuillin A, Cao C, Livingston G, Carlson CS, Bass NJ, Carlsson CM, Hardy J, Carney RM, Bras J, Carrasquillo MM, Guerreiro R, Allen M, Chui HC, Fisher E, Masullo C, Crocco EA, DeCarli C, Bisceglio G, Dick M, Ma L, Duara R, Graff-Radford NR, Evans DA, Hodges A, Faber KM, Scherer M, Fallon KB, Riemenschneider M, Fardo DW, Heun R, Farlow MR, Kölsch H, Ferris S, Leber M, Foroud TM, Heuser I, Galasko DR, Giegling I, Gearing M, Hüll M, Geschwind DH, Gilbert JR, Morris J, Green RC, Mayo K, Growdon JH, Feulner T, Hamilton RL, Harrell LE, Drichel D, Honig LS, Cushion TD, Huentelman MJ, Hollingworth P, Hulette CM, Hyman BT, Marshall R, Jarvik GP, Meggy A, Abner E, Menzies GE, Jin LW, Leonenko G, Real LM, Jun GR, Baldwin CT, Grozeva D, Karydas A, Russo G, Kaye JA, Kim R, Jessen F, Kowall NW, Vellas B, Kramer JH, Vardy E, LaFerla FM, Jöckel KH, Lah JJ, Dichgans M, Leverenz JB, Mann D, Levey AI, Pickering-Brown S, Lieberman AP, Klopp N, Lunetta KL, Wichmann HE, Lyketsos CG, Morgan K, Marson DC, Brown K, Martiniuk F, Medway C, Mash DC, Nöthen MM, Masliah E, Hooper NM, McCormick WC, Daniele A, McCurry SM, Bayer A, McDavid AN, Gallacher J, McKee AC, van den Bussche H, Mesulam M, Brayne C, Miller BL, Riedel-Heller S, Miller CA, Miller JW, Al-Chalabi A, Morris JC, Shaw CE, Myers AJ, Wiltfang J, O'Bryant S, Olichney JM, Alvarez V, Parisi JE, Singleton AB, Paulson HL, Collinge J, Perry WR, Mead S, Peskind E, Cribbs DH, Rossor M, Pierce A, Ryan NS, Poon WW, Nacmias B, Potter H, Sorbi S, Quinn JF, Sacchinelli E, Raj A, Spalletta G, Raskind M, Caltagirone C, Bossù P, Orfei MD, Reisberg B, Clarke R, Reitz C, Smith AD, Ringman JM, Warden D, Roberson ED, Wilcock G, Rogaeva E, Bruni AC, Rosen HJ, Gallo M, Rosenberg RN, Ben-Shlomo Y, Sager MA, Mecocci P, Saykin AJ, Pastor P, Cuccaro ML, Vance JM, Schneider JA, Schneider LS, Slifer S, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tang M, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Saba Y; Alzheimer Disease Genetics Consortium (ADGC); European Alzheimer’s Disease Initiative (EADI); Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE); Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Pilotto A, Bullido MJ, Peters O, Crane PK, Bennett D, Bosco P, Coto E, Boccardi V, De Jager PL, Lleo A, Warner N, Lopez OL, Ingelsson M, Deloukas P, Cruchaga C, Graff C, Gwilliam R, Fornage M, Goate AM, Sanchez-Juan P, Kehoe PG, Amin N, Ertekin-Taner N, Berr C, Debette S, Love S, Launer LJ, Younkin SG, Dartigues JF, Corcoran C, Ikram MA, Dickson DW, Nicolas G, Campion D, Tschanz J, Schmidt H, Hakonarson H, Clarimon J, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, O'Donovan MC, DeStefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, Pericak-Vance MA. Kunkle BW, et al. Nat Genet. 2019 Sep;51(9):1423-1424. doi: 10.1038/s41588-019-0495-7. Nat Genet. 2019. PMID: 31417202 Free PMC article.

Abstract

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 × 10-7), 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.

Conflict of interest statement

Competing interests

D. Blacker is a consultant for Biogen, Inc. R.C.P. is a consultant for Roche, Inc.; Merck, Inc.; Genentech, Inc.; Biogen, Inc.; GE Healthcare; and Eisai, Inc. A.R.W. is a former employee and stockholder of Pfizer, Inc., and a current employee of the Perelman School of Medicine at the University of Pennsylvania Orphan Disease Center in partnership with the Loulou. A.M.G. is a member of the scientific advisory board for Denali Therapeutics. N.E.-T. is a consultant for Cytox. J.Hardy holds a collaborative grant with Cytox cofunded by the Department of Business (Biz). F.J. acts as a consultant for Novartis, Eli Lilly, Nutricia, MSD, Roche and Piramal. Neither J.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.M. is currently participating in clinical trials of antidementia drugs from Eli Lilly and Company, Biogen and Janssen. J.M. serves as a consultant for Lilly USA. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grant nos. P50AG005681, P01AG003991, P01AG026276 and UF01AG032438. C.Cruchaga receives research support from Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. C.Cruchaga is a member of the advisory board of ADx Healthcare. M.R.F. receives grant/research support from AbbVie, Accera, ADCS Posiphen, Biogen, Eisai, Eli Lilly, Genentech, Novartis and Suven Life Sciences, Ltd. He is a consultant/advisory board/DSMB board member for Accera, Avanir, AZTherapies, Cognition Therapeutics, Cortexyme, Eli Lilly & Company, Longeveron, Medavante, Merck and Co. Inc., Otsuka Pharmaceutical, Proclara (formerly Neurophage Pharmaceuticals), Neurotrope Biosciences, Takeda, vTv Therapeutics and Zhejian Hisun Pharmaceuticals. He has a transgenic mouse model patent that is licensed to Elan. R.A.S. receives consulting fees as a member of the Alzheimer’s Disease Advisory Board, Biogen; and as member of the Executive Committee for AZD3293 Alzheimer’s Disease Studies, Eli Lilly. R.B.L. receives consulting fees from Merch, Inc. E.M.R. receives grant funding from several NIH grant and research contracts with Genentech/Roche, Novartis/ Amgen and Avid/Lilly. He is a compensated scientific advisor to Alkahest, Alzheon, Aural Analytics, Denali, Takeda and Zinfandel. He is an advisor to Roche and Roche Diagnostics, which reimburse his expenses only. T.G.B. has research support/contracts from the National Institutes of Health, State of Arizona, Michael J Fox Foundation, Avid Radiopharmaceuticals, Navida Biopharmaceuticals and Aprinoia Therapeutics. He is an advisory board member with Vivid Genomics and has consultancy work with Roche Diagnostics. A.G.S. conducts multiple industry-funded clinical trials, but all funds go to her academic institution. They have current (within last 12 months) research contracts with Eli Lilly, Novartis, Roche, Janssen, AbbVie, Biogen, NeuroEM, Suven and Merck. She does not receive personal compensations from these organizations. G.D.S. is a consultant for Biogen, Inc. J.M.B. is participating in clinical trials of antidementia drugs for Eli Lilly, Toyama Chemical Company, Merck, Biogen, AbbVie, vTv Therapeutics, Janssen and Roche. He has received research grants from Eli Lilly, Avid Radiopharmaceuticals and Astra Zeneca. He is a consultant for Stage 2 Innovations. L.F. is a consultant for Allergan, Eli Lilly, Avraham Pharmaceuticals, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, Lundbeck, MerckSharpe & Dohme, Novartis, Pfizer, Pharnext, Roche and Schwabe Pharma. M.B has consulted as an advisory board member for Araclon, Grifols, Lilly, Nutricia, Roche and Servier. She received fees for lectures and funds for research from Araclon, Grifols, Nutricia, Roche and Servier. She has not received personal compensations from these organizations. A.Ruiz has consulted for Grifols and Landsteiner Genmed. He received fees for lectures or funds for research and/or reimbursement of expenses for congresses attendance from Araclon and Grifols. He has not received personal compensations from these organizations. O.P. acts as a consultant for Roche and Biogen, Inc. He is currently participating in clinical trials of antidementia drugs from Novartis, Genentech, Roche and Pharmatrophix. B.T.H. is a consultant for Aztherapy, Biogen, Calico, Ceregene, Genentech, Lilly, Neurophage, Novartis and Takeda, and receives research support from Abbvie, Amgen, Deanli, Fidelity Biosciences, General Electric, Lilly, Merck, Sangamo and Spark therapeutics. BTH owns Novartis stock. H.Hampel serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid and MSD AVENIR (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE Healthcare and Oryzon Genomics, consultancy fees from Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostica. Harald Hampel is a co-inventor on numerous patents relating to biomarker measurement but has received no royalties from these patents. A.A.-C. has consultancies for GSK, Cytokinetics, Biogen Idec, Treeway Inc, Chronos Therapeutics, OrionPharma and Mitsubishi-Tanabe Pharma, and was Chief Investigator for commercial clinical trials run by OrionPharma and Cytokinetics.

Figures

Fig. 1 |
Fig. 1 |. Manhattan plot of meta-analysis of stage 1, 2, and 3 results for genome-wide association with Alzheimer’s disease.
The threshold for genomewide significance (P < 5 × 10−8) is indicated by the red line, while the blue line represents the suggestive threshold (P < 1 × 10−5). Loci previously identified by the Lambert et al. IGAP GWAS are shown in blue and newly associated loci are shown in red. Loci are named for the closest gene to the sentinel variant for each locus. Diamonds represent variants with the smallest P values for each genome-wide locus.
Fig. 2 |
Fig. 2 |. Top prioritized genes of 400 genes located in genome-wide-significant loci.
The criteria include: (1) deleterious coding, LOF or splicing variant in the gene; (2) significant gene-based tests; (3) expression in a tissue relevant to Alzheimer’s disease (astrocytes, neurons, microglia/macrophages, oligodendrocytes); (4) a HuMi microglial-enriched gene; (5) having an eQTL effect on the gene in any tissue, in Alzheimer’s disease–relevant tissue, and/ or a co-localized eQTL; (6) being involved in a biological pathway enriched in Alzheimer’s disease (from the current study); (7) expression correlated with the BRAAK stage; and (8) differential expression in a 1 + Alzheimer’s disease (AD) study. Novel genome-wide loci from the current study are listed first, followed by known genome-wide loci. Each category is assigned an equal weight of 1, with the priority score equaling the sum of all categories. Colored fields indicate that the gene meets the criteria. Genes with a priority score ≥ 4 are listed for each locus. If no gene reached a score of ≥ 5 in a locus, then the top ranked gene(s) is listed.

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